Genetics of hereditary colorectal cancer

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enetics of Hereditary Colorectal Canceron-Seok Jo and Daniel C. Chung

Genetic factors can dramatically influence the risk of colorectal cancer, and the molecularbases of many hereditary colorectal cancer syndromes, including familial adenomatouspolyposis (FAP), attenuated FAP (AFAP), and hereditary nonpolyposis colorectal cancer(HNPCC) have been elucidated. Additional syndromes continue to be defined as newgenes, including MYH, are linked to the development of colonic polyps and cancer. Therisks of colorectal cancer are variable and depend on the specific germline alterations.Some mutations are associated with a 100% lifetime risk of developing cancer, while othersare associated with only a mild increase in risk. Although there are overlapping clinicalfeatures in many of these syndromes, they can be distinguished by the age at cancerdiagnosis, inheritance pattern, number and distribution of polyps, specific histologic fea-tures of the cancers, and the presence of distinctive extracolonic features. The introductionand refinement of genetic testing has provided a new and invaluable tool for the diagnosisand assessment of cancer risk for suspected cases of hereditary colon cancer.Semin Oncol 32:11-23 © 2005 Elsevier Inc. All rights reserved.

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ietary and lifestyle modifications can reduce the risk ofcolon cancer, but other risk factors are not easily mod-

fied. Epidemiologic studies have estimated a relative risk of.8 if one first-degree relative is diagnosed with colon can-er.1,2 As many as 25% of all colon cancers are associated withfamily history of the disease, indicating that a substantial

raction of cases may be attributable to inherited genetic fac-ors.3 Approximately 3% to 5% of these cases are seen in indi-iduals with the well-recognized genetic syndromes familial ad-nomatous polyposis (FAP) or hereditary nonpolyposisolorectal cancer (HNPCC) (Table 1).4 However, the numberf hereditary colon cancer syndromes has been rapidly ex-anding and now includes, for example, the newly identifiedYH polyposis syndrome. Nevertheless, most cases of hered-

tary colon cancer have not yet been defined genetically. Theoal of this review is to highlight our current understandingf the inherited forms of colon cancer.Recognition of these syndromes is crucial because of the

pecialized approach to cancer risk assessment and cancercreening that is required for affected individuals, as well asamily members.

astrointestinal Unit and Department of Medicine, Massachusetts GeneralHospital, Harvard Medical School, Boston, MA.

upported by NIH RO1 CA92594.ddress reprint requests to Daniel C. Chung, MD, Gastrointestinal Unit and

Department of Medicine, Massachusetts General Hospital, Harvard Med-ical School, 50 Blossom St, Boston, MA 02114. E-mail: chung.daniel@

smgh.harvard.edu

093-7754/05/$-see front matter © 2005 Elsevier Inc. All rights reserved.oi:10.1053/j.seminoncol.2004.09.034

enetic Model ofolorectal Tumorigenesis

he study of colon cancer genetics established a paradigm forhe molecular pathogenesis of solid tumors. In 1990, a step-ise model for colorectal tumorigenesis was proposed inhich sequential alterations in the key growth regulatoryenes APC, K-ras, and TP53 culminated in the developmentf a malignant tumor.5 This so-called chromosomal instabil-ty pathway underlies the development of 85% of colorectalumors.6 Nearly all colon cancers arise from pre-existing ad-nomatous polyps, but not all adenomas progress to cancer.hose that do have accumulated the necessary combinationf genetic mutations in a prescribed chronological order. Inome familial colorectal cancer syndromes, the progressiono cancer is accelerated due to a pre-existing germline muta-ion in one of these key regulatory genes. In other cases, aermline mutation in one of several DNA repair genes createshypermutable environment in which somatic mutations

apidly accumulate.The genes implicated in colorectal carcinogenesis can be

ivided into three categories: tumor-suppressor genes, onco-enes, and DNA-repair genes. In the most general sense,umor-suppressor genes function to downregulate growth-timulatory pathways. In colon cancer, the tumor-suppressorenes that are most frequently inactivated include APC, TP53,nd p16INK4a.6 Consistent with the Knudson “two-hit hypoth-sis,” mutations in both alleles are required to fully inactivateene function.7 In autosomal dominant hereditary cancer
yndromes, one allele is mutated in the germline. The second
11

Table 1 Inherited Syndromes With an Increased Risk of Colorectal Cancer

Syndrome GenesLifetime Risk

of CRCInheritance

Pattern

Average Ageof Diagnosisof CRC (yr)

No. ofPolyps

PolypsHistology

PredominantLocation of

Polyps/Cancerin Colon Extracolonic Features

High riskClassic familial

adenomatouspolyposis (FAP)

APC 100% Autosomaldominant

39 Hundreds tothousands

Adenomatous Entire colon Fundic gland polypsDuodenal/ampullary adenomasDesmoid tumors, osteomas,

thyroid and brain tumorsCHRPE

Attenuated FAP(AFAP)

APC >80% Autosomaldominant

56 <100 Adenomatous Proximal colon Fundic gland polypsDuodenal/ampullary adenomas

Hereditary nonpolyposiscolorectalcancer (HNPCC)

MLH1MSH2MSH6

80% Autosomaldominant

45 Few Adenomatous Proximal colon Tumors of the uterus, ovary,stomach, kidney, urinarytract, biliary tree, smallintestine, and skin

MYH polyposis MYH �100%* Autosomalrecessive

5082 <100 Adenomatous Entire colon Undetermined

Moderate riskPeutz-Jegher’s

syndrome (PJS)LKB1 39%90 Autosomal

dominant4590 Few Hamartomatous Entire colon Mucocutaneous pigmentation

Tumors of the uterus, breast,lungs, reproductive organs,pancreas, and gallbladder

Juvenile polyposiscoli (JPC)

MADH4BMPR1A

10%-38%108-110 Autosomaldominant

34111 Few Hamartomatous Entire colon Tumors of the stomach andduodenum

Hyperplasticpolyposissyndrome (HPS)

Unknown 25%-35%†118,120 Unknown 66122 Many‡ Hyperplastic Entire colon None described

Low riskBloom’s syndrome BLM 8%128 Autosomal

recessive33128 Few Adenomatous Entire colon Leukemia

LymphomaCarcinomas of the head and

neck, respiratory tract,female reproductive organs,breast, and uppergastrointestinal tract

I1307K APCpolymorphism

APC 8%-11%134 Autosomaldominant

64-70136 Few Adenomatous Entire colon None described

Abbreviations: CRC, colorectal cancer; CHRPE, congenital hypertropy of the retinal pigmented epithelium.*Extrapolated from preliminary studies. Exact value remains to be determined.†These numbers represent prevalence of colorectal cancer among HPS patients. Lifetime risk has not been determined.‡See Table 6.

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Genetics of hereditary colorectal cancer 13

lteration is acquired somatically, and silencing of the secondllele can be achieved through a variety of mechanisms, in-luding chromosomal deletion, point mutation, or promoterypermethylation (Fig 1).Proto-oncogenes such as K-ras are components of signal-

ng pathways that normally promote cellular growth and pro-iferation. Oncogenic mutations result in a constitutively ac-ive gene product. In contrast to tumor-suppressor genes, autation in only one allele is sufficient to exhibit a tumori-

enic effect. To date, no colon cancer syndrome has beenttributed to an inherited mutation in a proto-oncogene.

Maintaining the integrity of the genome is a complex pro-ess essential for cellular homeostasis. Modification of indi-idual nucleotides can be introduced through biochemicaleactions that include UV cross-linking, alkylation, sponta-eous deamination, or oxidation. A highly orchestrated pro-ess called the “base excision repair system” corrects theserrors.8 A second way that errors are introduced is via mis-airing of nucleotides. Mismatch errors can occur duringormal DNA replication but are quickly repaired by theDNA mismatch-repair system.” When components of eitherf these DNA-repair systems are dysfunctional, a mutatorhenotype results in which deleterious mutations can accu-ulate in target genes that directly control cellular growth

nd proliferation. A dysfunctional DNA-repair process un-erlies the HNPCC, MYH polyposis, and Bloom’s syndromes.

ecognizing Hereditaryolon Cancer Syndromes

he recognition of a hereditary colon cancer syndrome first

igure 1 Knudson’s “two hit” hypothesis. For tumor-suppressorenes, inactivation of both alleles is required for cancer to develop.n autosomal dominant colon cancer syndromes, the “first hit” isrovided by the pre-existing germline mutation in one allele that isresent in every cell. The “second hit” occurs when an acquired, oromatic, mutation inactivates the other allele. In sporadic colonancer, both “hits” are acquired somatically.

egins with the astute clinician. In general, there are several C

eatures that should raise the suspicion of such a syndrome,ncluding (1) the diagnosis of colon cancer at an unusuallyoung age (�50 years), (2) the diagnosis of colonic polyps atn unusually young age (�45 years) or in large numbers�10 polyps), (3) the presence of distinctive extracolonicancers, or (4) a family history of any of the above. If any ofhese features is present, a more careful evaluation should benitiated.

The key clinical features of the known hereditary colonancer syndromes are described in detail below. The mostmportant advance in their diagnosis and management haseen the introduction of genetic testing for germline DNAlterations. There are two major implications. First, diagnos-ic criteria for these syndromes are no longer based purely onlinical features but now include genetic test results. In caseshere the phenotypic expression of a condition is pathogno-onic, such as the diffuse polyposis observed in FAP, genetic

esting may simply confirm the straightforward clinical diag-osis. However, when clinical features are more protean as inNPCC, genetic testing can provide an invaluable means of

stablishing a diagnosis. The second major implication is thathe accuracy of cancer risk assessment for potentially affectedamily members has substantially improved. This permitsntensive cancer screening to be targeted only to those whoarry a germline alteration and spares noncarriers from thesetherwise necessary measures.Genetic testing for cancer predisposition is a rapidly evolv-

ng area of medicine. One facet that can present a challenge ishe interpretation of test results. Although most cases aretraightforward, there are times when test results can be in-onclusive. For example, the absence of an identifiable mu-ation does not necessarily rule out the disorder. The absencef a mutation is a true “negative” result only when a clinicallyffected family member also tests “positive.” A particularlyifficult result to explain is the so-called missense mutationf uncertain significance. In contrast to mutations that resultn a prematurely truncated protein, a missense alteration mayr may not be associated with the disorder. Finally, althoughegislation has been passed in 47 states banning genetic dis-rimination for health insurance,9 some apprehension sur-ounding genetic testing lingers. Because of the many com-lexities inherent in the testing process, formal geneticounseling is recommended.

yndromes With a Highisk of Colorectal Cancer

amilial Adenomatousolyposis and Attenuated FAPAP is the most common adenomatous polyposis syndrome,ith an estimated prevalence between one in 5,000 to,500.10 It is inherited in an autosomal dominant mannerith a penetrance of 100%. Classic FAP is characterized by

he development of multiple colonic adenomas during thearly teenage years with progressive increases so that hun-reds to thousands of polyps are recognized by adulthood.
olonic adenocarcinomas are observed approximately 10 to

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14 W.-S. Jo and D.C. Chung

5 years after the appearance of polyposis, and almost alwaysy the age of 40 years. FAP-associated adenomas and cancersre distributed throughout the entire colon and are histolog-cally identical to those found in the general population.

Multiple gastric polyps can develop and are typically be-ign fundic gland polyps. Gastric adenomas and adenocarci-omas have also been documented, particularly in FAP fam-

lies from Japan and Korea, where there is an overall twofoldncreased risk of gastric cancer compared to the general pop-lation.11,12 Duodenal, peri-ampullary, or ampullary adeno-as eventually develop in nearly all FAP patients. Approxi-ately 10% will develop duodenal adenocarcinoma by age

0,13 making it the second most common malignancy inAP.14

Extraintestinal features include follicular and papillaryhyroid cancers, congenital hypertrophy of the retinal pig-ented epithelium (CHRPE), desmoid tumors, epidermoid

ysts, and osteomas. Rarely, hepatoblastomas are seen inoung children. Desmoid tumors typically develop after ab-ominal surgery and rank second as a cause of mortalityehind metastatic carcinoma.15 Turcot’s syndrome refers toereditary colon cancer families with central nervous systemumors. Medulloblastomas have been associated with FAP,hereas glioblastomas are the brain tumors primarily seen inNPCC kindreds.16

An attenuated version of FAP (AFAP) differs from the clas-ic form in that there are substantially fewer colonic polyps�100); these polyps tend to develop on the right side of theolon, and the average ages at which colorectal polyps andancer occur are delayed approximately 15 years. There are,owever, no appreciable differences in upper gastrointestinalract lesions, as multiple fundic gland polyps are invariablyresent and there is a similar risk of duodenal adenomas anddenocarcinomas.17 In some cases, fundic gland polyposisan actually precede the onset of colonic polyposis.17 Theresence of thousands of colonic polyps makes classic FAPasy to diagnose, but the attenuated form can be difficult toecognize when the polyp burden is very low or the onset isignificantly delayed (ie, after age 60 years). The features ofFAP can also overlap with HNPCC,18 and genetic testingan distinguish between the two syndromes.

The gene responsible for both FAP and AFAP was firstdentified in 1991 through linkage analysis and positionalloning.19-21 The adenomatous polyposis coli (APC) gene lo-ated on chromosome 5q21 is a tumor-suppressor that in-ibits the Wnt signaling pathway.6 The key component inhis pathway is �-catenin, which activates the transcription ofrowth-regulatory genes through its interaction with theranscription factor T-cell factor 4 (TCF4). APC targets-catenin for degradation, thereby acting as a negative regu-

ator of Wnt signaling (Fig 2). When APC is mutated, thehysical interaction between APC and �-catenin is impaired,nd excess �-catenin is translocated to the nucleus. The piv-tal role of APC in colorectal tumorigenesis is highlighted byhe fact that more than 70% of sporadic colon cancers harboromatic mutations in the APC gene.

Germline mutations are located throughout the entire APC
ene, and more than 90% of mutations introduce a prema- h
ure stop codon that results in a truncated protein prod-ct.22,23 There are fascinating genotype-phenotype correla-ions (Fig 3). Classic FAP is seen with mutations located inhe central region between codons 169 and 1393,24 and mu-ations between codons 1250 and 1464 have been associatedith particularly severe polyposis.25 In contrast, mutations

ocated at the 5= end (proximal to codon 157)26 or the 3= endf the gene (distal to codon 1596)27 are associated withFAP. One potential explanation for the delayed phenotype

s that mutations in AFAP give rise to a truncated but stillunctional APC protein.28 Thus, two additional somatic mu-ations are required to inactivate both the wild-type and theFAP allele, which would be predicted to require a longer

ime to occur.Genetic tests for FAP were one of the first cancer predis-

osition tests available commercially. The options includeNA sequencing, conformation strand gel electrophoresis,

he protein truncation test, and linkage analysis.29 Direct se-uencing of the entire APC gene is now considered to be theost accurate.30 In up to 20% of cases, genetic testing reveals

n APC mutation in an affected individual without a family

igure 2 The Wnt signaling pathway. The activation of the Wntignaling pathway involves the translocation of �-catenin from theell membrane into the nucleus where it interacts with the TCF4ranscription factor to promote transcription of TCF target genes,ncluding cyclin D1, myc, PPAR�, and VEGF. APC downregulates the

nt signaling pathway by preventing �-catenin from entering theucleus. When �-catenin is bound to a complex containing APC,xin, and GSK3�, GSK3� phosphorylates �-catenin and targets itor degradation. When APC is mutated, the Wnt pathway becomesctivated because phosphorylation of �-catenin does not occur, andt can then translocate to the nucleus.

istory of polyposis in either parent, indicating a de novo, or

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pontaneously acquired, germline mutation.29 These individ-als can pass on the disorder to their offspring in an autoso-al dominant manner.Annual flexible sigmoidoscopy in classic FAP or colonos-

opy in AFAP should be initiated by the age of 10 to 12 yearsr by age 25 years, respectively. Upper endoscopy using bothforward- and side-viewing instrument31 should be started at

he time of colectomy or by age 30 years and then repeatedvery 1 to 3 years. Annual thyroid ultrasounds should bebtained beginning at the age of 10 to 12 years. Annuallpha-fetoprotein levels and liver ultrasound are also recom-ended during the first decade of life to screen for hepato-

lastoma. Individuals in families with Turcot’s syndromehould also undergo periodic brain imaging.

Colectomy is the only definitive treatment and becomesnevitable once the colon is carpeted with adenomatous pol-ps. The preferred approach is a total proctocolectomy withleostomy or ileo-anal anastomosis. In select cases of FAP and

ost cases of AFAP where the rectal polyp burden is low, aubtotal colectomy with an ileorectal anastomosis can beonsidered.32,33 If the rectum is left intact, rigorous follow-upith sigmoidoscopy every 6 to 12 months is required. Che-opreventive agents may play an adjunctive role in individ-als with a residual rectum. Sulindac and the more selectiveyclooxygenase-2 inhibitors can significantly reduce theumber and size of colonic adenomas.34-36 However, a com-arable benefit for upper gastrointestinal adenomas has noteen convincingly demonstrated. Ampullary adenomas cane managed initially with endoscopic ampullectomy, butiven the risk of residual or recurrent adenomatous tissue,37

lose endoscopic surveillance or surgical management is re-uired.

ereditary Nonpolyposis Colorectal Cancermong the colon cancer syndromes, HNPCC is the mostommon and accounts for close to 1% of the colon cancerurden in the United States4 and nearly 2% in Europe.38 Also

igure 3 Genotype-phenotype correlations in FAP. Certain clinicaleatures in the FAP syndrome are correlated with the location of the

utation within the APC gene. There are 15 exons and 2843 codonsn the APC gene. Mutations that occur between codons 169 and393 have been associated with the classic FAP phenotype. AFAP,ttenuated familial adenomatous polyposis; CHRPE, congenital hy-ertrophy of the retinal pigmented epithelium.

eferred to as the Lynch syndrome, HNPCC exhibits an au- B

osomal dominant inheritance pattern, and affected individ-als carry an 80% lifetime risk of colorectal cancer.39 Colo-ectal cancers are diagnosed at an average age of 45 years. Thenite number (�10 to 20) of adenomas that develop aresually located in the right colon (�70% occur proximal tohe splenic flexure40) and appear flat endoscopically. Al-hough HNPCC-associated colorectal cancers have a signifi-antly greater depth of invasion at diagnosis compared withporadic tumors, their natural history is typically more favor-ble.41,42 Histologically, these tumors are described as poorlyifferentiated with mucinous and signet cell features. In ad-ition, there can be a Crohn’s-like inflammatory reaction athe periphery with dense tumor-infiltrating lymphocytes.43,44

he progression of adenomas to cancer is accelerated, witharcinomas emerging within as short a period as 2 years.

A unique set of extracolonic tumors is associated with theNPCC syndrome (Table 2). Type I HNPCC is defined by

he occurrence of only colorectal cancer, while families withype II HNPCC also display extracolonic tumors. The uteruss the most common site outside of the colon, but other sitesnclude the stomach, ovary, renal pelvis and urinary tract,iliary tract, and small intestine.45 Turcot’s and Muir-Torreyndromes are variants of HNPCC defined by the presence ofrain tumors (primarily glioblastomas16) and skin tumorskeratoacanthomas, squamous and basal cell carcinomas, se-aceous adenomas, or sebaceous adenocarcinomas46), re-pectively.

Clinical criteria for the diagnosis of HNPCC take into ac-ount the age of diagnosis of colon cancer, the number offfected family members, and the presence of extracolonicumors (Table 3). The original Amsterdam I criteria of 199047

re considered to be highly specific for the diagnosis ofNPCC. In order to develop less stringent guidelines, theodified Amsterdam and Amsterdam II criteria48 were pro-osed. In 1996, the Bethesda guidelines49 were formulated toncompass an even broader spectrum of at-risk patients,hereby maximizing sensitivity but necessarily reducingpecificity. These criteria were updated and simplified in004.50

The observation that HNPCC tumors exhibited a distinctolecular abnormality called DNA microsatellite instability

MSI) led to the identification of DNA mismatch-repair

able 2 Lifetime Risks for Cancer Associated WithNPCC148,149

Types of Cancer

Persons WithHNPCC

(%)

GeneralPopulation

(%)

olorectal 80-82 5-6ndometrial 50-60 2-3astric 13 1varian 12 1-2mall bowel 1-4 0.01ladder 4 1-3rain 4 0.6idney, renal, pelvis 3 1
iliary tract 2 0.6

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MMR) genes as the underlying basis for HNPCC.51-60 MMRroteins recognize and then correct the base pair mismatchesnd small insertions or deletions that can occur during nor-al DNA replication. Multiple genes from the mutS (hMSH2,

MSH3, hMSH6) and mutL (hMLH1, hMLH3, hPMS1, hPMS2)amilies interact to repair these mismatched DNAequences.61,62 Microsatellite DNA sequences, which are de-ned as short repetitive mononucleotide or dinucleotide se-uences, are particularly susceptible to errors of replication.ost microsatellite sequences are located in the noncoding

egions of the genome. However, microsatellite sequencesan be found within the coding regions of certain growth-egulatory genes, and loss of MMR proofreading activity re-ults in the accumulation of frameshift mutations in theseenes. These target genes include receptors for growth factorstransforming growth factor-� receptor II,63 insulin-like

able 3 Clinical Guidelines for the Diagnosis of Hereditaryonpolyposis Colorectal Cancer

Amsterdam I criteria1. Three relatives with colorectal cancer, one a first-

degree relative of the other two2. Cases that span at least two generations3. At least one colorectal cancer case diagnosed before

age 50 yearsAmsterdam II criteria

1. Three relatives with an HNPCC-associated cancer(colorectal, endometrial, small bowel, ureter, or renalpelvis), one a first-degree relative of the other two

2. Cases that span at least two generations3. At least one cancer case diagnosed before age 50

yearsModified Amsterdam criteria

1. In very small families, two colon cancer cases in first-degree relatives spanning at least two generations,one case diagnosed before age 55 years

2. In families with two first-degree relatives with coloncancer, a third relative with an unusual early-onsetcancer or endometrial cancer

Bethesda criteria (revised 2004)50

1. Colorectal cancer before age 50 years2. Synchronous or metachronous colorectal cancer or

other HNPCC-related cancer* regardless of age3. Colorectal cancer with MSI-H morphology

(characterized by the presence of tumor infiltratinglymphocytes, mucinous differentiation/signet ring cellcarcinoma, peritumoral Crohn’s-like lymphocyticreaction, medullary growth pattern) before age 60years

4. Colorectal cancer with one or more first-degreerelatives with colorectal cancer or other HNPCC-related cancer,* one of the cancers before age 50years

5. Colorectal cancer with two or more relatives withcolorectal cancer or other HNPCC-related cancer*regardless of age

Includes endometrial, ovarian, gastric, small bowel, urinary tract,biliary tract, pancreas, brain, and sebaceous gland.

rowth factor II receptor64), cell cycle regulators (E2F465), M

egulators of apoptosis (BAX66), and some of the MMR geneshemselves (hMSH3 and hMSH667).

More than 90% of HNPCC cases are accounted for byermline mutations in hMSH2 or hMLH139 (see www.fdht.nl). A broad spectrum of truncating, frameshift, andissense mutations has been observed. Inactivation of

MSH2 or hMLH1 results in tumors that exhibit a high level ofSI. The US National Cancer Institute defines tumors asSI-high (MSI-H) when two of five microsatellite markers

rom a standard panel are found to be unstable and MSI-lowMSI-L) when only one of five displays instability.68 Germlineutations in hMSH6 have been associated with an attenuated

ersion of HNPCC69 that is characterized by a delayed onsetf colorectal cancer (median age of 61 years),69,70 a higherncidence of endometrial cancer,71 and tumors that displayhe MSI-L phenotype.

Commercial genetic testing is currently available forMLH1, hMSH2 and hMSH6. A suggested algorithm for theolecular diagnosis of HNPCC is illustrated in Fig 4. If the

linical suspicion is high based on the fulfillment of the Am-terdam I criteria, then one can proceed directly to germlineutational analysis. If the diagnosis is suggested by the looserethesda criteria, testing for MSI in archived tumor tissuerom an affected individual should be performed first. Forumors that display the MSI-H phenotype, hMLH1 andMSH2 germline mutational analysis is then indicated. If theumor does not exhibit MSI; then hMLH1 and hMSH2 germ-ine testing is not warranted. hMSH6 germline testing can beonsidered for tumors that are MSI-L. Currently, the corre-ation between clinical criteria for HNPCC and genetic testesults is suboptimal. If all Amsterdam I criteria are fulfilled,here is only a 39% to 86% chance of identifying a germlineMLH1 or hMSH2 mutation.72-74 Between 6.5% and 20% ofases in which no mutation can be identified may be ac-

igure 4 Suggested algorithm for genetic testing of an affected pro-and from a suspected HNPCC kindred. MSI-H, high level of MSIMSI-H phenotype); MSI-L, low level of MSI (MSI-L phenotype);
SS, microsatellite stable; IHC, immunohistochemistry.149
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ounted for by large chromosomal deletions or rearrange-ents in hMLH1 or hMSH2 that are not routinely detected byNA sequencing.75-77

Once the diagnosis of HNPCC has been established byither clinical or molecular criteria, an aggressive cancercreening program should be initiated. Colonoscopy shouldegin between ages 20 and 25 years, or 10 years earlier thanhe age of diagnosis of the youngest case in the family, andhen repeated every 1 to 2 years.78 Annual colonoscopies arehen recommended after the age of 40 years. Annual trans-aginal ultrasounds and endometrial aspiration biopsies areecommended due to the high risk of endometrial cancer.here are no standardized guidelines for other extracolonic

umors, and screening is generally based on the specific fam-ly history. Screening for ovarian cancer would include an-ual transvaginal ultrasound and pelvic examination. Upperndoscopy can be considered every 2 years starting from age0 to 35 years, or 5 years earlier than the youngest case ofastric cancer. One approach to screening for tumors of theroepithelial tract would incorporate annual renal ultra-ound, urinalysis and urine cytology.

YH Polyposis Syndromehus far, the high risk colon cancer syndromes discussedave displayed an autosomal dominant pattern of inheri-ance. However, the discovery that biallelic mutations in thease excision repair gene, MYH, result in an increased risk ofolorectal adenomas and cancer led to the first description ofn autosomal recessive colon cancer syndrome.79 In Euro-ean populations, 22% to 29% of individuals with more than0 adenomatous polyps carried biallelic germline MYH mu-ations.79-84 The precise colon cancer risk has not yet beenscertained, but it is likely to approach the 100% level appre-iated in FAP. The mean ages of colon polyp and canceriagnosis are 46 and 49.7 years, respectively.82 The pheno-ype of MYH polyposis resembles AFAP in that patients typ-cally present with less than 100 polyps.85 However, there issubset that displays features of classic FAP. A total of 7.5%f individuals who exhibited diffuse colonic polyposis with-ut a detectable germline APC mutation were found to carryiallelic MYH mutations. These individuals resemble cases ofAP with de novo APC mutations, as there is no evidence ofolyposis in either parent. Although some extracolonic fea-ures such as congenital hypertrophy of the retinal pigmentpithelium, duodenal adenomas, osteomas, and gastric can-er have been observed rarely in these patients, a direct causalelationship has not yet been established.81-83

MYH is a DNA glycosylase that participates in the basexcision repair process.86 8-Oxo-guanine is a byproduct ofxidative DNA damage and it inappropriately pairs with ad-nines, leading to G:C3T:A mutations.87-89 The role of MYHs to excise the mispaired adenines. Dysfunction of MYHesults in the accumulation of somatic G:C3T:A mutationsn specific growth-regulatory genes, and APC appears to be areferred target.79,80

Genetic testing is now available, and analysis is focused on
xons 7 and 13 of the MYH gene. Two specific mutations in m
hese exons (Y165C and G382D) account for 87% of all MYHutations in the Northern European population.81 Patientsho display a phenotype suggestive of attenuated FAP butave tested negative for APC mutations can be offered testingor germline MYH mutations. Recognizing that the MYH syn-rome has important implications for genetic counseling, ashe cancer risk is limited primarily to siblings but not chil-ren. Thus far, there does not appear to be an increased riskf polyps or cancer in MYH heterozygote carriers.Until official guidelines are established, it is reasonable to

ollow the recommendations for colorectal cancer screeningn attenuated FAP. The role of chemoprevention has not yeteen studied.

yndromes With a Moderateisk of Colorectal Cancereutz-Jegher’s Syndromeeutz-Jegher’s syndrome (PJS) is an autosomal dominantamartomatous polyposis syndrome that carries a 39% life-ime risk of colon cancer.90 There is a striking 93% cumula-ive risk of developing any type of malignancy. The charac-eristic clinical feature in PJS is mucocutaneous pigmentedacules on the lips, perioral area, buccal mucosa, hands, and

eet. Patients also develop multiple hamartomatous polypshroughout the gastrointestinal tract, most prominently inhe small intestine. PJS polyps are unique hamartomatousesions characterized by glandular epithelium with a centralore of arborizing smooth muscle bands contiguous with theuscularis mucosae. These polyps cause intestinal obstruc-

ion and hemorrhage. Carcinomas of the stomach, duode-um, jejunum, ileum, and colon have been reported.90 Theseancers are believed to arise from adenomatous tissue thatevelops within PJS polyps.91 Extraintestinal tumors thatave been associated with PJS include melanoma, sex cordumors, uterine, breast, lung, pancreatic, gallbladder, andiliary cancer.92-98 The clinical diagnosis of PJS is outlined inable 4. The average age of PJS diagnosis is 23 to 26 years,hile the mean age of any cancer diagnosis is approximately0 to 50 years.91,99 The mean age of colorectal cancer diag-osis is 45.8 years.90

PJS has been linked to germline mutations of LKB1, aerine-threonine kinase located on chromosome 19p.100,101

mong its many functions, LKB1 can regulate p53-mediatedpoptosis.102 Recently, adenosine monophosphate (AMP) ac-ivated protein kinase has been identified as a direct phos-horylation target for LKB1, implicating LKB1 in the controlf cellular metabolism.103,104 Genetic testing for germlineutations in LKB1 is available, but only 50% to 60% ofatients with classic features of PJS will have identifiableermline mutations, suggesting there may be additional dis-ase loci yet to be identified.105 This observation reinforceshe general principle that the absence of a mutation in anffected individual must be viewed as an inconclusive testesult.

Because of the colon cancer risk, colonoscopy is recom-
ended every 3 years starting at age 18 years. In addition,

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pper endoscopy should be performed every 3 years startingt age 25 years,106,107 and screening for small bowel cancerhould also be undertaken with a small bowel series or videoapsule endoscopy every 2 years. Screening guidelines forxtraintestinal cancers are outlined in Table 4.

uvenile Polyposis Syndromeike PJS, the juvenile polyposis syndrome (JPS) is inherited

n an autosomal dominant pattern and characterized by theevelopment of hamartomatous intestinal polyps. JPS pa-ients exhibit a 10% to 38% lifetime risk of colon cancer,108-

10 and the average age of colon cancer diagnosis is 34ears.111 A clinical diagnosis of JPS is made when the criterian Table 5 have been fulfilled.

Juvenile polyps are characterized by a prominent laminaropria compartment with dilated cystic glands rather thanhe excessive number of epithelial cells that are seen in ad-

able 4 Diagnostic Criteria150 and Recommended Screeninguidelines107 for Peutz-Jegher’s Syndrome

iagnostic criteria1. Two or more PJS polyps in the gastrointestinal tract,

or2. One or more PJS polyp in conjunction with

characteristic mucocutaneous pigmentation, or3. One or more PJS polyp in conjunction with a family

history of PJS

creening guidelinesOrgan Recommendations

Colon Colonoscopy every 3 years startingat age 18 years

Stomach Upper endoscopy every 3 yearsstarting at age 25 years

Small bowel Small bowel series or video capsuleendoscopy every 2 years startingat age 25 years

Pancreas Endoscopic or abdominalultrasound every 1-2 yearsstarting at age 30 years

Breast Annual breast examination withmammogram every 2-3 yearsstarting at age 25 years

Uterus, ovaries Annual pelvic examination, PAPsmear, pelvic ultrasound startingat age 20 years

Testes Annual testicular examinationstarting at age 10 years; testicularultrasound if feminizing featuresare present

able 5 Clinical Diagnostic Criteria for Juvenile Polyposisyndrome111,151

1. Greater than 3 to 10 juvenile polyps in the colon, or2. Any juvenile polyp in the gastrointestinal tract outside

of the colon, or
3. Any juvenile polyp with a family history of JPS
nomatous polyps. Juvenile polyps can cause bleeding, in-ussusception, and obstruction, which are typically mani-ested during childhood. The average age at which symptomsevelop is 9.5 years.112 Like PJS, cancer is believed to arise

rom adenomatous tissue that develops within juvenile pol-ps.108 Patients also have a 15% to 21% lifetime risk of gastricnd duodenal cancers that arise from juvenile polyps in thepper gastrointestinal tract.108,109

Two genes, MADH4 and BMPR1A, have been linked to JPS.ADH4, located on chromosome 18q, encodes the Smad4 pro-

ein that regulates intracellular signaling of transforming growthactor-� (TGF-�).113 The BMPR1A gene on chromosome 10qncodes a receptor for bone morphogenetic protein, a memberf the TGF-� superfamily.114 Genetic testing for JPS consists ofirect sequencing for mutations in MADH4 and BMPR1A. Aathogenic mutation in one of these two genes will be detected

n only 40% to 50% of all JPS cases.115-117

Patients with JPS should have their first colonoscopy at age5 to 18 years, and this should be repeated every 1 to 2 years.pper endoscopy is recommended starting at the age of 25ears and then every 1 to 2 years.

yperplastic Polyposis Syndromeporadic hyperplastic polyps are encountered incidentally inhe distal sigmoid and rectum and have traditionally beenhought to not possess malignant potential. However, rarendividuals and families exhibit numerous hyperplastic pol-ps distributed throughout the colon,118,119 and approxi-ately 25% to 35% of these cases have been associated with

ynchronous colorectal cancers.118,120,121 This genetically un-efined entity has been termed hyperplastic polyposis syn-rome (HPS). A set of clinical criteria for the diagnosis of HPSas been proposed (Table 6).HPS patients typically have more than 20 hyperplastic pol-

ps in the colon, with some polyps greater than 1 cm inize.119,120 Large hyperplastic polyps are more commonlyound in the right colon and are associated with an increasedisk of proximal colon cancer. There may be a history ofyperplastic polyps and colorectal cancer in first- or second-egree family members, but this is not consistently observed.he mean age of colorectal diagnosis is 66 years.122

The molecular mechanisms responsible for this syndromeave not yet been elucidated. It has been proposed that hy-erplastic polyps may progress to cancer through an adeno-atous intermediate, either the admixed hyperplastic- ad-

nomatous polyp or the serrated adenoma.123 The genetic

able 6 Clinical Diagnostic Criteria for Hyperplastic Polypo-is Syndrome (HPS)152

1. Greater than five histologically diagnosed hyperplasticpolyps proximal to the sigmoid colon, two of whichmeasure greater than 10 mm in diameter, or

2. Any number of hyperplastic polyps proximal to thesigmoid colon in an individual with a first-degreerelative with HPS, or

3. Greater than 20 hyperplastic polyps of any size
distributed throughout the colon

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hanges in polyps from individuals with hyperplastic polyp-sis have been rather heterogeneous. For example, both MSInd chromosomal instability have been observed.119 An al-ernative pathway of colorectal tumorigenesis has been pro-osed in which the initiation of hyperplastic polyps resultsrom the inactivation of DNA-repair genes by promoter

ethylation.123

Cancer screening guidelines have not yet been established.owever, one strategy is to repeat a colonoscopy 1 year after

he diagnosis is made and then every 2 to 3 years.120 Colec-omy may be appropriate in cases where the polyp burden isnmanageable endoscopically.

yndromes With a Lowisk of Colorectal Cancerloom’s Syndrome

loom’s syndrome is an extremely rare autosomal recessiveisorder primarily seen in the Ashkenazi Jewish popula-ion.124,125 Affected individuals display short stature, photo-ensitive facial erythema, diabetes mellitus, infertility, immu-odeficiency, and a predisposition to cancer in multipleites.126 As of 1996, approximately 42% of the 168 patients inhe Bloom’s Syndrome Registry had developed cancer, oftent more than one primary site.127 The cancers included leu-emia, lymphoma, and carcinomas of the head and neck,espiratory tract, female reproductive organs, breast, upperastrointestinal tract, and colon. As of 2001, colorectal can-er had been observed in approximately 8% of the patients inhe registry, with a mean age of diagnosis of 33.2 years.128

he presence of multiple colonic adenomas in the proximalolon reminiscent of the AFAP phenotype has been describedn a single individual with Bloom’s syndrome.128

The gene underlying Bloom’s syndrome (BLM) is locatedn chromosome 15q and encodes a homologue of recQ he-icase.129 The 3= to 5= DNA helicase activity of BLM is essen-ial for chromosomal stability,130 as cells deficient in this pro-ein show a high frequency of sister chromatid exchanges anduadriradial configuration.126 BLM plays a role in repairingNA damage at stalled replication forks, thus maintaining

he fidelity of DNA replication.131

A provocative study in 2002 suggested that heterozygotearriers of the BLM mutation appeared to have an increasedisk (odds ratio, 2.76) of colorectal cancer.132 However, anndependent study failed to confirm this association.133

The diagnosis can be confirmed by cytogenetic analysis.lternatively, DNA can be probed with an oligonucleotidepecific for the BlmAsh mutation, a 6-bp deletion and 7-bpnsertion at nucleotide position 2281. This is the most com-

on mutation observed in Ashkenazi Jewish carriers.125

There are currently no guidelines for colorectal cancercreening in Bloom’s syndrome. It is reasonable to begin pe-iodic screening with colonoscopy early in the third decade ofife. The significance of heterozygous BLM mutations remains
o be determined. c
1307K APC Polymorphismpproximately 6% of the Ashkenazi Jewish population car-ies a variant in codon 1307 of the APC gene that substituteslysine for an isoleucine. I1307K carriers do not display

olyposis but do exhibit a small increase in the risk of colonancer (odds ratio, 1.4 to 1.9).134,135 The mean age of canceriagnosis is 64 to 70 years,135,136 which is not different fromhe general population. Family history is not predictive ofarrier status. The I1307K alteration does not directly alterhe function of the APC gene product but creates a region ofypermutability within the APC gene itself. The accumula-ion of additional somatic mutations in this hypermutableegion of APC then inactivates gene function. Genetic testingy direct analysis of codon 1307 is available. However, theelatively low odds ratio and the late onset of colon canceruggest that genetic test results may have little impact uponlinical management.

RCA1he co-occurrence of breast and colorectal cancers in manyomen has raised the possibility of an underlying “breast–

olon cancer” syndrome. Indeed, the relative risk of colorec-al cancer in women with a history of breast cancer has beenemonstrated to be between 1.1 and 3.0.137,138 BRCA1 wasroposed as a candidate gene because deletions near theRCA1 locus on chromosome 17 have been detected in al-ost 50% of sporadic colorectal cancers.139 BRCA1 is a tu-or-suppressor gene that plays a role in the repair of double-

trand DNA breaks through homologous recombination.140

ome have estimated the relative risk of BRCA1 mutationarriers for colorectal cancer to lie between 2 and 4.11.141,142

owever, the preponderance of the evidence does not sup-ort an association between BRCA1 germline mutation andn increased colon cancer risk.143-147 Until further studiesemonstrate otherwise, enhanced screening for colorectalancer is not recommended.

onclusionhere is a rapidly growing appreciation for the role of inher-

ted genetic factors and the development of cancer. In colonancer, a wide spectrum of genes can increase the risk of theisease when altered in the germline. The vast majority ofhese genes display a pattern of high penetrance but relativelyow prevalence in the population. Recognizing these geneticyndromes is the essential first step to appropriately manag-ng these individuals and their families, and a careful familyistory is a necessary component of this evaluation. The in-roduction of genetic testing has revolutionized the field ofancer risk assessment, and cancer prevention is a realisticoal for affected individuals who adhere to screening guide-ines. The next major challenge is the identification of germ-ine mutations or polymorphisms that may have low pen-trance but high prevalence, as these are the geneticlterations that are likely to have an even greater impact on
olon cancer risk in the population as a whole.

R


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Genetics of hereditary colorectal cancer