Ovarian and breast cancer risks to women in families with two or more cases of ovarian cancer

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  • OVARIAN AND BREAST CANCER RISKS TO WOMEN IN FAMILIES WITHTWO OR MORE CASES OF OVARIAN CANCERSiobhan SUTCLIFFE1, Paul D.P. PHAROAH1*, Douglas F. EASTON2, Bruce A.J. PONDER1 and theUKCCCR FAMILIAL OVARIAN CANCER STUDY GROUP1CRC Human Cancer Genetics Research Group, Department of Oncology, University of Cambridge, Cambridge, UK2CRC Genetic Epidemiology Unit, Department of Community Medicine, University of Cambridge, Cambridge, UK

    There are few published estimates of the risk of developingbreast or ovarian cancer in women with a strong familyhistory of ovarian cancer. As these women commonlypresent to family cancer clinics, accurate cancer risk esti-mates are needed. We have estimated these risks in womenfrom families with 2 or more confirmed ovarian cancers infirst-degree relatives using data from the UKCCCR FamilialOvarian Cancer Register. The number of cancers observed inmore than 10,000 person years of follow-up was comparedwith the number expected based on national-, age-, sex- andperiod-specific incidence rates. The relative risk of ovariancancer was found to be 7.18 (95% CI 3.8212.3), decliningfrom 16.0 (6.4032.9) in women under 50 to 4.38 (1.609.52)in women 50 years of age and older. For breast cancer, therelative risk for women under 50 was 3.74 (2.046.28) and1.79 (1.022.90) for women 50 years of age and older (aver-age RR 2.36, 1.593.37). These correspond to absolute risksby age 70 of 11% for ovarian cancer and 15% for breastcancer. When the analyses were restricted to families thathad been negative for mutations in the breast/ovarian cancersusceptibility genes, BRCA1 and BRCA2, the ovarian cancerrisk was 11.59 (3.1229.7) and that of breast cancer 3.32(1.526.31). As well as having clinical relevance, our findingmay suggest that other breast/ovarian cancer genes are seg-regating in these families, though the possibility of unde-tected BRCA1/2 mutations must also be considered. Int.J. Cancer 87:110117, 2000. 2000 Wiley-Liss, Inc.

    Many women who present to family cancer clinics with con-cerns about breast and ovarian cancer have a strong family historyof ovarian cancer, defined here as 2 or more first-degree relativeswith confirmed epithelial ovarian cancer. In order for family can-cer specialists to confidently advise and manage these women,accurate estimates of their risk of developing both of these diseasesneed to be determined.

    With the recent identification of several highly penetrant cancersusceptibility genes, such as the breast/ovary susceptibility genesBRCA1 (Miki et al., 1994) and BRCA2 (Wooster et al., 1995),genetic testing has permitted family cancer specialists to attributea proportion of the strong family histories of ovarian cancer tomutations in one of these genes. For women found to be mutationcarriers, there are now good estimates of their breast and ovariancancer risks (Easton et al., 1995; Ford et al., 1994, 1998; Struew-ing et al., 1997). However, in the case of women for whom agenetic cause has not been found, the risks of developing breastand ovarian cancer are less clear. In these cases, family cancerspecialists must rely on the results of epidemiological studiesperformed on families with similar strong histories of ovariancancer in order to estimate their patients risks.

    Although several studies have investigated the ovarian cancerrisk in women with one relative with ovarian cancer (Stratton etal., 1998), only 2 studies have estimated this risk in women with2 or more affected relatives, and these estimates have had wideconfidence limits (Easton et al., 1996; Schildkraut and Thompson,1988). Easton et al. (1996) found the relative risk of death fromovarian cancer to be 24.15 (95% CI 5 6.5861.85) in a popula-tion-based cohort study of women with 2 first-degree relatives withconfirmed ovarian cancer. By contrast, in a population-based case-control study, Schildkraut and Thompson (1988) found the relativerisk of developing ovarian cancer to be 2.10 (0.2012.9) for

    women with 2 affected relatives . A combined analysis of datafrom these studies estimated the relative risk of developing ovariancancer to be 11.7 (5.325.9) for these women (Stratton et al.,1998).

    Three studies have published estimates of the risk of developingbreast cancer for women with 2 or more relatives with ovariancancer. In the same study as described above, Easton et al. (1996)observed 3 breast cancer deaths compared with 0.68 expecteddeaths based on population death rates (RR 5 4.41, 0.8912.89).In a retrospective cohort study of women with 2 or more relativeswith reported ovarian cancer, Jishi et al. (1995) found the relativerisk of developing breast cancer to be 2.52 (1.683.65). Finally,Claus et al. (1993) calculated the lifetime risk of developing breastcancer to be 31% in a population-based case-control study ofwomen with 2 first-degree relatives with ovarian cancer. Thisapproximates to a relative risk of 3.5.

    Our purpose was to estimate ovarian and breast cancer relativeand cumulative risks for women in families with strong histories ofovarian cancer, according to the number of affected relatives andBRCA1/2 mutation status of each family.

    MATERIAL AND METHODSStudy design

    We carried out a prospective cohort analysis of women infamilies on the UKCCCR Familial Ovarian Cancer Register, com-paring the number of incident ovarian and breast cancers with thatexpected based on population incidence rates.

    UKCCCR Familial Ovarian Cancer StudyThe UKCCCR Familial Ovarian Cancer study documents fam-

    ilies with at least 2 first-degree relatives with confirmed epithelialovarian cancer (including fallopian tube and peritoneal cancerhistologically indistinguishable from ovarian cancer). Cancers areconfirmed by at least one of the following: histology, death cer-tificate, Cancer Registry records, medical records or written con-firmation from a physician.

    Families register with the study on the date that the secondovarian cancer diagnosis is confirmed. The first families to join thestudy were registered in January 1991. At enrollment, all first- andsecond-degree female relatives of family members with confirmedovarian or early breast cancer (under 50 years of age at diagnosis)and all living affected family members are invited to participate inthe study. Women who choose to participate complete an epide-miological questionnaire including a detailed family history andprovide a blood sample for genetic analyses. Approximately every2 years thereafter, participants complete a follow-up questionnaire

    UKCCCR Familial Ovarian Cancer Study Group Steering Committee:B. Ponder, D. Easton, G. Fraser, I. Jacobs, J. Mackay, P. Twentyman, T.Bishop, D. Lowe, S. Lakhani and M. Steel.

    *Correspondence to: Strangeways Research Laboratories, Worts Cause-way, Cambridge, CB1 8RN, UK. Fax 144 (0)1223 411609. E-mail:paul.pharoah@srl.cam.ac.uk

    Received 29 September 1999; Revised 8 December 1999

    Int. J. Cancer: 87, 110117 (2000) 2000 Wiley-Liss, Inc.

    Publication of the International Union Against Cancer

  • to update medical and family history information. Where possible,all relevant cancers reported at follow-up are confirmed as fororiginal affected cases.

    The study has been approved by all the appropriate local re-search ethics committees.

    ESTIMATION OF OVARIAN AND BREAST CANCER RISKS

    Women eligible for the analyses were all first- and second-degree relatives of family members diagnosed with ovarian orearly onset breast cancer before the date of registration and allaffected family members who remained at risk of developing asecond primary cancer. Relatives of family members diagnosedwith early onset breast cancer were included in the at-risk cohortsbecause there is a known familial association between breast andovarian cancer, most of which can be explained by the knownsusceptibility genes. Ovarian and breast cancer relative risks forthe at-risk women were estimated by comparing the number ofincident ovarian and breast cancer cases with the number expected,based on national-, age-, sex- and period-specific incidence ratesfor England and Wales (Ferlay et al., 1997) using the PERSONYEARS program. Ninety-five percent confidence intervals werecalculated according to standard methods. Where no date of birthwas available, birthdates were approximated using the dates ofbirth of parents, siblings and cousins.

    The entry date for each woman at risk was taken as the date ofregistration of her family. Therefore, women who had alreadyundergone a confirmed bilateral oophorectomy or a reported/con-firmed bilateral mastectomy prior to the date of registration wereexcluded from the relevant cohort. In addition, women affectedwith confirmed or unconfirmed ovarian cancer at registration wereexcluded from the cohort at risk of developing ovarian cancer.Likewise, women affected with breast cancer (confirmed or un-confirmed) at registration were excluded from the cohort at risk ofdeveloping breast cancer.

    Further, women who did not meet the eligibility criteria for theanalysis were women for whom the study did not have accuratefollow-up information, including those not in contact with familymembers participating in the study. These women represent 15%of all first- and second-degree relatives. Women over the age of 85at registration were also excluded to avoid problems associatedwith miscertification of causes of death at older ages.

    The number of families in the cohort at risk of developingovarian cancer differs slightly from that of developing breastcancer because of differences in the configuration of each familypedigree. For some families on the register, no unaffected first- orsecond-degree relatives could be included in the analyses becausethey all failed to meet the eligibility criteria. Thus, the onlyremaining individuals who could be included were the affectedfamily members. Consequently, in the case of 3 families, one ofthe remaining family members affected with ovarian cancer waseligible for the breast cancer risk analysis but not for the ovariancancer risk analysis. The number of unaffected individuals in eachcohort differs as well because of the greater number of womenaffected with ovarian cancer than with breast cancer and thegreater occurrence of bilateral oophorectomies than of prophylac-tic bilateral mastectomies in women on the register.

    Women in the cohort at risk of developing ovarian cancer werecensored at the first occurrence of one of the following events:diagnosis of ovarian (including possible ovarian), peritoneal orfallopian tube cancer, confirmed bilateral oophorectomy, death,attainment of age 85 or the last date at which they or anothermember of their family completed a follow-up questionnaire.Women in the cohort at risk of developing breast cancer wereconsidered to remain at risk until diagnosis of breast cancer,reported/confirmed bilateral mastectomy, death, attainment of age85 or the last date at which they or another member of their familycompleted a follow-up questionnaire.

    Ovarian cancer cases included in the observed group for relativerisk calculations were all the confirmed ovarian, peritoneal andfallopian tube cancer diagnoses but not the possible ovarian cancerdiagnoses. Breast cancer cases included in the observed groupwere all reported breast cancer diagnoses; not all of these wereconfirmed.

    Subgroup analyses were carried out based on the number offamily members with confirmed or unconfirmed ovarian cancer atregistration, the presence or absence of family members with earlybreast cancer at registration and the BRCA1 and BRCA2 mutationstatus of each family (see below). The cohorts at risk were initiallysubdivided into those families with only 2 confirmed ovariancancer diagnoses at registration and those with 3 or more. Thissubdivision of families was complicated by the presence of indi-viduals with unconfirmed ovarian cancer. Although at least 2ovarian cancer diagnoses in each family must be confirmed forinclusion in the UKCCCR Familial Ovarian Cancer Register,several families on the register have additional reported ovariancancer cases, which are not possible to confirm. To avoid bothignoring these potential ovarian cancer cases and including themas confirmed ovarian cancer cases, a separate category was createdfor the purpose of the analyses. This category (21 case) consistedof all families with only 2 confirmed ovarian cancer cases and 1 ormore unconfirmed cases. The subcategory of 2-case-only familieswas further subdivided into those with and without membersaffected with early breast cancer at registration.

    Affected family members from 112 of the families eligible foranalysis have been tested for BRCA1 and BRCA2 mutations byanalysis of the entire coding region of both genes (Gayther et al.,1996, 1999). These families were divided into those in which onemember had tested positive for a mutation and those in which nomutation had been found. The remainder of the families weregrouped together as BRCA1/2 untested families.

    RESULTS

    A total of 2,147 women from 316 families were eligible for theovarian cancer risk analysis and provided 10,893 person years atrisk follow-up. For the breast cancer risk analysis, 2,304 womenfrom 319 families contributed 11,936 person years at risk (TableI). The number of observed cancers for each family category at riskand the expected number based on national-, age-, sex- and period-specific incidence rates for England and Wales are also presentedin Table I.

    The ovarian and breast cancer relative risks for each subcate-gory and their associated 95% confidence limits are presented inFigures 1 and 2, respectively. The average relative risk of devel-oping ovarian cancer was 7.18 (95% CI 3.8212.3), declining from16.0 (6.4032.9) in women under 50 to 4.38 (1.609.52) inwomen 50 years of age and older. For breast cancer, the relativerisk for women under 50 was 3.74 (2.046.28) and 1.79 (1.022.90) for women 50 years of age and older (average RR 2.36,1.593.37). Both of these trends were found to be statisticallysignificant (p 5 0.020 and p 5 0.034, respectively).

    The ovarian cancer relative risks observed for 21 and $3-casefamilies, 17.60 (5.6741.1) and 7.45 (2.0019.1), respectively,were higher than that observed for 2-case-only families (4.04,1.0910.4). This finding suggests that the majority of unconfirmedovarian cancers in the 21 case families are likely to be trueovarian cancers, which would place most of these families in a3-or-more-case family category. However, even when the resultsfrom the 21 and $3-case family analyses were combined (RR 510.98, 5.0120.8) and compared with that of the 2-case-onlyfamilies, the resulting difference was not found to be statisticallysignificant (p 5 0.073). The ovarian cancer relative risk for womenfrom the 2-case-only families did not alter appreciably whenfamilies with early breast cancer cases were excluded from theanalyses (5.14, 1.3813.2) .

    111CANCER RISKS IN OVARIAN CANCER FAMILIES

  • TABL

    EI

    INCI

    DEN

    TO

    VA

    RIA

    NA

    ND

    BR

    EAST

    CAN

    CERS

    BY

    FAM

    ILY

    HIS

    TORY

    CATE

    GO

    RY

    Fam

    ilyca

    tego

    ry1

    Ova

    rian

    cance

    rB

    reas

    tcan

    cer

    Num

    bero

    ffam

    ilies

    Num

    beru

    naf

    fect

    edPe

    rson

    year

    sIn

    cide

    ntovar

    ian

    cance

    rN

    umbe

    roff

    amili

    esN

    umbe

    runaf

    fect

    edPe

    rson

    year

    sIn

    cide

    ntbr

    east

    cance

    r

    Obs

    erve

    dEx

    pect

    edO

    bser

    ved

    Expe

    cted

    BRCA

    1/2

    neg

    ativ

    e$

    3ca

    se10

    9860

    31

    0.09

    510

    102

    630

    50.

    6721

    2ca

    se5

    2512

    12

    0.02

    15

    2815

    20

    0.19

    2ca

    se41

    259

    1,40

    21

    0.23

    4230

    51,

    666

    41.

    852

    case

    no

    brea

    stca

    nce

    r333

    196

    1,01

    81

    0.15

    3423

    71,

    261

    31.

    36To

    tal4

    5638

    22,

    126

    40.

    3557

    435

    2,44

    89

    2.71

    BRCA

    1/2

    unte

    sted

    $3

    case

    2520

    896

    10

    0.16

    2521

    41,

    032

    21.

    1021

    case

    3122

    397

    52

    0.20

    3123

    41,

    077

    11.

    312

    case

    150

    810

    4,03

    12

    0.68

    151

    854

    4,32

    611

    4.58

    Tota

    l20

    61,

    241

    5,96

    74

    1.04

    207

    1,30

    26,

    435

    146.

    99BR

    CA1/

    2po

    sitiv

    eTo

    tal

    5452

    42,

    800

    50.

    4255

    567

    3,05

    37

    3.00

    Who

    lese

    t$

    3ca

    se62

    643

    3,44

    24

    0.54

    6268

    33,

    710

    103.

    7321

    case

    4433

    11,

    507

    50.

    2844

    345

    1,64

    53

    1.91

    2ca

    se21

    01,

    173

    5,94

    44

    0.99

    213

    1,27

    66,

    581

    177.

    062

    case

    no

    brea

    stca

    nce

    r17

    392

    94,

    703

    40.

    7817

    61,

    036

    5,32

    314

    5.81

    All

    first-

    degr

    eere

    lativ

    es30

    993

    34,

    469

    111.

    0931

    31,

    084

    5,39

    527

    8.20

    All

    seco

    nd-

    degr

    eere

    lativ

    es28

    41,

    214

    6,42

    42

    0.72

    283

    1,22

    06,

    541

    34.

    50

    Tota

    l31

    62,

    147

    10,8

    9313

    1.81

    319

    2,30

    411

    ,936

    3012

    .71 A

    ccor

    ding

    toth

    enum

    ber

    of

    confir

    med

    ovar

    ian

    cance

    rca

    ses

    atre

    gistr

    atio

    n.2

    Incl

    udes

    all

    fam

    ilies

    with

    only

    2co

    nfir

    med

    and

    1or

    more

    unco

    nfir

    med

    ovar

    ian

    cance

    rca

    ses

    atre

    gistr

    atio

    n.3

    Incl

    udes

    allf

    amili

    esw

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    2co

    nfir

    med

    ovar

    ian

    cance

    rca

    ses

    and

    no

    brea

    stca

    nce

    rca

    sebe

    low

    age

    50or

    unco

    nfir

    med

    ovar

    ian

    cance

    rca

    ses

    atre

    gistr

    atio

    n.

    4 Tot

    alofa

    ll$

    3,21

    and

    2ovar

    ian

    cance

    rfa

    mili

    esw

    ithin

    the

    sam

    esu

    bcat

    egor

    y.

    112 SUTCLIFFE ET AL.

  • FIGURE 1 Relative risk of ovarian cancer to women with a strong family history of ovarian cancer by family history category.

    113CANCER RISKS IN OVARIAN CANCER FAMILIES

  • FIGURE 2 Relative risk of breast cancer to women with a strong family history of ovarian cancer by family history category.

    114 SUTCLIFFE ET AL.

  • As expected, first-degree relatives had substantially higher rel-ative risks for both ovarian cancer (10.09, 5.0318.1) and breastcancer (3.29, 2.174.79) than second-degree relatives (2.78, 0.3110.0 and 0.67, 0.131.95, respectively). This difference was sta-tistically significant for breast cancer (p 5 0.0016) but not forovarian cancer (p 5 0.060).

    Although women from BRCA1 and BRCA2 mutation-positivefamilies had a significantly increased relative risk of developingovarian cancer (11.9, 3.8327.7), their breast cancer relative riskwas only slightly elevated (2.33, 0.934.80). However, it was notclear which individuals in these families were actually mutationcarriers. Women in BRCA1 and BRCA2 mutation-negative familieshad significantly increased relative risks for both ovarian (11.6,3.1229.7) and breast cancer (3.32, 1.526.31). For ovarian can-cer, this risk declined from 24.6 (2.7688.7) in women under 50to 7.58 (0.8527.36) in women 50 years of age and older (p 50.238), while for breast cancer, it was marginally higher in womenunder 50 (3.90, 0.7811.4) compared with those over 50 (3.10,1.136.74) (p 5 0.494). Women in BRCA1 and BRCA2 untestedfamilies had only moderately elevated relative risks for both ovar-ian (3.83, 1.039.81) and breast cancer (2.00, 1.093.36). Theovarian cancer relative risk declined from 12.2 (2.4635.7) inwomen under 50 to 1.25 (0.026.97) in women 50 years of age andolder (p 5 0.043), while for breast cancer, this risk declined from3.41 (1.377.03) in women under 50 to 1.42 (0.572.92) in women50 years of age and older (p 5 0.084).

    In order to counsel at-risk individuals effectively, risks need tobe presented in absolute terms rather than as relative risks. Wehave therefore used the method of Dupont (1989) to estimate theabsolute risks of developing ovarian and breast cancer by anygiven age using our age-specific relative risk estimates, nationalcancer incidence figures and all-cause mortality data (Figs. 3 and4). These risks are presented according to family BRCA1 andBRCA2 mutation status.

    DISCUSSION

    We have carried out a prospective cohort analysis using datafrom the UKCCCR Familial Ovarian Cancer Register in order toestimate the relative risks of developing ovarian and breast cancerin women with a strong family history of ovarian cancer. Ourresults need to be interpreted in the light of any potential biases.

    The ascertainment of ovarian cancer diagnoses in women whocompleted follow-up questionnaires is likely to be accurate, sinceall diagnoses were independently confirmed. However, in the caseof women whose follow-up was through another family member,there may have been some underreporting of ovarian cancer. Webelieve this bias to be minimal because women taking part in thisstudy are particularly aware of familial ovarian cancer and aremotivated to report to the study. Overreporting was avoided byconfirming all new ovarian cancer diagnoses. In the case of thebreast cancer risk analysis, not all incident breast cancer diagnoseswere confirmed. Therefore, the possibility exists for bias due toeither underreporting or overreporting of breast cancer for bothwomen who completed a follow-up questionnaire and womenwhose follow-up was through another family member. Again, webelieve this bias to be minimal because reported breast cancer infamily members has been shown to be both sensitive and specific(Kerber and Slattery, 1997).

    Women for whom no follow-up data were available, such asname, date of birth or vital status, were excluded from the analy-ses. This may have introduced some bias, as it is likely thatcomplete data were preferentially available for affected women.However, the extent of this bias is unclear.

    Women who had undergone a confirmed bilateral oophorectomyor mastectomy were censored at the date of their operation, sincethese operations reduce the risk of developing ovarian and breastcancer. The fact that they do not eliminate these risks entirely washighlighted by the diagnosis of para-aortic lymph node cancercompatible with ovarian origin 4 years after a bilateral oophorec-tomy in one woman on the register. Despite this evidence for

    FIGURE 3 Absolute risk of developing ovarian cancer by age.

    115CANCER RISKS IN OVARIAN CANCER FAMILIES

  • continued possible risk, women were censored at the date of theirconfirmed operation to avoid including person years at reduced butindeterminate risk in the analyses. Women who had undergone abilateral oophorectomy for which no confirmation was availablewere not censored at the date of their operation because otherpelvic operations, such as hysterectomies, are sometimes mistak-enly reported as oophorectomies. Although this policy ensured thatall operation censoring dates were correct, it may have also biasedthe results toward the inclusion of additional person years at risk inthe ovarian cancer risk analysis. However, women reporting un-confirmed bilateral oophorectomies contribute at most 400 personyears of follow-up post-operation compared with more than 10,000person years in total. In the case of women who had undergone abilateral mastectomy, the dates of both confirmed and unconfirmedmastectomies were used, as it was felt that women were less likelyto misunderstand the nature of and reasons for this procedure. Itshould also be noted that although women were censored ondiagnosis of a first primary breast cancer, they remain at risk ofbreast cancer, as demonstrated by 5 women on the register whodeveloped a second primary.

    Although the extent to which the above-mentioned biases mayhave affected relative risk calculations is unclear, their effect isunlikely to be significant since our results are consistent with thoseof other studies that have used different study designs. In addition,these biases apply equally to all subgroup analyses, so between-group comparisons remain valid.

    Our overall estimate of ovarian cancer relative risk differs fromthose of 2 previously published studies (24.15 and 2.10), but it isclose to the result of these 2 studies combined (11.7) (Stratton etal., 1998). Furthermore, the risk estimates published by thesestudies, one of which was a retrospective cohort analysis of ovar-ian cancer mortality and the other a case-control study of incidentovarian cancer, were substantially different from one another andboth had wide confidence intervals. Our overall estimate of breastcancer relative risk to women with a family history of ovarian

    cancer (2.4) was also of a similar magnitude as those previouslypublished (2.54.1).

    The finding that our breast cancer risk estimate for women fromBRCA1/2 mutation-positive families was not particularly high isintriguing. The proportion of unaffected relatives in these familiesthat are mutation carriers is not clear and so this risk does notprovide a direct penetrance estimate. However, it has previouslybeen shown that mutations in specific regions of the BRCA1 andBRCA2 genes either increase ovarian cancer risk or decrease breastcancer risk as compared with mutations outside these regions(Gayther et al., 1995, 1997). All of the mutations that occur in ourtested families lie within these regions, so our data suggest thatthese mutations may in fact be responsible for decreasing breastcancer risk rather than increasing ovarian cancer risk as comparedwith mutations in other parts of the genes.

    The observation that ovarian and breast cancer risks are elevatedin families that tested negative for BRCA1/2 mutations is also animportant one. This finding may be due to the insensitivity ofBRCA1/2 mutation testing or to the presence of other breast/ovarian cancer susceptibility genes. Most of the increase in riskseen in the families with 3 or more cases of ovarian cancer can beaccounted for by undetected mutations (Gayther et al., 1999), sincethe sensitivity of mutation detection may be as low as 64% (Narodet al., 1995). However, even taking into account this lack ofsensitivity, BRCA1/2 can only explain one-third of the 2-case-onlyfamilies (Gayther et al., 1999). The elevated risk of ovarian cancerseen in these families, though not statistically significant, suggeststhat other genes might contribute to risk. Moreover, these riskestimates should be considered when counselling women fromhigh-risk families for whom a genetic cause has not been identi-fied.

    The ovarian and breast cancer risks for all BRCA1/2 untestedfamilies were lower than those for tested families (p 5 0.0485 andp 5 0.2296, respectively), whether or not a mutation was found.The reasons for this are not clear but in part can be explained by

    FIGURE 4 Absolute risk of developing breast cancer by age.

    116 SUTCLIFFE ET AL.

  • the selection of families for mutation testing. Only those familieswith a living member affected with ovarian cancer can be testedfor mutations in BRCA1/2, but at registration, some families willhave no living affected member. During follow-up those familiesin which further cases are diagnosed become eligible for testing.The risks in these families will be higher than in those families thatremain ineligible for testing because no incident cases occur afterregistration.

    The data on which we have based our risk estimates come fromone of the largest and best documented registers of familial ovariancancer in the world. This has enabled us to determine ovarian andbreast cancer risks to women for whom no such estimates werepreviously available. Altogether, the estimates presented hereshould prove of value for the management and counselling ofwomen in families with a strong history of ovarian cancer andespecially for whom a genetic cause has not been identified.

    Long-term follow-up of these families will provide more preciserisk estimates. This will be particularly important for establishingthe true risk to women from 2-case-only families.

    ACKNOWLEDGEMENTS

    The UKCCCR Familial Ovarian Cancer Register is funded bythe Cancer Research Campaign (CRC) and the Imperial CancerResearch Fund (ICRF). SS was funded by a grant from the EastAnglian NHS R & D; BAJP is a Gibb Fellow of the CRC; PDPPis a CRC Senior Clinical Research Fellow; and DFE is funded bythe CRC. We thank Ms. A. Taylor, Ms. C. Pye, Ms. M. Cook andMs. L. McGuffog for help with collating family data; Dr. S.Gayther, Ms. P. Harrington and Mr. P. Russell for the mutationanalysis; and the families and their clinicians for their cooperation.

    REFERENCES

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    117CANCER RISKS IN OVARIAN CANCER FAMILIES

    MATERIAL AND METHODSESTIMATION OF OVARIAN AND BREAST CANCER RISKSRESULTSTABLE IFIGURE 1FIGURE 2FIGURE 3

    DISCUSSIONFIGURE 4

    ACKNOWLEDGEMENTSREFERENCES

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