The Genetic Epidemiology of Breast Cancer Genes
Journal of Mammary Gland Biology and Neoplasia, Vol. 9, No. 3, July 2004 ( C 2004)The Genetic Epidemiology of Breast Cancer GenesDeborah Thompson1 and Douglas Easton1,2Genetic susceptibility to breast cancer in women is conferred by a large number of genes,of which six have so far been identified. In the context of multiple-case families, BRCA1and BRCA2 are the most important. Mutations in these genes confer high lifetime risks ofbreast cancer and ovarian cancer, and more moderate risks of prostate cancer and some othercancer types. Mutations in theCHEK2 andATM genes, by contrast, cause much more modest(24 fold) risks of breast cancer. Genes so far identified explain approximately 20% of thefamilial aggregation of breast cancer. The remaining susceptibility genes have, so far, provedillusive, suggesting that they are numerous and confer moderate risks. A variety of techniquesincluding genome-wide association studies, use of quantitative intermediate endpoints, andresequencing of genes may be required to identify them. The identification of such genes canprovide a basis for targeted prevention of breast cancer.KEYWORDS: breast cancer; BRCA1; BRCA2; ATM; CHEK2; TP53; PTEN.INTRODUCTIONA womans risk of breast cancer is determinedby both genetic and lifestyle factors. While thevariation in breast cancer between populations islargely explicable in terms of lifestyle factors suchas reproductive patterns and diet, there is sub-stantial variation between individuals that is ge-netically determined. In this paper we review thegenetic epidemiology of the known breast cancersusceptibility genes, concentrating specifically onBRCA1, BRCA2, ATM, and CHEK2. We also dis-cuss the prospects of the identification of furthergenes.The overall genetic variation in disease riskcan be quantified by the familial aggregation ofthe disease. Overall, breast cancer is approximatelytwice as common in women with an affected first-degree relative; this risk increases with the number1 Cancer Research U.K. Genetic Epidemiology Unit, Universityof Cambridge, Cambridge, U.K.2 To whom correspondence should be addressed at Cancer Re-search U.K. Genetic Epidemiology Unit, Strangeways ResearchLaboratory, Worts Causeway, Cambridge, CB1 8RN, U.K.;e-mail: email@example.com affected relatives and is greater for women withrelatives affected at a young age (1). Twin stud-ies have demonstrated a substantially higher riskto monozygotic twins of affected relatives than todizygotic twins, suggesting that most of the famil-ial aggregation is determined by genetic susceptibil-ity rather than lifestyle or environmental risk factors(2,3).BRCA1 AND BRCA2In addition to systematic epidemiological evi-dence, certain families display a very high degreeof clustering of early-onset breast cancer cases, con-sistent with the inheritance of a high-risk mutation(e.g., 4). Such multiple-case families provided theimpetus for identification of high-risk susceptibilitygenes, using linkage analysis to identify markers thatcosegregate with the disease. This approach led toAbbreviations used: AT, aaxia telangiectasia; BCLC, breast can-cer linkage consortium; BIC, Breast Cancer Information Core;BMI, body mass index; ER, estrogen receptor; LFS, Li-FraumeniSyndrome; LOD, logarithm of the odds; OCCR, ovarian cancercluster region.2211083-3021/04/0700-0221/0 C 2004 Springer Science+Business Media, Inc.222 Thompson and Eastonthe demonstration of linkage to chromosome 17q (5)and to chromosome 13q (6) in subsets of breast can-cer families. Subsequent positional cloning lead tothe identification of the BRCA1 and BRCA2 geneswith mutations in families linked to these regions(79). Many families linked to BRCA1 and BRCA2also contain multiple cases of ovarian cancer, consis-tent with epidemiological observations of significantcoaggregation of breast and ovarian cancer in fami-lies (10,11).Although neither BRCA1 nor BRCA2 has anapparent close homologue in the human genome,they have several features in common. Both are rea-sonably large genes: BRCA1 has 22 exons, spans ap-proximately 100kb of genomic DNA, and encodes a1863 amino acid protein, while BRCA2 has 27 ex-ons, spans around 70kb, and encodes a protein of3418 amino acids (Fig. 1). Both are ubiquitously ex-pressed in humans, with the highest levels in thetestis, ovaries, and thymus, and both are relativelypoorly conserved between species. Breast and ovar-ian tumours in carriers show frequent loss of thewild-type chromosome 17q or 13q, consistent witha tumour suppressor gene (12,13). The functions ofBRCA1 and BRCA2 are discussed in detail else-where (e.g., 14).Mutations in BRCA1 and BRCA2BRCA1 and BRCA2 are the most importantbreast cancer susceptibility genes in high-risk fam-ilies, and identification of mutations in these genesforms an important component of the managementof high-risk women. The Breast Cancer InformationCore (BIC) database had recorded (as of February2004) 1220 distinct germline BRCA1 mutations and1384 BRCA2 mutations. Of these, 697 (57%) and870 (63%) have been reported just once. Mutationsappear to be reasonably evenly distributed acrossthe coding sequences, with no obvious mutationhot-spots. Most mutations found in breast and/orovarian cancer families are predicted to truncate theprotein product. The most common types of muta-tion are small frameshift insertions or deletions, non-sense mutations, or mutations affecting splice sitesresulting in deletion of complete or partial exons orinsertion of intronic sequence. The Breast CancerLinkage Consortium (BCLC) has estimated that ap-proximately 70% of BRCA1 mutations and 90% ofBRCA2 mutations in linked families are of this type(D. Easton, personal communication).Large-scale rearrangements, including inser-tions, deletions, or duplications of more than 500kbFig. 1. The BRCA1 and BRCA2 genes, showing some functional domains, founder mutations, and other features described inthe text.The Genetic Epidemiology of Breast Cancer Genes 223of DNA, have also been identified, but as these arenot identifiable by exonic sequencing or other con-ventional screening techniques they are likely to beunderreported. To date there have been reports ofat least 19 distinct large genomic rearrangements inBRCA1 and two in BRCA2, identified using protein-truncation analyses or Southern blots. The majorityare deletions of one or more exons (reviewed in 15).The higher density of Alu repetitive sequences in theBRCA1 gene (42% vs. 20%) (16) is thought to con-tribute to the larger number of large deletions andduplications observed in this gene.In addition to protein-truncating mutations,large numbers of amino-acid substitutions have beenidentified in both BRCA1 and BRCA2. A small num-ber of these, principally involving cysteine residuesin the BRCA1 RING domain, have occurred con-sistently in high-risk families and are regarded asdisease-associated (missense mutations), but the sta-tus of the majority (termed unclassified variants) isuncertain. Given their frequency and the fact thatmany occur in patients with another, deleterious, mu-tation, it is clear that the large majority of these vari-ants cannot be strongly associated with disease. Atpresent no reliable functional assay exists to deter-mine whether such a variant is likely to be delete-rious, and only the epidemiological evidence on thefrequency of the variant in breast cancer cases andcontrols, and on the cosegregation of the variant withdisease in families, can be regarded as definitive. Un-fortunately this evidence is lacking for most variants.Only two variants outside known functional domainsof BRCA1 are classified as missense mutations byBIC, and for some of these the evidence that they arepathogenic is not totally convincing. No clearly dele-terious missense BRCA2 mutations have yet beendefined.It has been suggested that common polymor-phisms in BRCA1 and BRCA2 may be associatedwith moderately increased risks of breast or ovar-ian cancer. This hypothesis has been tested by com-paring polymorphism frequencies in cases and con-trols, but there is no consistent evidence that anyof the BRCA1 polymorphisms tested so far con-fers an increased risk of breast cancer (17,18). Onecommon BRCA2 variant, N372H, has been shownto be associated with a moderately increased riskof breast cancer (19,20). Intriguingly, among femalecontrols including newborns, the frequency of ho-mozygotes was significantly lower than that expectedunder Hardy-Weinberg equilibrium, whereas amongnewborn males a deficit of heterozygotes was identi-fied, suggesting that BRCA2 has different roles in thefoetal development of males and females, leading todifferential selection (19).Founder MutationsWhilst the majority of BRCA1 and BRCA2 mu-tations are infrequently observed, certain mutationsin BRCA1 and BRCA2 have been observed multi-ple times. Haplotype analysis using markers flank-ing the genes has demonstrated that, in most cases,these recurrent mutations are descended from a sin-gle founder. Such mutations tend to be common inspecific populations, and absent elsewhere, indicatingthat most mutations observed now have arisen overthe past few hundred years.Although BRCA1 and BRCA2 mutations arerare in most populations, mutations can be morefrequent if the population has risen from a relativelyrecent small founder population. The best character-ized examples occur in the Icelandic and the Ashke-nazi Jewish population.Ashkenazi Jewish Founder MutationsThree mutations are commonly found inthe Ashkenazi Jewish population: 185delAG and5382insC in BRCA1 (21) and 6174delT in BRCA2(9). Carriers of each mutation share a commonhaplotype. These three mutations account for almostall the BRCA1 and BRCA2 mutations found inthis population, facilitating quicker, cheaper, andmore complete mutation testing. Although thelarge majority of 185delAG carrier families areAshkenazi, the mutation has also been reported inother Jewish groups, indicating an older origin (22).In addition, this mutation has been seen embeddedin a completely different haplotype in non-Jews,including three UK families (23) and six families ofSpanish/Latin American ancestry (24), implying twoor more separate mutation-events at this position.The 6174delT mutation appears to be virtually re-stricted to the Ashkenazim, and has only once beenreported in anyone of proven non-Ashkenazi Jewishheritage (25). The 5382insC mutation is, however,more widespread, being common in Poland, Russia,and other parts of Eastern Europe and occurring inmost European populations.The frequency of these mutations is muchhigher than BRCA1 and BRCA2 mutations in other224 Thompson and Eastonpopulations, and in consequence they are foundin a high proportion of breast and ovarian cancerpatients and families in this population. On the basisof a pooled analysis of five population studies, thefrequencies of the 185delAG and 6174delT muta-tions in the Ashkenazim have been estimated to beabout 1 in 100, with the frequency of 5382insC beingabout 1 in 400 (26). These mutations are present inapproximately 30% of breast cancer cases diagnosedbelow age 40 years (2731) and in 4060% of ovariancancer cases (32,33).The Icelandic BRCA2 Founder MutationA single BRCA2 mutation, 999del5, has beenidentified in the geographically isolated populationof Iceland, and is present in the majority of multiple-case breast cancer families in this population (34,35).About 1 in 200 Icelanders are thought to carry a999del5 mutation, a much higher frequency than thatof all mutations in larger, more heterogeneous pop-ulations (36,37). The 999del5 mutation is estimatedto account for around 8% of ovarian cancers and fe-male breast cancers, rising to 24% of female breastcancers diagnosed before age 40 years, and 38% ofmale breast cancer cases (35,36).Homozygous MutationsIndividuals carrying both a BRCA1 mutationand a BRCA2 mutation have been found in sev-eral breastovarian cancer families, and their phe-notype appears similar to that of carriers of eithermutation alone. Individuals homozygous for BRCA1or BRCA2 mutations are, however, extremely rare.An investigation of around 1500 Ashkenazim withbreast or ovarian cancer or a family history of ei-ther cancer revealed no carriers homozygous forany of the three Ashkenazi founder mutations (38).Similar arguments apply to the Icelandic BRCA2999del5 mutation. These results suggest reduced ho-mozygote viability in humans, consistent with reportsof embryonic lethality or severe developmental ab-normalities in mice homozygous for various brca1or brca2 mutations (e.g., 39,40). A single case of awoman homozygous for the BRCA1 2800delA mu-tation has been reported, but this may be artefactual(41,42).However, a recent study has found that certainindividuals with Fanconi Anaemia complementationgroup D1 carried two distinct germline BRCA2 mu-tations (43). This phenotype is consistent with thehypothesized functions of BRCA2. Interestingly, inall cases at least one of the two mutations was to-wards the 3 end of BRCA2, so that, for example,the RAD51 binding domain was retained. This mayexplain the apparent viability of these double muta-tions as compared with homozygotes for the 999del5or 6174delT mutations.Penetrance of BRCA1 and BRCA2 MutationsThe cancer risks associated with BRCA1 andBRCA2mutations are critical for genetic counselling,and have been the subject of considerable con-troversy. Ultimately, estimates of penetrance basedon prospective follow-up of unaffected carriers willbecome available, but current estimates are de-rived from retrospective data. Penetrance estimateshave been derived from high-risk families (the so-called maximum LOD score approach) and frompopulation-based studies based on the incidence ofcancer in relatives of carriers identified in a se-ries of cases not selected for family history (thekin-cohort approach). Estimates based on high-risk families are directly relevant to that type of fam-ily, but may overestimate the risk to randomly se-lected carriers in the population. Population studiesmay give results that are more applicable to the ma-jority of mutation carriers, but a degree of selectionremains since the cohort are all, by definition, rela-tives of cancer patients. The low frequency of muta-tions means that even large studies often detect onlya small number of carriers, resulting in imprecise esti-mates. Straightforward case-control studies avoid thepotential selection due to other familial factors, butare also severely limited by the low frequency of mu-tations. They are only possible in populations withfounder mutations, and even then the estimates lackprecision.Penetrance estimates from a recent meta-analysis of 22 population studies are shown in Fig. 2(44). The cumulative risks of both breast and ovar-ian cancer are lower in BRCA1 carriers than BRCA2carriers, but the difference is more marked for ovar-ian cancer (39% vs. 11% by age 70). The difference isalso more marked for breast cancer at younger ages.This is a consequence of the fact that BRCA1 breastcancer incidence rates rise steeply to approximately34% per annum in the 4049 age group, and areroughly constant thereafter, whereas the BRCA2The Genetic Epidemiology of Breast Cancer Genes 225Fig. 2. BRCA1 and BRCA2 breast and ovarian cancer penetrance estimates, based on ameta-analysis of 22 population-based studies (44).rates show a pattern similar to that in the generalpopulation (though approximately 10-fold higher),rising steeply up to age 50 and more slowly there-after. Ovarian cancer risks in BRCA1 carriers arevery low below age 40, rising thereafter to 12% perannum, whereas BRCA2 risks are very low below age50 but then increase sharply.For comparison, Fig. 3 shows the correspondingpenetrance estimates derived from two BCLC col-laborative studies of high risk families (45,46). It isnotable that the risks are somewhat higher than thosein Fig. 1, especially the breast cancer risks forBRCA2carriers. These differences in risk suggest the exis-tence of additional familial factors modifying the can-cer risk in carriers. Although it has become generallyaccepted that penetrance estimates from population-based studies are lower than estimates based on high-risk families, one recent study based on New YorkAshkenazi Jewish breast cancer patients, unselectedfor age or family history of cancer, found risks ofbreast cancer by age 80 of 81% and 85% for BRCA1and BRCA2 mutation carriers respectively, and ovar-ian cancer risks of 54% and 23% respectively by age80 years (47), more similar to the estimates fromhigh-risk families.The New York Ashkenazi Jewish study foundthat the risk of breast cancer by age 50 in carri-ers of a BRCA1 or BRCA2 founder mutation was24% in women born prior to 1940, but 67% inthose born after this date (47). The meta-analysisof population-based studies also found the relativerisk of breast cancer associated with a BRCA1 mu-tation to be significantly higher for more recent birthcohorts (the same trend was seen for BRCA2, butFig. 3. BRCA1 and BRCA2 breast and ovarian cancer penetrance estimates, based onhigh-risk BCLC families (45,46).226 Thompson and Eastonwas not statistically significant) (44). This could re-flect less accurate reporting of cancers in the ear-lier decades. However, changes in a wide range oflifestyle factors including diet, exercise, reproductivefactors such as age at first pregnancy, family size,breast-feeding preferences, and oral contraceptiveuse, or in other environmental factors, might also becontributory factors.The above estimates assume that all mutationsconfer the same cancer risks. Although most re-ported deleterious mutations are protein-truncating,some expression is still present in the majority ofcases, and it is plausible that gene-products truncatedto differing degrees may confer different cancer risks.There is some evidence that BRCA1 mutations in acentral region of the gene (nucleotides 24014191)confer a lower breast cancer risk than other muta-tions, whereas mutations towards the 3 end confera lower risk of ovarian cancer (Fig. 1) (48,49). ForBRCA2, mutations in a central region referred to asthe Ovarian Cancer Cluster Region (OCCR; nu-cleotides 30356629; Fig. 1) appear to be associatedwith a lower breast cancer risk and a higher ovar-ian cancer risk than other BRCA2 mutations (50,51).This association may be explained by the fact thatthe OCCR is coincident with the RAD51 binding do-main of BRCA2.Contribution of BRCA1 and BRCA2to Breast and Ovarian CancerBRCA1 and BRCA2 mutations are commonamong families with an extreme history of breast can-cer. For example, of 237 BCLC families with four ormore cases of breast cancer diagnosed below age 60years, it was estimated that 84% were linked to ei-ther BRCA1 or BRCA2, with an even higher preva-lence among families with an ovarian cancer or amale breast cancer case (45). However, the preva-lence in the more common types of family with fewercases is markedly lower; two studies have estimatedthat between 15 and 20% of the excess familial riskof breast cancer is due to mutations in these genes(52,53). The most likely explanation for these obser-vations is that, whilst BRCA1 and BRCA2 are themost important high penetrance breast cancer sus-ceptibility genes, other genes conferring lower risksexplain the majority of the familial aggregation.Numerous studies have sought to estimate theoverall prevalences of BRCA1 and BRCA2 muta-tions in unselected breast and ovarian cancer cases,as opposed to cases with a family history. The major-ity of the breast cancer studies have been restrictedto women with a young age at diagnosis; pool-ing the results from eight population-based studiesgives estimated frequencies of BRCA1 and BRCA2mutations among patients diagnosed below theirmid-thirties of 4.6% and 3.5% respectively (5259).In contrast, the Anglian Breast Cancer Study (thelargest population-based study to date) found theprevalences among cases diagnosed between 45 and54 years of age to be just 0.3% and 1.0% respectively(53). These values underestimate the true prevalenceby perhaps 3040% given the mutation detectiontechniques used (45). Nevertheless, the overall frac-tion of breast cancer patients in outbred populationscarrying BRCA1 and BRCA2 mutations is probablyclose to 12% for each gene.The overall frequencies of BRCA1 and BRCA2mutations within large outbred populations (as dis-tinct from the Ashkenazi Jewish and Icelandic pop-ulations) have not been estimated directly, butinferred estimates vary between 0.050.26% forBRCA1 and between 0.080.34% for BRCA2 (52,6062).The risk of male breast cancer associated withBRCA2 mutations is estimated to be around 80 timeshigher than in the general population, suggestingthat BRCA2 mutations account for approximately10% of all male breast cancers (50). Pooling the re-sults from studies of male breast cancer patients un-selected for family history gives a similar estimate(11%) (6367). The association betweenBRCA1mu-tations and male breast cancer appears to be con-siderably weaker. Although male breast cancer casesare found in BRCA1-linked families, the size of therisk is unclear.PathologyThe morphology of breast tumours arising inBRCA1 carriers is markedly different from those oc-curring in noncarriers. Several studies have demon-strated that BRCA1-associated tumours tend to behigh grade (usually grade 3) and, more specifically,have high mitotic count (68,69). The majority ofBRCA1-associated tumours are infiltrating ductal,but there is a significantly higher frequency of tu-mours classified as medullary or atypical medullarytype than in noncarriers (21% vs. 2% in the BCLCstudy). Conversely, BRCA1 tumours are less likelyto be lobular or to be associated with ductal orThe Genetic Epidemiology of Breast Cancer Genes 227lobular carcinoma in situ. More detailed analysis hasdemonstrated that BRCA1 tumours are more likelyto exhibit continuous pushing margins and lympho-cytic infiltration. Consistent with their higher grade,BRCA1 tumours have been shown to more often beaneuploid, with a higher average S-phase fraction(70,71). Other studies have suggested that BRCA1tumours are larger (7274) and more often associatedwith axillary lymph node involvment (75), althoughthe evidence for these associations is less convincingthan for grade. Some studies have indicated that so-matic p53 mutations are more common in these tu-mours (76), although the evidence from immunohis-tochemical staining with TP53 antibodies is less clear(77).Several studies have shown that BRCA1 tu-mours are likely to be estrogen receptor (ER) neg-ative (and also progesterone receptor negative); inthe largest study, over 90% of BRCA1 tumours ex-hibited no staining for ER (77). This finding sug-gests that breast tumours arising in BRCA1 carriersare less likely to be responsive to hormonal thera-pies such as tamoxifen, and moreover that tamoxifenmight be unable to prevent breast cancer in BRCA1carriers, although this has not always been seen inpractice (e.g., 78). Tumours in BRCA1 carriers arealso less likely to be c-erb-B2 positive (71,77). Morerecently, microarray studies have suggested thatBRCA1 tumours fall into a category of basal-liketumours, recognized by staining for cytokeratins(79), an association confirmed by immunostaining(80). Such immunohistochemical markers may pro-vide a powerful basis for identifying likely BRCA1carriers.The distribution of clinical and pathologi-cal characteristics in BRCA1 carriers (high grade,ER negative, node positive) would suggest thatthe prognosis in these patients is likely to bepoor. Direct evidence of the prognosis in BRCA1carriers is, however, still conflicting (e.g., 69,70,73,81).The pathological characteristics of tumours inBRCA2 are less clear than for BRCA1, and overalltheir behaviour appears to be more similar to those innoncarriers. The BCLC study found some evidenceof a higher average grade in BRCA2 tumours thanin those occurring in noncarriers, but the effect wasweaker than for BRCA1 and appeared to be relatedto lack of tubule formation rather than mitotic count(69). However, this result has yet to be replicatedelsewhere. The distribution of ER and PR is similarto that in noncarriers (82).Risks of Other Cancers in BRCA1and BRCA2 Mutation CarriersIn addition to the marked excess of breast andovarian cancer in BRCA1 and BRCA2 carriers, thereis also evidence of more moderate risks of other can-cer types. The largest study of cancer risks in BRCA1carriers, based on 699 carrier families, found an over-all cancer risk in male carriers very close to that in thegeneral population, but the risk of cancers other thanbreast or ovarian in female carriers was increased byapproximately twofold (83). Specifically, significantexcesses were seen for cancers of the corpus uteri,the cervix, the fallopian tubes, and the peritoneum.There was also some evidence of a twofold relativerisk of pancreatic cancer in carriers of both sexes, andof prostate cancer below age 65.In a parallel study, based on 173 BRCA2 fam-ilies, the risk of other cancers was approximatelytwofold in both male and female carriers (84). Thelargest excess risk was for prostate cancer, with an es-timated 4.7-fold relative risk, increasing to sevenfoldin men below age 65. A 3.5-fold risk of pancreaticcancer was also found, and significant excesses werealso seen for cancers of the stomach, buccal cavityand pharynx, gallbladder and bile duct, and fallopiantube, and for melanoma.Other studies have also demonstrated an asso-ciation between prostate cancer and BRCA2 mu-tations. For example, two Icelandic studies foundprostate cancer relative risks of between three andfive among the first degree relatives of BRCA2 mu-tation carriers (37,85). In addition, a study of 263prostate cancer cases diagnosed below age 56 years,unselected for family history, estimated a BRCA2carrier frequency of nearly 3% (86). However, sev-eral other studies have failed to detect any elevationin the frequency of BRCA1 or BRCA2 mutations inprostate cancer patients (e.g. 87,88), although this isnot inconsistent given the low population frequencyof mutations.Risk Modifying FactorsThe age-specific penetrance estimates for carri-ers define the average risks to carriers in defined pop-ulations, but these risks may be adjusted by knowl-edge of other risk factors. Epidemiological studieshave identified a number of important risk factorsfor breast and ovarian cancer, and an important is-sue is to determine whether any of these are also risk228 Thompson and Eastonfactors in carriers. Evaluating such lifestyle factors incarriers presents a number of difficulties as a result ofthe limited sample size and potential biases inherentin studying risk factors in high risk women. As a re-sult, the effects of most lifestyle risk factors are still amatter of debate.In the general population, increasing parity isprotective for both breast cancer and ovarian cancer(89,90). The effect of parity in carriers is less clear, inpart because of limited sample sizes and because thedecision to undergo testing may be influenced by par-ity. Most, but not all, studies to date have pointed toa reduction in breast and ovarian cancer risk in carri-ers with increasing parity, broadly in line with thatseen in the general population (9193). One large,matched case-control study found that use of oralcontraceptives was associated with a slight increasein breast cancer risk inBRCA1 carriers. No increasedrisk was observed in BRCA2 carriers, but the num-bers involved were smaller and the relative risks inboth groups would appear compatible with those ob-served in noncarriers (94). One study has indicatedthat early oophorectomy may substantially reducerisk (95). The effects of other known breast cancerrisk factors, including breast-feeding, BMI, and alco-hol consumption have not been clearly established incarriers.Polymorphisms in a number of other genes havebeen suggested as modifying breast or ovarian can-cer risk in BRCA1 or BRCA2 carriers, though nonehas been convincingly replicated to date. There havebeen reports of an increased risk of breast cancer inBRCA1 mutation carriers associated with polymor-phisms in the androgen receptor (96,97) and AIB1(93,98). The I1307K allele in the APC gene has beenreported to increase breast cancer risk in carriers ofeither BRCA1 or BRCA2 mutations (99), as has theRAD51 135G>C allele (100102).CHEK2CHEK2 is a G2 checkpoint kinase that plays acritical role in DNA repair. In mammalian cells it isactivated in response to ionising radiation throughphosphorylation by ATM. Activation of CHEK2also phosphorylates other key cell cycle proteins, in-cluding BRCA1 and p53. The role of CHEK2 inbreast cancer susceptibility was first suggested by theidentification of a truncating mutation in CHEK2(1100delC) in a family with Li-Fraumeni syndrome(LFS). This mutation, which eliminates kinase activ-ity, was subsequently found in two early-onset breastcancer patients from families suggestive but not typ-ical of this syndrome (103,104). The same mutationwas subsequently found in seven breast cancer casesfrom a family showing linkage to chromosome 22close to CHEK2 (105). Further screening revealedthat this mutation was present in over 5% of breastcancer cases with a family history of breast cancerand no BRCA1 or BRCA2 mutation, compared witha frequency of approximately 1% in controls. Simi-lar results were reported in a study of Finnish breastcancer families (106).Segregation analysis estimated that CHEK21100delC conferred an increased risk of breast cancerof approximately 2-fold in noncarriers of BRCA1/2mutations. This risk has been confirmed in a collabo-rative analysis of over 10,000 breast cancer cases andmatched controls (107). CHEK21100delC is, there-fore, not a high penetrance mutation, but rather a rel-atively common variant conferring a more moderaterisk of breast cancer. The initial finding of the variantin a LFS family now appears to have been coinciden-tal, since there is no evidence of an association withany other LFS tumours. The CHEK2 1100delC vari-ant does not appear to increase the risk of breast can-cer in carriers of BRCA1 or BRCA2 mutations, pos-sibly reflecting functional interactions between thethree genes. There is, as yet, no evidence that otherCHEK2 variants predispose to breast cancer to thesame extent as 1100delC (108,109).ATMCarriers of homozygous or compound heterozy-gous mutations in the ATM gene suffer from the rarerecessive disorder ataxia-telangiectasia (AT). AT isa degenerative disorder, characterized by progres-sive cerebellar ataxia, a weakened immune system,greatly increased susceptibility to cancer, high sen-sitivity to ionizing radiation, and distinctive dilatedblood vessels in the eyes and skin. The ATM pro-tein is activated in response to DNA damage byionizing radiation. Studies based on relatives of ATcases have suggested that female heterozygous carri-ers, who are otherwise clinically unaffected, are at athree to fourfold increased risk of breast cancer (re-viewed by Easton et al., 110). The carrier frequencyof ATM mutations may be as high as 1%, suggestingthat ATM mutations may be responsible for a higherfraction of cases than BRCA1 or BRCA2, althoughthe association with breast cancer has not beenThe Genetic Epidemiology of Breast Cancer Genes 229directly established in case-control studies (e.g., 111).More recently there has been interest in the possibil-ity that certain ATM missense mutations, for exam-ple, 7271T>G, may be more strongly associated withbreast cancer (112). However, initial reports of sub-stantially increased risks of breast cancer associatedwith other specific variants such as IVS10-6T>G and1420L>F (113,114) have not been replicated in sub-sequent studies (115) (D. Thompson, personal com-munication).DISCUSSIONThe identification of breast cancer susceptibilitygenes, particularly BRCA1 and BRCA2, has revolu-tionised the management of women with a family his-tory of the disease. Elucidating the functions of thesegenes has also provided insight into the pathogenesisof breast cancer in general.It is striking that all but one of the breast cancersusceptibility genes so far identified are involved inprocesses related to DNA repair and cell-cycle con-trol. From an epidemiological viewpoint this is some-what surprising. Although breast cancer is related toionizing radiation, the association is weaker than forother cancers. Moreover, despite the well-establishedstrong relationship between exposure to steroid hor-mones (notably oestradiol) and breast cancer, noclear relationship between hormones and breast can-cer susceptibility has been identified. However, therecent identification of polymorphisms in CYP19 andSHBG related to oestradiol and sex-hormone bind-ing globulin levels suggests that further susceptibil-ity genes in this pathway may be identified with suffi-ciently large studies (116).A second general observation is site-specificity.Despite the fundamental roles of these genes inDNA repair, the mutations appear to confer risks ofcancer that are largely restricted to the breast andovary. The reasons for this remain obscure, but pre-sumably reflect in some way the relative importanceof different DNA lesions in different tissues at dif-ferent times. Epidemiological studies indicate littlefamilial aggregation between breast and other can-cers, suggesting that other susceptibility genes will besimilarly site-specific.The currently known breast cancer susceptibil-ity genes only account for around one fifth of theexcess risk of breast cancer in relatives, suggestingstrongly that further genes remain to be identified(117). The characteristics of such genes are unclear.One recent segregation analyses suggested that, afterallowing for BRCA1 and BRCA2, familial aggrega-tion of breast cancer may be best explained by a largenumber of low-penetrance genes interacting in a mul-tiplicative fashion, although the existence of furthermajor dominant or recessive genes cannot be ruledout (118).One approach to locating new breast cancergenes is by conducting linkage studies in families un-linked to BRCA1 and BRCA2. The only genome-wide search that has thus far been reported identifiedno clear linkage peaks, and only moderately sugges-tive evidence of linkage to a region on chromosome2q (119). Previous studies have suggested linkage onchromosomes 8p and 13q, but neither has been repli-cated (120123). The failure of these linkage searchesto identify further susceptibility loci may reflect thereduced power of this approach to detect lowerpenetrance alleles, perhaps compounded by ge-netic heterogeneity. Further searches, including sev-eral hundred multiple-case families, are in progress,and these will provide greater power. It is un-likely, however, that the linkage approach will detectgenes that explain less than 2025% of the familialrisk.An alternative approach has been to use case-control studies to examine directly associations be-tween variants and risk. This approach has greaterpower than linkage studies to detect low penetrancegenes, but is not yet feasible on a genome-widescale, though this may become possible in the nextfew years. Such studies have tended to focus oncandidate genes, such as those involved in hor-mone regulation or DNA repair. Moreover (with theexception of CHEK2) the studies have necessarilyconcentrated on common variants. Although someassociations have been reported, no definitive as-sociations with common polymorphisms have beenestablished by this approach (124). The use of anintermediate quantitative phenotype known to be as-sociated with breast cancer risk, such as mammo-graphic breast density or hormone levels, may im-prove the power of such studies.All of the susceptibility alleles identified to dateare rare, with frequencies of less than 1%, even incombination (Table I). The rarity of the alleles mustreflect selective disadvantage, perhaps as a result ofhomozyotes being nonviable (as with BRCA1) orseriously disadvantaged (as with ATM). Detectionof rare susceptibility alleles is problematic for as-sociation studies, which rely on linkage disequilib-rium between common polymorphisms and disease.230 Thompson and EastonTable I. Summary of Six Breast Cancer Susceptibility GenesPopulation Risk of breastcarrier cancer by ageGene Location frequency 70 (95% CI)a Other cancers associated with mutationsBRCA1 17q 1 in 860b 65% (4478%)c Ovarian, fallopian tube, peritoneum, pancreatic, prostatedBRCA2 13q 1 in 740b 45% (3156%)c Ovarian, fallopian tube, male breast, prostate, pancreatic, gallbladderand bileducteCHEK2 22q 1 in 90f 11% (914%)f ColorectalgATM 11q 1 in 100h 23% (1339%)i Lymphomas and leukemias (in homozygote carriers with ataxia-telangiectasia)TP53 17p 1 in 5,000j 5060% by age 45k Li-Fraumeni Syndrome, inc. Sarcomas, brain tumours and leukemiasPTEN 10q 1 in 250,000l 3050%l Cowdens Disease (multiple hamartomas, thyroid cancer, muccocutaneous lesions) or BannayanRileyRuvalcaba syndrome.Note. Numerous other associations between polymorphisms and breast cancer have been reported but not replicated (e.g., 124).aRisks are based on available large studies, but may depend on mutation type and context (e.g., degree of family history). The breast cancerrisks for CHEK2 and ATM are based on reported relative risk estimates and cancer incidence data for England and Wales between 1993and 1997 (129), according to which the population risk by age 70 is 6.6%.b(Ref. 61); c(Ref. 44); d(Ref. 83); e(Ref. 84); f (Ref. 105); g(Ref. 125); h(Ref. 111); ireviewed in (Ref. 110); j (Ref. 126); k(Ref. 127); lreviewedin (Ref. 128).It remains to be seen whether the same will be trueof the remaining susceptibility genes, but, if so, evenlarge case-control studies would not have sufficientpower to detect an association, and direct resequenc-ing of candidate genes may be the only approach toidentify them.ACKNOWLEDGMENTThe authors are supported by Cancer ResearchUK.REFERENCES1. Collaborative Group on Hormonal Factors in Breast Cancer(2001). Familial breast cancer: Collaborative reanalysis ofindividual data from 52 epidemiological studies including58,209 women with breast cancer and 101,986 women withoutthe disease. Lancet 358:13891399.2. P. Lichtenstein, N. V. Holm, P. K. Verkasalo, A. Iliadou,J. Kaprio, M. Koskenvuo, E. Pukkala, A. Skytthe, and K.Hemminki (2000). Environmental and heritable factors inthe causation of cancerAnalyses of cohorts of twins fromSweden, Denmark, and Finland. N. Engl. J. Med. 343:7885.3. J. Peto, and T. M. Mack (2000). High constant incidence intwins and other relatives of women with breast cancer. Nat.Genet. 26:411414.4. D. T. Bishop, L. Cannon-Albright, T. McLellan, E. J.Gardner, and M. H. Skolnick (1988). Segregation and link-age analysis of nine Utah breast cancer pedigrees. Genet.Epidemiol. 5:151169.5. J. M. Hall, M. K. Lee, B. Newman, J. E. Morrow, L. A.Anderson, B. Huey, and M. C. King (1990). Linkage ofearly-onset familial breast cancer to chromosome 17q21.Science 250:16841689.6. R. Wooster, S. L. Neuhausen, J. Mangion, Y. Quirk, D.Ford, N. Collins, K. Nguyen, S. Seal, T. Tran, D. Averill, P.Fields, G. Marshall, S. Narod, G. M. Lenoir, H. Lynch, J.Feunteun, P. Devilee, C. J. Cornelisse, F. H. Menko, P. A.Daly, W. Ormiston, R. McManus, C. Pye, C. M. Lewis, L. A.Cannon-Albright, J. Peto, B. A. J. Ponder, M. H. Skolnick,D. F. Easton, D. E. Goldgar, and M. R. Stratton (1994).Localization of a breast cancer susceptibility gene, BRCA2,to chromosome 13q1213. Science 265:20882090.7. Y. Miki, J. Swensen, D. Shattuck-Eidens, P. A. Futreal,K. Harshman, S. Tavtigian, Q. Liu, C. Cochran, L. M.Bennett, W. Ding, R. Bell, J. Rosenthal, C. Hussey, T. Tran,M. McClure, C. Frye, T. Hattier, R. Phelps, A. Haugen-Strano, H. Katcher, K. Yakumo, Z. Gholami, D. Shaffer, S.Stone, S. Bayer, C. Wray, G. Bogdan, P. Dayananth, J. Ward,P. Tonin, S. Narod, P. K. Bristow, F. H. Norris, L. Helvering,P. Morrison, P. Rosteck, M. Lai, J. C. Barrett, C. Lewis, S.Neuhausen, L. Cannon-Albright, D. Goldgar, R. Wiseman,A. Kamb, and M. H. Skolnick (1994). A strong candidate forthe breast and ovarian cancer susceptibility gene BRCA1.Science 266:6671.8. R. Wooster, G. Bignell, J. Lancaster, S. Swift, S. Seal,J. Mangion, N. Collins, S. Gregory, C. Gumbs, andG. Micklem (1995). Identification of the breast cancersusceptibility gene BRCA2. Nature 378:789792.9. S. V. Tavtigian, J. Simard, J. Rommens, F. Couch, D.Shattuck-Eidens, S. Neuhausen, S. Merajver, S. Thorlacius,K. Offit, D. Stoppa-Lyonnet, C. Belanger, R. Bell, S. Berry,R. Bogden, Q. Chen, T. Davis, M. Dumont, C. Frye, T.Hattier, S. Jammulapati, T. Janecki, P. Jiang, R. Kehrer, J. F.Leblanc, J. T. Mitchell, J. McArthur-Morrison, K. Nguyen,Y. Peng, C. Samson, M. Schroeder, S. C. Snyder, L. Steele, M.Stringfellow, C. Stroup, B. Swedlund, J. Swensen, D. Teng,A. Thomas, T. Tran, M. Tranchant, J. Weaver-Feldhaus, A.K. C. Wong, H. Shizuya, J. E. Eyfjord, L. Cannon-Albright,F. Labrie, M. Skolnick, B. Weber, A. Kamb, and D. E.Goldgar (1996). The complete BRCA2 gene and mutationsin chromosome 13q-linked kindreds. Nat. Genet. 12:333337.The Genetic Epidemiology of Breast Cancer Genes 23110. D. F. Easton, F. E. Matthews, D. Ford, A. J. Swerdlow,and J. Peto (1996). Cancer mortality in relatives of womenwith ovarian cancer: The OPCS Study. Office of PopulationCensuses and Surveys. Int. J. Cancer. 65:284294.11. J. Peto, D. F. Easton, F. E. Matthews, D. Ford, and A. J.Swerdlow (1996). Cancer mortality in relatives of womenwith breast cancer: The OPCS Study. Office of PopulationCensuses and Surveys. Int. J. Cancer. 65:275283.12. N. Collins, R. McManus, R. Wooster, J. Mangion, S. Seal,S. R. Lakhani, W. Ormiston, P. A. Daly, D. Ford, D. F.Easton, and M. R. Stratton (1995). Consistent loss of thewild type allele in breast cancers from a family linked to theBRCA2 gene on chromosome 13q1213. Oncogene 10:16731675.13. S. A. Smith, D. F. Easton, D. G. Evans, and B. A. Ponder(1992). Allele losses in the region 17q1221 in familial breastand ovarian cancer involve the wild-type chromosome. Nat.Genet. 2:128131.14. P. L. Welcsh, and M. C. King (2001). BRCA1 and BRCA2and the genetics of breast and ovarian cancer. Hum. Mol.Genet. 10:705713.15. M. Montagna, P. M. Dalla, C. Menin, S. Agata, A. De Nicolo,L. Chieco-Bianchi, and E. DAndrea (2003). Genomic rear-rangements account for more than one-third of the BRCA1mutations in northern Italian breast/ovarian cancer families.Hum. Mol. Genet. 12:10551061.16. T. M. Smith, M. K. Lee, C. I. Szabo, N. Jerome, M. McEuen,M. Taylor, L. Hood, and M. C. King (1996). Completegenomic sequence and analysis of 117 kb of human DNAcontaining the gene BRCA1. Genome Res. 6:10291049.17. F. Durocher, D. Shattuck-Eidens, M. McClure, F. Labrie,M. H. Skolnick, D. E. Goldgar, and J. Simard (1996). Com-parison of BRCA1 polymorphisms, rare sequence variantsand/or missense mutations in unaffected and breast/ovariancancer populations. Hum. Mol. Genet. 5:835842.18. A. M. Dunning, M. Chiano, N. R. Smith, J. Dearden, M.Gore, S. Oakes, C. Wilson, M. Stratton, J. Peto, D. Easton,D. Clayton, and B. A. Ponder (1997). Common BRCA1variants and susceptibility to breast and ovarian cancer in thegeneral population. Hum. Mol. Genet. 6:285289.19. C. S. Healey, A. M. Dunning, M. D. Teare, D. Chase, L.Parker, J. Burn, J. Chang-Claude, A. Mannermaa, V. Kataja,D. G. Huntsman, P. D. Pharoah, R. N. Luben, D. F. Easton,and B. A. Ponder (2000). A common variant in BRCA2 isassociated with both breast cancer risk and prenatal viability.Nat. Genet. 26:362364.20. A. B. Spurdle, J. L. Hopper, X. Chen, G. S. Dite, J. Cui, M. R.McCredie, G. G. Giles, S. Ellis-Steinborner, D. J. Venter, B.Newman, M. C. Southey, and G. Chenevix-Trench (2002).The BRCA2 372 HH genotype is associated with risk ofbreast cancer in Australian women under age 60 years.Cancer Epidemiol. Biomarkers Prev. 11:413416.21. J. Simard, P. Tonin, F. Durocher, K. Morgan, J. Rommens,S. Gingras, C. Samson, J. F. Leblanc, C. Belanger, F. Dion,Q. Liu, M. Skolnick, D. Goldgar, D. Shattuck-Eidens, F.Labrie, and S. A. Narod (1994). Common origins of BRCA1mutations in Canadian breast and ovarian cancer families.Nat. Genet. 8:392398.22. R. B. Bar-Sade, A. Kruglikova, B. Modan, E. Gak,G. Hirsh-Yechezkel, L. Theodor, I. Novikov, R. Gershoni-Baruch, S. Risel, M. Z. Papa, G. Ben Baruch, and E.Friedman (1998). The 185delAG BRCA1 mutation orig-inated before the dispersion of Jews in the diaspora andis not limited to Ashkenazim. Hum. Mol. Genet. 7:801805.23. C. F. Xu, J. A. Chambers, H. Nicolai, M. A. Brown, Y.Hujeirat, S. Mohammed, S. Hodgson, D. P. Kelsell, N. K.Spurr, D. T. Bishop, and E. Solomon (1997). Mutations andalternative splicing of the BRCA1 gene in UK breast/ovariancancer families. Genes Chromosomes Cancer 18:102110.24. L. G. Mullineaux, T. M. Castellano, J. Shaw, L. Axell,M. E. Wood, S. Diab, C. Klein, M. Sitarik, A. M.Deffenbaugh, and S. L. Graw (2003). Identification ofgermline 185delAG BRCA1 mutations in non-JewishAmericans of Spanish ancestry from the San Luis Valley,Colorado. Cancer 98:597602.25. D. B. Berman, J. Costalas, D. C. Schultz, G. Grana, M. Daly,and A. K. Godwin (1996). A common mutation in BRCA2that predisposes to a variety of cancers is found in bothJewish Ashkenazi and non-Jewish individuals. Cancer Res.56:34093414.26. F. H. Fodor, A. Weston, I. J. Bleiweiss, L. D. McCurdy,M. M. Walsh, P. I. Tartter, S. T. Brower, and C. M. Eng(1998). Frequency and carrier risk associated with commonBRCA1 and BRCA2 mutations in Ashkenazi Jewish breastcancer patients. Am. J. Hum. Genet. 63:4551.27. M. G. FitzGerald, D. J. MacDonald, M. Krainer, I. Hoover,E. ONeil, H. Unsal, S. Silva-Arrieto, D. M. Finkelstein, P.Beer-Romero, C. Englert, D. C. Sgroi, B. L. Smith, J. W.Younger, J. E. Garber, R. B. Duda, K. A. Mayzel, K. J.Isselbacher, S. H. Friend, and D. A. Haber (1996). Germ-lineBRCA1 mutations in Jewish and non-Jewish women withearly- onset breast cancer. N. Engl. J. Med. 334:143149.28. E. Warner, W. Foulkes, P. Goodwin, W. Meschino, J.Blondal, C. Paterson, H. Ozcelik, P. Goss, D. Allingham-Hawkins, N. Hamel, L. Di Prospero, V. Contiga, C. Serruya,M. Klein, R. Moslehi, J. Honeyford, A. Liede, G. Glendon,J. S. Brunet, and S. Narod (1999). Prevalence and pene-trance of BRCA1 and BRCA2 gene mutations in unselectedAshkenazi Jewish women with breast cancer. J. Natl. Cancer.Inst. 91:12411247.29. J. M. Satagopan, K. Offit, W. Foulkes, M. E. Robson, S.Wacholder, C. M. Eng, S. E. Karp, and C. B. Begg (2001).The lifetime risks of breast cancer in Ashkenazi Jewish car-riers of BRCA1 and BRCA2 mutations. Cancer Epidemiol.Biomarkers Prev. 10:467473.30. S. Neuhausen, T. Gilewski, L. Norton, T. Tran, P. McGuire,J. Swensen, H. Hampel, P. Borgen, K. Brown, M. Skolnick,D. Shattuck-Eidens, S. Jhanwar, D. Goldgar, and K. Offit(1996). Recurrent BRCA2 6174delT mutations in Ashke-nazi Jewish women affected by breast cancer. Nat. Genet.13:126128.31. K. Offit, T. Gilewski, P. McGuire, A. Schluger, H. Ham-pel, K. Brown, J. Swensen, S. Neuhausen, M. Skolnick, L.Norton, and D. Goldgar (1996). Germline BRCA1 185de-lAG mutations in Jewish women with breast cancer. Lancet347:16431645.32. R. Moslehi, W. Chu, B. Karlan, D. Fishman, H. Risch, A.Fields, D. Smotkin, Y. Ben David, J. Rosenblatt, D. Russo,P. Schwartz, N. Tung, E. Warner, B. Rosen, J. Friedman,J. S. Brunet, and S. A. Narod (2000). BRCA1 and BRCA2mutation analysis of 208 Ashkenazi Jewish women withovarian cancer. Am. J. Hum. Genet. 66:12591272.232 Thompson and Easton33. D. Abeliovich, L. Kaduri, I. Lerer, N. Weinberg, G. Amir,M. Sagi, J. Zlotogora, N. Heching, and T. Peretz (1997). Thefounder mutations 185delAG and 5382insC in BRCA1 and6174delT in BRCA2 appear in 60% of ovarian cancer and30% of early-onset breast cancer patients among Ashkenaziwomen. Am. J. Hum. Genet. 60:505514.34. J. Gudmundsson, G. Johannesdottir, A. Arason, J. T.Bergthorsson, S. Ingvarsson, V. Egilsson, and R. B.Barkardottir (1996). Frequent occurrence of BRCA2 linkagein Icelandic breast cancer families and segregation of acommon BRCA2 haplotype. Am. J. Hum. Genet. 58:749756.35. S. Thorlacius, G. Olafsdottir, L. Tryggvadottir, S. Neuhausen,J. G. Jonasson, S. V. Tavtigian, H. Tulinius, H. M.Ogmundsdottir, and J. E. Eyfjord (1996). A single BRCA2mutation in male and female breast cancer families from Ice-land with varied cancer phenotypes. Nat. Genet. 13:117119.36. G. Johannesdottir, J. Gudmundsson, J. T. Bergthorsson, A.Arason, B. A. Agnarsson, G. Eiriksdottir, O. T. Johannsson,A. Borg, S. Ingvarsson, D. F. Easton, V. Egilsson, andR. B. Barkardottir (1996). High prevalence of the 999del5mutation in Icelandic breast and ovarian cancer patients.Cancer Res. 56:36633665.37. S. Thorlacius, S. Sigurdsson, H. Bjarnadottir, G. Olafsdottir,J. G. Jonasson, L. Tryggvadottir, H. Tulinius, and J. E.Eyfjord (1997) Study of a single BRCA2 mutation with highcarrier frequency in a small population. Am. J. Hum. Genet.60:10791084.38. E. Friedman, B. R. Bar-Sade, A. Kruglikova, S. Risel, E.Levy-Lahad, D. Halle, E. Bar-On, R. Gershoni-Baruch,E. Dagan, I. Kepten, T. Peretz, I. Lerer, N. Wienberg, A.Shushan, and A. D. Abeliovich (1998). Double heterozy-gotes for the Ashkenazi founder mutations in BRCA1 andBRCA2 genes. Am. J. Hum. Genet. 63:12241227.39. F. Connor, D. Bertwistle, P. J. Mee, G. M. Ross, S. Swift,E. Grigorieva, V. L. Tybulewicz, and A. Ashworth (1997).Tumorigenesis and a DNA repair defect in mice with atruncating Brca2 mutation. Nat. Genet. 17:423430.40. L. C. Gowen, B. L. Johnson, A. M. Latour, K. K. Sulik, andB. H. Koller (1996). Brca1 deficiency results in early embry-onic lethality characterized by neuroepithelial abnormalities.Nat. Genet. 12:191194.41. M. Boyd, F. Harris, R. McFarlane, H. R. Davidson, andD. M. Black (1995). A human BRCA1 gene knockout.Nature 375:541542.42. B. Kuschel, S. A. Gayther, D. F. Easton, B. A. Ponder, andP. D. Pharoah (2001). Apparent human BRCA1 knockoutcaused by mispriming during polymerase chain reaction:implications for genetic testing. Genes Chromosomes Cancer31:9698.43. N. G. Howlett, T. Taniguchi, S. Olson, B. Cox, Q. Waisfisz, C.Die-Smulders, N. Persky, M. Grompe, H. Joenje, G. Pals, H.Ikeda, E. A. Fox, and A. D. DAndrea (2002). Biallelic inac-tivation of BRCA2 in Fanconi anemia. Science 297:606609.44. A. Antoniou, P. D. Pharoah, S. Narod, H. A. Risch, J. E.Eyfjord, J. L. Hopper, N. Loman, H. Olsson, O. Johannsson,A. Borg, B. Pasini, P. Radice, S. Manoukian, D. M. Eccles,N. Tang, E. Olah, H. Anton-Culver, E. Warner, J. Lubinski,J. Gronwald, B. Gorski, H. Tulinius, S. Thorlacius, H.Eerola, H. Nevanlinna, K. Syrjakoski, O. P. Kallioniemi, D.Thompson, C. Evans, J. Peto, F. Lalloo, D. G. Evans, andD. F. Easton (2003). Average risks of breast and ovarian can-cer associated with BRCA1 or BRCA2 mutations detectedin case series unselected for family history: A combinedanalysis of 22 studies. Am. J. Hum. Genet. 72:11171130.45. D. Ford, D. F. Easton, M. Stratton, S. Narod, D. Goldgar,P. Devilee, D. T. Bishop, B. Weber, G. Lenoir, J. Chang-Claude, H. Sobol, M. D. Teare, J. Struewing, A. Arason, S.Scherneck, J. Peto, T. R. Rebbeck, P. Tonin, S. Neuhausen,R. Barkardottir, J. Eyfjord, H. Lynch, B. A. Ponder, S. A.Gayther, M. Zelada-Hedman, and The Breast CancerLinkage Consortium (1998). Genetic heterogeneity andpenetrance analysis of the BRCA1 and BRCA2 genes inbreast cancer families. Am. J. Hum. Genet. 62:676689.46. D. F. Easton, D. Ford, D. T. Bishop, and Breast CancerLinkage Consortium (1995). Breast and ovarian cancerincidence in BRCA1-mutation carriers. Am. J. Hum. Genet.56:265271.47. M. C. King, J. H. Marks, and J. B. Mandell (2003). Breast andovarian cancer risks due to inherited mutations in BRCA1and BRCA2. Science 302:643646.48. S. A. Gayther, W. Warren, S. Mazoyer, P. A. Russell, P.A. Harrington, M. Chiano, S. Seal, R. Hamoudi, E. J. vanRensburg, A. M. Dunning, R. Love, G. Evans, D. Easton,D. Clayton, M. R. Stratton, and B. A. J. Ponder (1995).Germline mutations of the BRCA1 gene in breast andovarian cancer families provide evidence for a genotypephenotype correlation. Nat. Genet. 11:428433.49. D. Thompson, and D. Easton (2002). Breast Cancer LinkageConsortium. Variation in BRCA1 cancer risks by mutationposition. Cancer Epidemiol. Biomarkers Prev. 11:329336.50. D. Thompson, and D. Easton (2001). Variation in cancerrisks, by mutation position, in BRCA2 mutation carriers.Am. J. Hum. Genet. 68:410419.51. S. A. Gayther, J. Mangion, P. Russell, S. Seal, R. Barfoot, B.A. Ponder, M. R. Stratton, and D. Easton (1997). Variationof risks of breast and ovarian cancer associated with dif-ferent germline mutations of the BRCA2 gene. Nat. Genet.15:103105.52. J. Peto, N. Collins, R. Barfoot, S. Seal, W. Warren, N.Rahman, D. F. Easton, C. Evans, J. Deacon, and M. R.Stratton (1999). Prevalence of BRCA1 and BRCA2 genemutations in patients with early-onset breast cancer. J. Natl.Cancer Inst. 91:943-949.53. Anglian Breast Cancer Study Group (2000). Prevalenceand penetrance of BRCA1 and BRCA2 mutations in apopulation-based series of breast cancer cases. Br. J. Cancer83:13011308.54. M. Krainer, S. Silva-Arrieta, M. G. FitzGerald, A. Shimada,C. Ishioka, R. Kanamaru, D. J. MacDonald, H. Unsal, D. M.Finkelstein, A. Bowcock, K. J. Isselbacher, and D. A. Haber(1997). Differential contributions of BRCA1 and BRCA2 toearly-onset breast cancer. N. Engl. J. Med. 336:14161421.55. D. M. Eccles, P. Englefield, M. A. Soulby, and I. G.Campbell (1998). BRCA1 mutations in southern England.Br. J. Cancer 77:21992203.56. K. E. Malone, J. R. Daling, J. D. Thompson, C. A. OBrien,L. V. Francisco, and E. A. Ostrander (1998). BRCA1 muta-tions and breast cancer in the general population: Analysesin women before age 35 years and in women before age 45years with first-degree family history. JAMA 279:922929.57. B. Newman, H. Mu, L. M. Butler, R. C. Millikan, P. G.Moorman, and M. C. King (1998). Frequency of breastcancer attributable to BRCA1 in a population-based seriesof American women. JAMA 279:915921.The Genetic Epidemiology of Breast Cancer Genes 23358. J. L. Hopper, M. C. Southey, G. S. Dite, D. J. Jolley,G. G. Giles, M. R. McCredie, D. F. Easton, D. J. Venter, andAustralian Breast Cancer Family Study (1999). Population-based estimate of the average age-specific cumulative risk ofbreast cancer for a defined set of protein-truncating muta-tions in BRCA1 and BRCA2. Cancer Epidemiol. BiomarkersPrev. 8:741747.59. N. Loman, O. Johannsson, U. Kristoffersson, H. Olsson, andA. Borg (2001). Family history of breast and ovarian cancersand BRCA1 and BRCA2 mutations in a population-basedseries of early-onset breast cancer. J. Natl. Cancer Inst.93:12151223.60. D. Ford, D. F. Easton, and J. Peto (1995). Estimates of thegene frequency of BRCA1 and its contribution to breast andovarian cancer incidence. Am. J. Hum. Genet. 57:14571462.61. A. C. Antoniou, P. D. Pharoah, G. McMullan, N. E. Day,M. R. Stratton, J. Peto, B. J. Ponder, and D. F. Easton(2002). A comprehensive model for familial breast cancerincorporating BRCA1, BRCA2 and other genes. Br. J.Cancer 86:7683.62. A. C. Antoniou, S. A. Gayther, J. F. Stratton, B. A. Ponder,and D. F. Easton (2000). Risk models for familial ovarianand breast cancer. Genet. Epidemiol. 18:173190.63. F. J. Couch, L. M. Farid, M. L. Deshano, S. V. Tavtigian,K. Calzone, L. Campeau, Y. Peng, B. Bogden, Q. Chen, S.Neuhausen, D. Shattuck-Eidens, A. K. Godwin, M. Daly,D. M. Radford, S. Sedlacek, J. Rommens, J. Simard, J.Garber, S. Merajver, and B. L. Weber (1996). BRCA2germline mutations in male breast cancer cases and breastcancer families. Nat. Genet. 13:123125.64. L. S. Friedman, S. A. Gayther, T. Kurosaki, D. Gordon,B. Noble, G. Casey, B. A. Ponder, and H. Anton-Culver(1997). Mutation analysis of BRCA1 and BRCA2 in amale breast cancer population. Am. J. Hum. Genet. 60:313319.65. K. Haraldsson, N. Loman, Q. X. Zhang, O. Johannsson,H. Olsson, and A. Borg (1998). BRCA2 germ-line mutationsare frequent in male breast cancer patients without a familyhistory of the disease. Cancer Res. 58:13671371.66. E. Kwiatkowska, M. Teresiak, K. M. Lamperska, A.Karczewska, D. Breborowicz, M. Stawicka, D. Godlewski,W. J. Krzyzosiak, and A. Mackiewicz (2001). BRCA2germline mutations in male breast cancer patients in thePolish population. Hum. Mutat. 17:73.67. E. Mavraki, I. C. Gray, D. T. Bishop, and N. K. Spurr (1997).Germline BRCA2 mutations in men with breast cancer. Br.J. Cancer 76:14281431.68. S. R. Lakhani, J. Jacquemier, J. P. Sloane, B. A. Gusterson,T. J. Anderson, M. J. van de Vijver, L. M. Farid, D. Venter,A. Antoniou, A. Storfer-Isser, E. Smyth, C. M. Steel, N.Haites, R. J. Scott, D. Goldgar, S. Neuhausen, P. A. Daly, W.Ormiston, R. McManus, S. Scherneck, B. A. Ponder, D. Ford,J. Peto, D. Stoppa-Lyonnet, Y. J. Bignon, J. P. Struewing,N. K. Spurr, D. T. Bishop, J. G. M. Klijn, P. Devilee, C.Cornelisse, C. Lasset, G. Lenoir, R. B. Barkardottir, V.Egilsson, U. Hamann, J. Chang-Claude, H. Sobol, B. Weber,M. R. Stratton, and D. F. Easton (1998). Multifactorialanalysis of differences between sporadic breast cancers andcancers involving BRCA1 and BRCA2 mutations. J. Natl.Cancer Inst. 90:11381145.69. Breast Cancer Linkage Consortium (1997). Pathology offamilial breast cancer: Differences between breast cancers incarriers of BRCA1 or BRCA2 mutations and sporadic cases.Lancet 349:15051510.70. J. N. Marcus, P. Watson, D. L. Page, S. A. Narod, G. M.Lenoir, P. Tonin, L. Linder-Stephenson, G. Salerno, T. A.Conway, and H. T. Lynch (1996). Hereditary breast cancer:Pathobiology, prognosis, and BRCA1 and BRCA2 genelinkage. Cancer 77:697709.71. O. T. Johannsson, I. Idvall, C. Anderson, A. Borg, R. B.Barkardottir, V. Egilsson, and H. Olsson (1997). Tumourbiological features of BRCA1-induced breast and ovariancancer. Eur. J. Cancer 33:362371.72. U. Hamann, and H. P. Sinn (2000). Survival and tumorcharacteristics of German hereditary breast cancer patients.Breast Cancer Res. Treat. 59:185192.73. D. Stoppa-Lyonnet, Y. Ansquer, H. Dreyfus, C. Gautier, M.Gauthier-Villars, E. Bourstyn, K. B. Clough, H. Magdelenat,P. Pouillart, A. Vincent-Salomon, A. Fourquet, and B.Asselain (2000). Familial invasive breast cancers: Worseoutcome related to BRCA1 mutations. J. Clin. Oncol.18:40534059.74. D. Turchetti, L. Cortesi, M. Federico, C. Bertoni, L.Mangone, S. Ferrari, and V. Silingardi (2000). BRCA1mutations and clinicopathological features in a sample ofItalian women with early-onset breast cancer. Eur. J. Cancer36:20832089.75. M. Robson, T. Gilewski, B. Haas, D. Levin, P. Borgen,P. Rajan, Y. Hirschaut, P. Pressman, P. P. Rosen, M. L.Lesser, L. Norton, and K. Offit (1998). BRCA-associatedbreast cancer in young women. J. Clin. Oncol. 16:16421649.76. K. A. Phillips, K. Nichol, H. Ozcelik, J. Knight, S. J. Done, P.J. Goodwin, and I. L. Andrulis (1999). Frequency of p53 mu-tations in breast carcinomas from Ashkenazi Jewish carriersof BRCA1 mutations. J. Natl. Cancer Inst. 91:469473.77. S. R. Lakhani, M. J. van de Vijver, J. Jacquemier, T. J.Anderson, P. P. Osin, L. McGuffog, and D. F. Easton(2002). The pathology of familial breast cancer: Predictivevalue of immunohistochemical markers estrogen receptor,progesterone receptor, HER-2, and p53 in patients withmutations in BRCA1 and BRCA2. J. Clin. Oncol. 20:23102318.78. S. A. Narod, J. S. Brunet, P. Ghadirian, M. Robson, K.Heimdal, S. L. Neuhausen, D. Stoppa-Lyonnet, C. Lerman,B. Pasini, R. P. de los, B. Weber, H. Lynch, and HereditaryBreast Cancer Clinical Study Group (2000). Tamoxifenand risk of contralateral breast cancer in BRCA1 andBRCA2 mutation carriers: A case-control study. Lancet356:18761881.79. C. M. Perou, T. Sorlie, M. B. Eisen, van de RM, S. S. Jeffrey,C. A. Rees, J. R. Pollack, D. T. Ross, H. Johnsen, L. A.Akslen, O. Fluge, A. Pergamenschikov, C. Williams, S. X.Zhu, P. E. Lonning, A. L. Borresen-Dale, P. O. Brown, andD. Botstein (2000). Molecular portraits of human breasttumours. Nature 406:747752.80. W. D. Foulkes, I. M. Stefansson, P. O. Chappuis, L. R. Begin,J. R. Goffin, N. Wong, M. Trudel, and L. A. Akslen (2003).Germline BRCA1 mutations and a basal epithelial pheno-type in breast cancer. J. Natl. Cancer Inst. 95:14821485.81. H. Eerola, P. Vahteristo, L. Sarantaus, P. Kyyronen, S.Pyrhonen, C. Blomqvist, E. Pukkala, H. Nevanlinna, and R.Sankila (2001). Survival of breast cancer patients in BRCA1,BRCA2, and non-BRCA1/2 breast cancer families: A rela-tive survival analysis from Finland. Int. J. Cancer 93:368372.234 Thompson and Easton82. A. A. Jazaeri, C. J. Yee, C. Sotiriou, K. R. Brantley, J. Boyd,and E. T. Liu (2002). Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. J. Natl.Cancer Inst. 94:9901000.83. D. Thompson, and D. F. Easton (2002). Cancer incidencein BRCA1 mutation carriers. J. Natl. Cancer Inst. 94:13581365.84. Breast Cancer Linkage Consortium (1999). Cancer risks inBRCA2 mutation carriers. J. Natl. Cancer Inst. 91:13101316.85. S. Sigurdsson, S. Thorlacius, J. Tomasson, L. Tryggvadottir,K. Benediktsdottir, J. E. Eyfjord, and E. Jonsson (1997).BRCA2 mutation in Icelandic prostate cancer patients. J.Mol. Med. 75:758761.86. S. M. Edwards, Z. Kote-Jarai, J. Meitz, R. Hamoudi, Q.Hope, P. Osin, R. Jackson, C. Southgate, R. Singh, A.Falconer, D. P. Dearnaley, A. Ardern-Jones, A. Murkin,A. Dowe, J. Kelly, S. Williams, R. Oram, M. Stevens, D. M.Teare, B. A. Ponder, S. A. Gayther, D. F. Easton, and R. A.Eeles (2003). Two percent of men with early-onset prostatecancer harbor germline mutations in the BRCA2 gene. Am.J. Hum. Genet. 72:112.87. S. A. Gayther, K. A. de Foy, P. Harrington, P. Pharoah,W. D. Dunsmuir, S. M. Edwards, C. Gillett, A. Ardern-Jones, D. P. Dearnaley, D. F. Easton, D. Ford, R. J. Shearer,R. S. Kirby, A. L. Dowe, J. Kelly, M. R. Stratton, B. A.Ponder, D. Barnes, R. A. Eeles, and The Cancer ResearchCampaign/British Prostate Group United Kingdom FamilialProstate Cancer Study Collaborators (2000). The frequencyof germ-line mutations in the breast cancer predispositiongenes BRCA1 and BRCA2 in familial prostate cancer.Cancer Res. 60:45134518.88. A. Vazina, J. Baniel, Y. Yaacobi, A. Shtriker, D. Engelstein,I. Leibovitz, M. Zehavi, A. A. Sidi, Y. Ramon, T. Tischler, P.M. Livne, and E. Friedman (2000). The rate of the founderJewish mutations in BRCA1 and BRCA2 in prostate cancerpatients in Israel. Br. J. Cancer 83:463466.89. F. Clavel-Chapelon, E3N-EPIC Group (2002). Differentialeffects of reproductive factors on the risk of pre- and post-menopausal breast cancer. Results from a large cohort ofFrench women. Br. J. Cancer 86:723727.90. A. S. Whittemore, R. Harris, and J. Itnyre (1992). Character-istics relating to ovarian cancer risk: Collaborative analysisof 12 US case-control studies. II: Invasive epithelial ovariancancers in white women. Collaborative Ovarian CancerGroup. Am. J. Epidemiol. 136:11841203.91. L. Tryggvadottir, E. J. Olafsdottir, S. Gudlaugsdottir,S. Thorlacius, J. G. Jonasson, H. Tulinius, and J. E. Eyfjord(2003). BRCA2 mutation carriers, reproductive factors andbreast cancer risk. Breast Cancer Res. 5:R121R128.92. B. Modan, P. Hartge, G. Hirsh-Yechezkel, A. Chetrit,F. Lubin, U. Beller, G. Ben Baruch, A. Fishman, J. Menczer,S. M. Ebbers, M. A. Tucker, S. Wacholder, J. P. Struewing,E. Friedman, and B. Piura (2001). Parity, oral contraceptives,and the risk of ovarian cancer among carriers and noncar-riers of a BRCA1 or BRCA2 mutation. N. Engl. J. Med.345:235240.93. T. R. Rebbeck, Y. Wang, P. W. Kantoff, K. Krithivas,S. L. Neuhausen, A. K. Godwin, M. B. Daly, S. A. Narod,J. S. Brunet, D. Vesprini, J. E. Garber, H. T. Lynch, B. L.Weber, and M. Brown (2001). Modification of BRCA1- andBRCA2-associated breast cancer risk by AIB1 genotype andreproductive history. Cancer Res. 61:54205424.94. S. A. Narod, M. P. Dube, J. Klijn, J. Lubinski, H. T.Lynch, P. Ghadirian, D. Provencher, K. Heimdal, P. Moller,M. Robson, K. Offit, C. Isaacs, B. Weber, E. Friedman,R. Gershoni-Baruch, G. Rennert, B. Pasini, T. Wagner,M. Daly, J. E. Garber, S. L. Neuhausen, P. Ainsworth, H.Olsson, G. Evans, M. Osborne, F. Couch, W. D. Foulkes,E. Warner, C. Kim-Sing, O. Olopade, N. Tung, H. M. Saal,J. Weitzel, S. Merajver, M. Gauthier-Villars, H. Jernstrom,P. Sun, and J. S. Brunet (2002). Oral contraceptives andthe risk of breast cancer in BRCA1 and BRCA2 mutationcarriers. J. Natl. Cancer Inst. 94:17731779.95. T. R. Rebbeck, A. M. Levin, A. Eisen, C. Snyder, P. Watson,L. Cannon-Albright, C. Isaacs, O. Olopade, J. E. Garber,A. K. Godwin, M. B. Daly, S. A. Narod, S. L. Neuhausen,H. T. Lynch, and B. L. Weber (1999). Breast cancer risk afterbilateral prophylactic oophorectomy in BRCA1 mutationcarriers. J. Natl. Cancer Inst. 91:14751479.96. T. R. Rebbeck, P. W. Kantoff, K. Krithivas, S. Neuhausen,M. A. Blackwood, A. K. Godwin, M. B. Daly, S. A. Narod,J. E. Garber, H. T. Lynch, B. L. Weber, and M. Brown(1999). Modification of BRCA1-associated breast cancer riskby the polymorphic androgen-receptor CAG repeat. Am. J.Hum. Genet. 64:13711377.97. L. Kadouri, D. F. Easton, S. Edwards, A. Hubert,Z. Kote-Jarai, B. Glaser, F. Durocher, D. Abeliovich,T. Peretz, and R. A. Eeles (2001). CAG and GGC repeatpolymorphisms in the androgen receptor gene and breastcancer susceptibility in BRCA1/2 carriers and noncarriers.Br. J. Cancer 85:3640.98. L. Kadouri, Z. Kote-Jarai, D. F. Easton, A. Hubert, R.Hamoudi, B. Glaser, D. Abeliovich, T. Peretz, and R. A.Eeles (2004). Polyglutamine repeat length in the AIB1 genemodifies breast cancer susceptibility in BRCA1 carriers. Int.J. Cancer 108:399403.99. M. Redston, K. L. Nathanson, Z. Q. Yuan, S. L. Neuhausen,J. Satagopan, N. Wong, D. Yang, D. Nafa, J. Abrahamson, H.Ozcelik, D. Antin-Ozerkis, I. Andrulis, M. Daly, L. Pinsky,D. Schrag, S. Gallinger, M. Kaback, M. C. King, T. Woodage,L. C. Brody, A. Godwin, E. Warner, B. Weber, W. Foulkes,and K. Offit (1998). The APCI1307K allele and breast cancerrisk. Nat. Genet. 20:1314.100. E. Levy-Lahad, A. Lahad, S. Eisenberg, E. Dagan, T.Paperna, L. Kasinetz, R. Catane, B. Kaufman, U. Beller,P. Renbaum, and R. Gershoni-Baruch (2001). A single nu-cleotide polymorphism in the RAD51 gene modifies cancerrisk in BRCA2 but not BRCA1 carriers. Proc. Natl. Acad.Sci. U. S. A. 98:32323236.101. W. W. Wang, A. B. Spurdle, P. Kolachana, B. Bove, B.Modan, S. M. Ebbers, G. Suthers, M. A. Tucker, D. J.Kaufman, M. M. Doody, R. E. Tarone, M. Daly, H. Levavi,H. Pierce, A. Chetrit, G. H. Yechezkel, G. Chenevix-Trench,K. Offit, A. K. Godwin, and J. P. Struewing (2001). Asingle nucleotide polymorphism in the 5 untranslated regionof RAD51 and risk of cancer among BRCA1/2 mutationcarriers. Cancer Epidemiol. Biomarkers Prev. 10:955960.102. A. Jakubowska, S. A. Narod, D. E. Goldgar, M.Mierzejewski, B. Masojc, K. Nej, J. Huzarska, T. Byrski, B.Gorski, and J. Lubinski (2003). Breast cancer risk reductionassociated with the RAD51 polymorphism among carriers ofthe BRCA1 5382insC mutation in Poland. Cancer Epidemiol.Biomarkers Prev. 12:457459.The Genetic Epidemiology of Breast Cancer Genes 235103. D. W. Bell, J. M. Varley, T. E. Szydlo, D. H. Kang, D. C.Wahrer, K. E. Shannon, M. Lubratovich, S. J. Verselis, K. J.Isselbacher, J. F. Fraumeni, J. M. Birch, F. P. Li, J. E. Garber,and D. A. Haber (1999). Heterozygous germ line hCHK2mutations in Li-Fraumeni syndrome. Science 286:25282531.104. P. Vahteristo, A. Tamminen, P. Karvinen, H. Eerola, C.Eklund, L. A. Aaltonen, C. Blomqvist, K. Aittomaki, and H.Nevanlinna (2001). p53, CHK2, and CHK1 genes in Finnishfamilies with Li-Fraumeni syndrome: Further evidenceof CHK2 in inherited cancer predisposition. Cancer Res.61:57185722.105. H. Meijers-Heijboer. (2002). CHK2 1100delC is a low pen-etrance familial breast cancer susceptibility allele that doesnot elevate breast cancer in BRCA1/2 mutation carriers. Nat.Genet. 31:5559.106. P. Vahteristo, J. Bartkova, H. Eerola, K. Syrjakoski, S. Ojala,O. Kilpivaara, A. Tamminen, J. Kononen, K. Aittomaki, P.Heikkila, K. Holli, C. Blomqvist, J. Bartek, O. P. Kallioniemi,and H. Nevanlinna (2002). A CHEK2 genetic variant con-tributing to a substantial fraction of familial breast cancer.Am. J. Hum. Genet. 71:432438.107. CHEK2 Breast Cancer Case-Control Consortium (2004).CHEK21100delC and susceptibility to breast cancer: Acollaborative analysis involving 10,860 breast cancer casesand 9065 controls from 10 studies. Am. J. Hum. Genet.74:11751182.108. B. Kuschel, A. Auranen, C. S. Gregory, N. E. Day, D. F.Easton, B. A. Ponder, A. M. Dunning, and P. D. Pharoah(2003). Common polymorphisms in checkpoint kinase 2 arenot associated with breast cancer risk. Cancer Epidemiol.Biomarkers Prev. 12:809812.109. M. Schutte, S. Seal, R. Barfoot, H. Meijers-Heijboer, M.Wasielewski, D. G. Evans, D. Eccles, C. Meijers, F. Lohman,J. Klijn, O. A. van den, P. A. Futreal, K. L. Nathanson, B. L.Weber, D. F. Easton, M. R. Stratton, and N. Rahman (2003).Variants in CHEK2 other than 1100delC do not make amajor contribution to breast cancer susceptibility. Am. J.Hum. Genet. 72:10231028.110. D. F. Easton (1994). Cancer risks in A-T heterozygotes. Int.J. Radiat Biol. 66:S177S182.111. M. G. FitzGerald, J. M. Bean, S. R. Hegde, H. Unsal,D. J. MacDonald, D. P. Harkin, D. M. Finkelstein, K. J.Isselbacher, and D. A. Haber (1997). Heterozygous ATMmutations do not contribute to early onset of breast cancer.Nat. Genet. 15:307310.112. T. Stankovic, A. M. Kidd, A. Sutcliffe, G. M. McGuire,P. Robinson, P. Weber, T. Bedenham, A. R. Bradwell,D. F. Easton, G. G. Lennox, N. Haites, P. J. Byrd, andA. M. Taylor (1998). ATM mutations and phenotypes inataxia-telangiectasia families in the British Isles: Expressionof mutant ATM and the risk of leukemia, lymphoma, andbreast cancer. Am. J. Hum. Genet. 62:334345.113. Y. R. Thorstenson, A. Roxas, R. Kroiss, M. A. Jenkins, K.M. Yu, T. Bachrich, D. Muhr, T. L. Wayne, G. Chu, R. W.Davis, T. M. Wagner, and P. J. Oefner (2003). Contributionsof ATM mutations to familial breast and ovarian cancer.Cancer Res. 63:33253333.114. G. Chenevix-Trench, A. B. Spurdle, M. Gatei, H. Kelly, A.Marsh, X. Chen, K. Donn, M. Cummings, D. Nyholt, M. A.Jenkins, C. Scott, G. M. Pupo, T. Dork, R. Bendix, J. Kirk,K. Tucker, M. R. McCredie, J. L. Hopper, J. Sambrook,G. J. Mann, and K. K. Khanna (2002). Dominant negativeATM mutations in breast cancer families. J. Natl. CancerInst. 94:205215.115. C. I. Szabo, M. Schutte, A. Broeks, J. Houwing-Duistermaat,Y. R. Thorstenson, F. Durocher, R. A. Oldenburg, M.Wasielewski, F. Odefrey, D. Thompson, A. N. floore, J.Kraan, J. Klijn, A. M. van den Ouweland, the BRCA-XConsortium, CFRBCS, INHERIT BRCAs, T. M. Wagner,P. Devilee, J. Simard, L. J. van t Veer, D. Goldgar, and H.Meijers-Heijboer (2004). Are ATM mutations 7271T>G andIVS10-6T>G really high-risk breast cancer-susceptibilityalleles? Cancer Res.64:840843.116. A. M. Dunning, M. Dowsett, C. S. Healey, L. Tee, R. N.Luben, E. Folkerd, K. L. Novik, L. Kelemen, S. Ogata, P.D. Pharoah, D. F. Easton, N. E. Day, and B. A. Ponder(2004). Polymorphisms associated with circulating sex hor-mone levels in postmenopausal women. J. Natl. Cancer Inst.96(12):936945.117. D. F. Easton (1999). How many more breast cancer pre-disposition genes are there? Breast Cancer Res. 1:1417.118. A. C. Antoniou, P. D. Pharoah, G. McMullan, N. E. Day,B. A. Ponder, and D. Easton (2001). Evidence for furtherbreast cancer susceptibility genes in addition to BRCA1and BRCA2 in a population-based study. Genet. Epidemiol.21:118.119. P. Huusko, S. H. Juo, E. Gillanders, L. Sarantaus, T. Kainu,P. Vahteristo, M. Allinen, M. Jones, K. Rapakko, H. Eerola,C. Markey, P. Vehmanen, D. Gildea, D. Freas-Lutz, C.Blomqvist, J. Leisti, G. Blanco, U. Puistola, J. Trent, J.Bailey-Wilson, R. Winqvist, H. Nevanlinna, and O. P.Kallioniemi (2004). Genome-wide scanning for linkage inFinnish breast cancer families. Eur. J. Hum. Genet. 12:98104.120. T. Kainu, S. H. Juo, R. Desper, A. A. Schaffer, E. Gillanders,E. Rozenblum, D. Freas-Lutz, D. Weaver, D. Stephan,J. Bailey-Wilson, O. P. Kallioniemi, M. Tirkkonen, K.Syrjakoski, T. Kuukasjarvi, P. Koivisto, R. Karhu, K.Holli, A. Arason, G. Johannesdottir, J. T. Bergthorsson,H. Johannsdottir, V. Egilsson, R. B. Barkardottir, O.Johannsson, K. Haraldsson, T. Sandberg, E. Holmberg, H.Gronberg, H. Olsson, A. Borg, P. Vehmanen, H. Eerola, P.Heikkila, S. Pyrhonen, and H. Nevanlinna (2000). Somaticdeletions in hereditary breast cancers implicate 13q21 as aputative novel breast cancer susceptibility locus. Proc. Natl.Acad. Sci. U. S. A. 97:96039608.121. N. Rahman, M. D. Teare, S. Seal, H. Renard, J. Mangion,C. Cour, D. Thompson, Y. Shugart, D. Eccles, P. Devilee,H. Meijers, K. L. Nathanson, S. L. Neuhausen, B. Weber, J.Chang-Claude, D. F. Easton, D. Goldgar, and M. R. Stratton(2000). Absence of evidence for a familial breast cancersusceptibility gene at chromosome 8p12-p22. Oncogene19:41704173.122. S. Seitz, K. Rohde, E. Bender, A. Nothnagel, K. Kolble,P. M. Schlag, and S. Scherneck (1997). Strong indication fora breast cancer susceptibility gene on chromosome 8p12-p22:Linkage analysis in German breast cancer families. Oncogene14:741743.123. D. Thompson, C. I. Szabo, J. Mangion, R. A. Oldenburg,F. Odefrey, S. Seal, R. Barfoot, K. Kroeze-Jansema, D.Teare, N. Rahman, H. Renard, C. KConFab, G. Mann, J.L. Hopper, S. S. Buys, I. L. Andrulis, R. Senie, M. B. Daly,D. West, E. A. Ostrander, K. Offit, T. Peretz, A. Osorio, J.236 Thompson and EastonBenitez, K. L. Nathanson, O. M. Sinilnikova, E. Olah, Y. J.Bignon, P. Ruiz, M. D. Badzioch, H. F. Vasen, A. P. Futreal,C. M. Phelan, S. A. Narod, H. T. Lynch, B. A. Ponder, R. A.Eeles, H. Meijers-Heijboer, D. Stoppa-Lyonnet, F. J. Couch,D. M. Eccles, D. G. Evans, J. Chang-Claude, G. Lenoir, B. L.Weber, P. Devilee, D. F. Easton, D. E. Goldgar, and M. R.Stratton (2002). Evaluation of linkage of breast cancer to theputative BRCA3 locus on chromosome 13q21 in 128 multiplecase families from the Breast Cancer Linkage Consortium.Proc. Natl. Acad. Sci. U. S. A. 99:827831.124. A. M. Dunning, C. S. Healey, P. D. Pharoah, M. D. Teare,B. A. Ponder, and D. F. Easton (1999). A systematic reviewof genetic polymorphisms and breast cancer risk. CancerEpidemiol. Biomarkers Prev. 8:843854.125. H. Meijers-Heijboer, J. Wijnen, H. Vasen, M. Wasielewski,A. Wagner, A. Hollestelle, F. Elstrodt, B. R. van den,A. de Snoo, G. T. Fat, C. Brekelmans, S. Jagmohan, P.Franken, P. Verkuijlen, O. A. van den, P. Chapman, C.Tops, G. Moslein, J. Burn, H. Lynch, J. Klijn, R. Fodde,and M. Schutte (2003). The CHEK2 1100delC mutationidentifies families with a hereditary breast and colorectalcancer phenotype. Am. J. Hum. Genet. 72:13081314.126. F. Lalloo, J. Varley, D. Ellis, A. Moran, L. ODair,P. Pharoah, and D. G. Evans (2003). Prediction of pathogenicmutations in patients with early-onset breast cancer by familyhistory. Lancet 361:11011102.127. A. Chompret, L. Brugieres, M. Ronsin, M. Gardes,F. Dessarps-Freichey, A. Abel, D. Hua, L. Ligot, M. G.Dondon, B. Bressac-de Paillerets, T. Frebourg, J. Lemerle,C. Bonaiti-Pellie, and J. Feunteun (2000). P53 germlinemutations in childhood cancers and cancer risk for carrierindividuals. Br. J. Cancer 82:19321937.128. S. Ball, M. Arolker, and A. D. Purushotham (2001). Breastcancer, Cowden disease and PTEN-MATCHS syndrome.Eur. J. Surg. Oncol. 27:604606.129. D. M. Parkin, S. L. Whelan, J. Ferlay, L. Teppo, and D. B.Thomas (2002). Cancer Incidence in Five Continents. IARC,Lyon, France.