principles of gender-specific medicine || gender differences in hereditary cancer syndromes

Chapter 44

Gender Dif ferences in hereditary Cancer Syndromes: risks, Management, and testing for Inherited predisposition to Cancer

Wendy K. Chung

Herbert Irving Assistant Professor of Pediatrics and Medicine, Director of Clinical Genetics, Columbia University, New York, NY, USA

CanCer genetiCs: Overview

The specific cause of cancer in most individuals is largely unknown but likely involves a combination of environmen-tal and inherited genetic factors. For a minority of individu-als there is an inherited predisposition to cancer resulting from a monogenic cancer predisposing mutation with high penetrance or likelihood that an individual will develop disease if he or she has inherited the genetic susceptibil-ity. With advances in the field of human genetics, several of these genes that underlie cancer susceptibility have been identified, and clinical diagnostic tests to identify mutations in these genes have been developed. These tests are availa-ble to physicians to be used in overall assessment of the risk of an individual’s susceptibility to cancer so that an appro-priately individualized management plan can be developed for each patient for prevention or early detection of cancer based on individual genetic predisposition. However, pre-dictions for any one individual mutation carrier are limited because of the uncertainty of if, when, or in what organ a cancer may develop because predictions are based on popu-lation studies that cannot yet account for all individual vari-ation in other interacting genes or environmental exposures. Furthermore, many of the hereditary cancer syndromes dis-cussed in this chapter have different manifestations in men and women because they predispose to cancers of organs that are sex-specific. Recently, several less highly penetrant, common polymorphisms have been identified to predispose to cancers through genome-wide association studies,1 but how these genetic variants with relatively modest relative risk of 1.2–1.4 will be used clinically is yet to be deter-mined. In the future, additional genes and important gene

4Principles of Gender-Specific Medicine

environmental interactions will likely be identified to ena-ble better strategies for cancer prevention.

Most individuals who develop cancer do not carry muta-tions in the inherited cancer genes that are discussed in this chapter. Individuals with mutations in highly penetrant genes can be clinically distinguished on the basis of their strong family history with multiple individuals in multiple genera-tions affected with cancer, early age of onset of cancer, mul-tiple primary cancers in a single individual, and clustering of particular types of cancer within either the individual or the family. In some cases, ethnicity also may be a predisposing factor. Although all ethnic groups have been found to carry mutations in these genes, certain ethnic groups may carry particular founder mutations at higher frequency. In addition to rare but highly penetrant monogenic (single gene) cancer susceptibility syndromes, another 5–30% of cancer is famil-ial and likely represents the interaction of a small number of cancer susceptibility genes that in combination with each other and the environment increase the susceptibility to can-cer. In families with familial rather than monogenic cancer susceptibility, the age of onset is often older and the number of affected family members is often fewer.

Most highly penetrant inherited cancer susceptibility genes are autosomal dominantly inherited. Autosomal dom-inant conditions are characterized by a 50% chance for both males and females to inherit a mutated gene from a carrier parent; they may pass it on to their children if and only if they are carriers. Although both males and females may carry a genetic mutation, this mutation may have different disease manifestations or expression in the two genders largely because of anatomic or hormonal differences between the sexes. This may give the appearance of ‘skipping

Copyright 2010, Elsevier Inc. All rights reserved.81 2010

SeCt Ion 7 l Oncology482

a generation,’ if the gene is passed through an individual less likely to express disease (i.e., a male for a breast can-cer gene). As discussed in further detail, the cancer spec-trum differs by gender in cancer syndromes involving breast, prostate, ovarian, endometrial, and testicular cancer. Regardless of whether an individual manifests disease, indi-viduals can still pass on this mutation to the next generation. This has important implications when taking a family his-tory to assess risk of cancer because susceptibility is equally likely to be inherited through the paternal as the maternal side. For instance, when taking a family history for breast cancer, one should always ask about cases of breast cancer in paternal aunts, cousins, and grandmothers.

Although not commonly pursued, because of the auto-somal dominant manner in which these mutations are inher-ited, an individual carrying one of these cancer susceptibility genes may seek either prenatal diagnosis or preimplanta-tion genetic diagnosis (PGD) to avoid transmission of the mutation to future generations.2 Prenatal testing can be per-formed as early as 10–11 weeks of gestation via chorionic villus sampling with results generally available within 2 weeks. PGD requires in vitro fertilization, molecular genetic test development in each family, is not frequently covered by insurance, is associated with diagnostic errors in 2–3% of cases, and has only a 20–25% take-home baby rate/cycle.3 However, the main advantage of PGD is avoidance of the ethical difficulty for some couples of pregnancy termination.

Although most cancer susceptibility genes are inherited in an autosomal dominant manner, they act recessively at a cellular level. Most cancer susceptibility genes are tumor suppressor genes that protect the cell from progression to uncontrolled growth. Although an individual has inherited a defect in one of these tumor suppressor genes, as long as the second copy of that gene functions normally, unregulated cell growth will still be suppressed. However, over time, the normal copy of the tumor suppressor gene may become somatically mutated. Such somatic mutations are not in the germline and are not passed down to the next generation, but these somatic mutations allow those somatic cells car-rying two mutated genes to begin the process of tumor pro-gression. The two-hit hypothesis was originally described by Knudson for retinoblastoma,4 but it is equally relevant to most of the other cancer syndromes that are discussed in this chapter. In the two-hit hypothesis, the first hit or mutation is inherited and the second hit is acquired somatically. Because a second somatic mutation must be acquired, an inherited mutation in a tumor suppressor gene greatly increases the likelihood of cancer but does not make cancer inevitable.

Breast CanCer

Hereditary Breast Cancer syndromes

The hereditary breast cancer syndromes account for approx-imately 5–10% of all breast cancer and include a broad

group of hereditary predisposition syndromes in which breast cancer is a component tumor. Among the heredi-tary breast cancers are hereditary breast–ovarian cancer (HBOC) syndrome, Cowden syndrome (CS), Li–Fraumeni syndrome (LFS), Peutz–Jeghers syndrome (PJS), and ataxia telangiectasia (ATM). The National Comprehensive Cancer Network (NCCN) Genetics Familial High Risk Panel5 has developed criteria for consideration of a hereditary breast cancer syndrome including (1) multiple cases of breast and/or ovarian cancer in the same individual or in close rela-tives; (2) clustering of breast cancer with male breast cancer, thyroid cancer, sarcoma, adrenocortical carcinoma, brain tumors, and/or leukemia and lymphoma in the same family; and (3) a member of a family with a known mutation in a breast cancer susceptibility gene. Although hereditary breast cancer syndromes primarily cause breast and ovarian can-cer in women, men can be carriers of a cancer susceptibility gene and have increased risks for associated cancers.

Hereditary Breast–Ovarian CanCer syndrOme

Hereditary breast–ovarian cancer syndrome has variable expression and can present in families with breast cancer only, ovarian cancer only, or with both breast and ovarian cancers. One should consider HBOC when two or more first-degree relatives have breast and/or ovarian cancer, especially if the cancer onset is in young patients, if there is multifocal or bilateral disease, if breast and ovarian can-cer occur in a single individual, and if a case of male breast cancer is present in the family. In addition, Ashkenazi Jewish ancestry is associated with a higher prevalence of breast and ovarian cancers resulting from HBOC.

There are two major HBOC cancer susceptibility genes, BRCA1 and BRCA2, both of which are tumor suppressor genes. Mutations in BRCA1 and BRCA2 are characterized by high lifetime risks for development of breast cancer (55–85%) and ovarian cancer (20–44%), as well as much lower risks of prostate cancer, colon cancer, pancreatic can-cer, melanoma, male breast cancer, and other cancers.6,7 More than 2000 distinct pathogenic mutations have been identified in these two genes. There are founder mutations in certain populations, such as the Ashkenazim,8,9 Dutch,10,11 Icelandics,12 and French Canadians.12 Importantly, one of the three founder mutations in Ashkenazi Jewish individu-als, 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2, account for 20–35% of early onset breast cancer and ovarian cancer at any age in Ashkenazi individuals7 as compared with other populations in which germline BRCA1 and BRCA2 mutations are detected in only 5–10% of young patients with breast cancer or ovarian cancer.13,14

DNA-based testing for BRCA1 and BRCA2 cancer-predisposing mutations is available on a clinical basis for individuals identified by personal or family history to be at increased risk for having a germline BRCA1/BRCA2 muta-tion and for at-risk relatives of an individual with an iden-tified BRCA1/BRCA2 mutation. At present, the available

Chapter 44 l Gender Differences in hereditary Cancer Syndromes 483

clinical testing includes direct sequence analysis of all cod-ing exons and splice sites and analysis of common dele-tions. BART testing which includes more extensive testing for deletions, duplications, and complex re-arrangements in BRCA1/BRCA2 became available in 2007, but is only per-formed by request or reflexively for patients with normal BRCA1/BRCA2 sequence and a high pretest probability of carrying a mutation. Current clinical testing is estimated to be at least 90% sensitive but could theoretically fail to detect intronic or regulatory variants that would alter splic-ing or gene expression. Furthermore, variants of uncertain significance (VUS) may be identified, especially in minor-ity populations with whom there is less experience to know which variants are benign polymorphisms segregating in the population without functional effects on BRCA1/BRCA2. With additional experience in testing larger num-bers of patients, segregation analysis within families, and functional studies in some cases, some VUS have been reclassified as either benign polymorphisms or pathogenic mutations,15 and revised reports are issued as this informa-tion becomes available.

Given the substantially increased risk of breast, ovar-ian, and other cancers in HBOC, the management of indi-viduals with BRCA1/BRCA2 cancer-predisposing mutations includes discussion of enhanced cancer screening protocols, chemoprevention strategies, and options for prophylactic mastectomy and/or salpingo-oophorectomy. None of these strategies has been assessed by randomized clinical trials or case control studies in high-risk women, and current recom-mendations are made on the basis of retrospective studies and expert clinical opinion.

Recommendations of the National Comprehensive Cancer Network16 for cancer screening of individuals with a BRCA1/BRCA2 mutation include the following:

n Breast cancer screening l Monthly breast self-examination starting in early

adulthood l Semiannual clinical breast examination beginning at

age 25–35 years l Annual mammography beginning at age 25–35 years l Annual MRI.

Men with BRCA2 cancer-predisposing mutations may also be at increased risk for breast cancer, and evaluation of any breast mass or change is advisable; however, there are insufficient data to recommend a formal program of surveillance.

n Ovarian cancer screening l Annual or semiannual pelvic examination beginning at

age 25–35 years l Annual or semiannual transvaginal ultrasound examina-

tion with color Doppler beginning at age 25–35 years. l Annual serum CA-125 concentration beginning at age

25–35 years

n Colon cancer screening l Annual stool occult blood testing beginning at age 50

years l Colonoscopy every 3–5 years beginning at age 50

years.n Prostate cancer screening l Prostate-specific antigen (PSA) serum screening

starting at age 50 l Clinical digital rectal examination starting at age 50.

Chemoprevention strategies should be discussed with BRCA1/BRCA2 mutation carriers. The efficacy of tamoxifen for breast cancer risk reduction in women with BRCA1 and BRCA2 mutations is controversial. Although a randomized clinical trial of treatment with tamoxifen in women iden-tified by the Gail model to have an increased breast can-cer risk reported a 49% reduction in breast cancer in the treated group,17 tamoxifen reduced the incidence of breast cancers that were estrogen receptor positive but not estro-gen receptor negative. Because breast cancers occurring in women with BRCA1 mutations are more likely to be estro-gen receptor negative, it is difficult to estimate the benefit of tamoxifen prophylaxis in BRCA1 carriers although there does appear to be some benefit. It is possible that premalig-nant lesions in BRCA1 carrier are estrogen responsive and amenable to tamoxifen prophylaxis at least at some point during the premalignant phase.

The efficacy of oral contraceptives for ovarian cancer risk reduction in women with BRCA1 or BRCA2 mutations is unclear. One case control study found a decreased risk of ovarian cancer in women with BRCA1 or BRCA2 carri-ers who took oral contraceptives for more than 3 years.18 However, a more recent study did not confirm these find-ings and raised the concern that oral contraceptive use may increase the risk of breast cancer in women with BRCA1 or BRCA2 cancer-predisposing mutations.19

Because early detection does not prevent cancer, it is necessary to discuss the options of risk-reducing sur-gery including prophylactic mastectomy and prophylactic salpingo-oophorectomy. Tissue removed prophylactically should be carefully examined for malignancy, a finding that could alter medical management. At the time of pro-phylactic oophorectomy, ovarian or Fallopian tube cancer is detected in 2–5% of cases. Theoretical modelling and epidemiologic studies suggest that prophylactic surgeries do significantly decrease the risk of developing these can-cers by greater than 90% but do not completely eliminate all cancer risk. Prophylactic mastectomy can be effectively performed with skin-sparing procedures with reconstruc-tion. Prophylactic mastectomy can also be performed with nipple preservation, but this procedure has a higher residual risk of breast cancer. Prophylactic oophorectomy can decrease the risk of breast cancer by up to 50% if performed at the age of 40 and not followed by hormone replacement. However, hormone replacement is acceptable


and does not significantly increase the risk of breast cancer above the baseline in BRCA1 and BRCA2 mutation carri-ers. Consideration is also made for total abdominal hyster-ectomy to either decrease the risk of endometrial cancer if tamoxifen is considered or to use unopposed estrogens for hormone replacement which many be associated with less breast cancer risk than estrogen/progesterone replacement. Even after prophylactic oophorectomy, there is still a small residual risk of primary peritoneal cancer.

Cancer-predisposing mutations in BRCA1 and BRCA2 are inherited in an autosomal dominant manner; both men and women are equally likely to be mutation carriers. The most informative genetic result in a family is obtained by identify-ing the specific cancer-predisposing mutation in an affected family member before offering molecular genetic testing to asymptomatic at-risk family members. Without knowing if there is a BRCA1 or BRCA2 mutation segregating in the family, a negative genetic test result in an unaffected fam-ily member is ambiguous and cannot be easily interpreted. Therefore, genetic testing within a family should ideally begin with an individual with a history of breast and/or ovarian cancer. If there are multiple members in the family who are affected, the highest yield from the genetic testing is obtained by initially testing the youngest affected family member, an affected family member with breast and ovarian cancer, or an affected family member with bilateral breast cancer. First-degree relatives (parents, children, siblings) of individuals with a BRCA1 or BRCA2 mutation each have an independent 50% chance of inheriting the gene mutation.

COwden syndrOme

Cowden syndrome is a rare cause of hereditary breast can-cer characterized by multiple benign hamartomas including the pathognomonic trichilemmoma (a benign tumor of the infundibulum of the hair follicle), breast cancer, and thy-roid cancer resulting from autosomal dominantly inherited mutations in the tumor suppressor gene Phosphatase and Tensin Homolog deleted on chromosome ten (PTEN). Other clinical manifestations of CS include acral keratoses, verru-coid or papillomatous papules, goiter or thyroid adenoma, fibrocystic breasts, hamartomatous intestinal polyps, mac-rocephaly, autism, and uterine leiomyomas. An increase in endometrial cancer has been reported. By age 40, most affected individuals develop the mucocutaneous features of CS. For carriers of PTEN mutations there is a 3–10% life-time risk of nonmedullary thyroid carcinoma, usually fol-licular.20,21 Females with CS have a 67% risk of developing fibrocystic breast disease and a 25–50% lifetime risk of developing breast cancer.20,21 The age of diagnosis of breast cancer is approximately 10 years earlier than average21,22 but rarely before age 30. The estimated gene frequency for CS is 1 in a million,23 but it has been argued that this may be a gross underestimate resulting from underdiagnosis because of the variable and subtle clinical manifestations.24

With increased recognition of PTEN mutations as a cause of developmental delay and autism associated with macro-cephaly in children, PTEN carriers are increasingly iden-tified through autistic probands rather than due to their cancer family histories.

Clinical genetic testing of PTEN is available and can be useful in assessing risk to family members. The most specific clinical feature is trichilemmomas. Families with only thyroid and breast cancers without mucocutaneous lesions have only a 2% probability of having PTEN muta-tions.25 PTEN mutations carriers should have annual physi-cal examinations of the thyroid beginning in their late teens and annual breast examinations beginning in their mid 20s. Screening for endometrial cancer should begin at age 35. Annual mammograms and breast ultrasounds should be started at age 30 or 10 years before the earliest breast can-cer in the family, whichever is younger.

Li–Fraumeni syndrOme

Li-Fraumeni syndrome is another rare cancer syndrome associated with a wide variety of pediatric and adult onset cancers. The clinical criteria for the diagnosis in an indi-vidual are bone or soft tissue sarcoma before the age of 45 with a family history significant for a first-degree rela-tive with cancer before the age of 45 and a first- or second-degree relative with cancer before age 45 or sarcoma at any age. The most frequently associated cancers are soft tissue sarcomas and early onset breast cancer, often before the age of 30. Other less frequently occurring tumors include acute leukemias, brain, lung, pancreatic, skin, and adrenocorti-cal tumors. Adrenocortical carcinoma is relatively specific to LFS, and as many as 50% of children with adrenocorti-cal carcinoma even without a family history supportive of LFS have germline mutations in TP53.26,27 Three percent of children with osteosarcomas28 and 9% of children with rhabdosarcomas29 regardless of family history have inher-ited TP53 mutations with as many as 50% of those families not yet fulfilling clinical criteria for diagnosis. Cancer often develops in the parent of an affected child after the child has been diagnosed and emphasizes the need to constantly re-evaluate the dynamic family history over time. Affected individuals often have multiple primary cancers.30 The rela-tive risk of developing a second primary for TP53 carriers is 5.3 with a 57% chance of having a second primary in the 30-year period following diagnosis of the first cancer.30 This cancer syndrome is autosomal dominantly inherited and is caused by missense mutations in the tumor suppressor gene TP53 that acts as a transcription factor to regulate expression of genes controlling cell growth. The mutation frequency is approximately 1 in 50 000 with a penetrance of 50% by age 30 and 90% by age 60.31 Age-specific penetrance is higher for females because of the association with breast cancer. The relative risk of mutation carriers in developing child-hood cancer is 100 times the background. Somatic rather


than inherited germline mutations of TP53 also commonly occur in a variety of cancers but are not associated with LFS.

Genetic testing for germline mutations in TP53 is avail-able. However, it is currently unclear what effective ther-apeutic intervention options are available to mutations carriers. Patients with LFS should avoid excessive radiation, either for therapeutic or diagnostic purposes. Therefore, the most common reason to pursue genetic testing is to deter-mine safety of radiation treatment. The cancers associated with LFS are difficult to cure with the exception of early stage breast cancer, childhood acute lymphoblastic leuke-mia, and germ cell tumors of the testis. Some had advocated PET MRI for cancer surveillance, but there are not data suf-ficient to support its efficacy. The only effective interven-tion is increased and earlier surveillance for breast cancer in at-risk women.32 For that reason, diagnostic genetic test-ing should be done only after careful genetic counseling to explore the impact of a genetic diagnosis on a given indi-vidual. Presymptomatic carrier testing of minors is appro-priate since pediatric cancers are associated with LFS.

Peutz–JegHers syndrOme

Peutz–Jeghers syndrome, a rare breast cancer syndrome, is characterized by mucocutaneous melanin pigmentation and intestinal hamartomatous polyposis33 resulting from autosomal dominantly inherited inactivating mutations in the serine/threonine kinase LKB1. The melanotic pig-mentation is seen in and around the mouth, on the hands and feet, and in the axilla. The pigmentation may be mild or even absent in some individuals. More specific are the hamartomatous polyps that have a core of smooth muscle cells with an arborizing pattern that extends to the lamina propria and that have overlying folded epithelium without evidence of neoplasia. Neoplastic changes can arise within these polyps. The numbers of polyps is usually small but can be as many as several dozen. The polyps are usually located in the small intestine and may present as a bowel obstruction. Unlike some of the other oncogenetic associa-tions, the variety of neoplasms associated with PJS is large. Patients with this syndrome are predisposed to a variety of cancers, including breast, cervical, ovarian, and gastrointes-tinal. Benign ovarian and testicular lesions such as granu-losa cell tumors and Sertoli cell tumors, respectively, are also more common in patients with PJS.33 The frequency of the syndrome itself is low (1 in 8300 to 1 in 29 000),34 making accurate delineation of the clinical features diffi-cult. The rate of de novo mutations is also relatively high, so that not all affected individuals have a significant family history.35 The lifetime risk of all cancer in carriers is 18-fold higher in women and 6.2-fold higher in men.36

Genetic testing for germline mutations in LKB1 can be useful in some families because the pigmentation findings are variable and not specific to PJS. There are no highly prev-alent founder mutations, and most mutations are specific to the individual family. Once a mutation is identified within the

family, other family members can then be genetically tested to stratify risk. At-risk individuals should then be monitored for gastrointestinal, breast, and gynecologic tumors.

ataxia teLangieCtasia

Ataxia telangiectasia is an autosomal recessive condition for which carriers may have a slightly higher risk of breast cancer. Ataxia telangiectasia is associated with progressive cerebellar ataxia, ocular apraxia, telangiectasias, and cardio-myopathy in affected individuals. The gene ATM encodes a large protein kinase and is thought to interact with proteins upstream of p53 in sensing DNA damage associated with double-stranded breaks. The incidence of ATM mutations is 1 in 40 000 live births and, therefore, the heterozygous ATM mutation carrier frequency is 1%. All ethnic groups are affected. Female ATM mutation carriers were initially reported to have a five-fold increase in breast cancer.37,38 However, subsequent studies have not replicated these ini-tial findings.39–42 The exact type of mutation, missense or nonsense, may be associated with different cellular pheno-types. It is possible that only missense mutations are asso-ciated with increased breast cancer susceptibility through a dominant negative effect.43 It appears that ATM mutations account for a small proportion of inherited or familial breast cancer but may play a role in the more common apparently sporadic breast cancer that is due to the interaction of envi-ronmental factors with many low-penetrance genes.

LOw PenetranCe genes

Genome-wide association studies using thousands of cases of breast cancer and thousands of controls, largely in white populations, have identified single nucleotide polymor-phisms in five genes that confer a modest relative risk of 1.2–1.4 of breast cancer.1 The most consistently associ-ated gene across multiple independent studies is FGFR2. Individuals with the at-risk genotype for any one gene are at such modestly increased risk of breast cancer, it is not yet clear how to use this information effectively. However, there are a small percentage of women who will carry at-risk genotypes for the majority of these genes, for whom there may be additive or multiplicative interactions between genes that will place them at significantly increased risk that would approach the risk conferred by some of the monogenic disorders discussed above. Although genetic testing is currently offered by DECODE, 23 and me, and Navigenics, the clinical utility of these tests has not yet been validated and should not be used for routine clinical practice until more data are available.

endOmetrial and gastrOintestinal CanCer

Most individuals with colorectal cancer have sporadic disease without a family history. However, in approximately 20%


of individuals with colon cancer there is a definable genetic component.44,45 Germline mutations conferring high lifetime risk of colorectal cancer account for 5–6% of all colorectal cancer cases. The two best-defined colorectal cancer genetic syndromes are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC).

Familial adenomatous Polyposis

Familial adenomatous polyposis is a colon cancer predispo-sition syndrome in which hundreds to thousands of precan-cerous colonic polyps develop, beginning at a mean age of 16 years (range 7–36 years).46 Seven percent of untreated patients with FAP develop colon cancer by age 21 years, 87% by 45 years, and 93% by 50 years with a mean age of colon cancer diagnosis of 39 years.47 Associated extra-colonic neoplasms include duodenal carcinomas, especially around the ampulla of Vater; follicular or papillary thyroid cancer; childhood hepatoblastoma; gastric carcinoma; and central nervous system tumors, predominantly medullob-lastomas. Other benign manifestations include gastric and duodenal polyps, osteomas, dental anomalies, congenital hypertrophy of the retina pigment epithelium (CHRPE), and desmoid tumors.48 The desmoid tumors can be particu-larly difficult to manage since they often wrap around vital abdominal structures and are difficult to completely resect. Both sexes are equally affected.

Familial adenomatous polyposis is diagnosed clinically in individuals with greater than 100 colorectal adenomatous polyps or with fewer than 100 adenomatous polyps if there is a family history of FAP. Attenuated FAP is associated with fewer colonic adenomas than seen in classic FAP, and polyps are located predominantly in the proximal colon.49 Colon cancer risk in attenuated FAP is usually delayed by approximately 12 years relative to classic FAP. Genetic test-ing is considered standard of care in families with FAP and should be performed in children by the age of 10 to deter-mine if an individual is at risk and should begin screening.

Familial adenomatous polyposis is caused by inherited mutations in the APC gene,50 a tumor suppressor gene with more than 300 different disease-associated muta-tions.51 Genetic testing of APC detects up to 95% of dis-ease-causing mutations and is clinically available. Genetic testing is most often used to confirm the clinical diagnosis of FAP and to identify presymptomatic carriers in affected families. Protein truncating mutations in the extreme 5’ or 3’ end of the gene are associated with attenuated FAP.52,53 Polymorphisms in APC have been identified and one spe-cific missense mutation (Ile1307Lys), found exclusively in Ashkenazi Jewish individuals, results in a two-fold relative risk of colonic adenomas and adenocarcinomas.54 In con-trast to classic FAP, this polymorphism does not predispose to the polyposis phenotype.

Familial adenomatous polyposis is autosomal domi-nantly inherited. Approximately 75–80% of individuals

with FAP have an affected parent, and the mutation can be passed either from the maternal or paternal line. About 25% of cases present represent de novo mutations. Each child of an affected individual has a 50% chance of inheriting the familial mutation.

Early recognition of FAP and attenuated FAP allow for increased surveillance and surgical prophylaxis that improve survival. For this reason, FAP is one of the few cancer syndromes for which genetic testing is appropri-ate in children. Genetic testing for FAP should be offered to children at age 8–10 years before the commencement of colon cancer screening. For attenuated FAP, genetic testing is offered at age 18.

The American Gastroenterological Association55 rec-ommends surveillance of individuals with a known APC mutation or who are at 50% risk of FAP based on a family history. This surveillance includes the following:

n Annual screening for hepatoblastoma from birth to 5 years of age

n Sigmoidoscopy every 1–2 years beginning at age 10–12 years

n Colonoscopy once polyps are detectedn Upper endoscopy when colonic polyposis is detected or

by age 25 and repeated every 1–3 years, the frequency of which is dependent on the severity of duodenal adenomas

n Small bowel x-ray when duodenal adenomas are detected or prior to colectomy, repeated every 1–3 years depend-ing on findings and presence of symptoms

n Attention to extraintestinal manifestationsn Annual physical examination including palpation of the

thyroid.

The recommended surveillance of persons at risk for attenuated FAP includes the following:

n Colonoscopy every 2–3 years beginning at 18–20 years of age, depending on the number of polyps

n Colectomy should be considered when polyps emerge with timing depending on the size and number of adeno-matous polyps.

n For individuals with attenuated FAP, colectomy may ulti-mately be necessary but may be deferred until polyps become difficult to individually remove.

Hereditary nonpolyposis Colon Cancer

Hereditary nonpolyposis colon cancer (HNPCC) or Lynch syndrome is an autosomal dominantly inherited predispo-sition to colon carcinoma that is not associated with poly-posis, unlike FAP. Several other types of cancer can also be associated with HNPCC including endometrial, small intestinal, ovarian, stomach, urinary tract, and brain can-cer.56–58 HNPCC is genetically heterogeneous and involves inactivating mutations in one of several mismatch repair genes including MHS2, MLH1, MSH6, PMSl, and PMS2.


Mutations in MSH2 and MLH1 account for 31% and 33% of families with HNPCC, whereas 32% of families have mutations in yet undefined genes.59 Identification of the underlying genetic basis for HNPCC revealed a new mecha-nism of cancer progression with hypermutability leading to accumulation of changes in the DNA that ultimately lead to uncontrolled cell growth and division. This hypermutability can be detected in colonic polyps as acquired microsatellite instability (MSI), resulting from mutations of simple repeti-tive elements (usually dinucleotide repeats) called micros-atellites. This hypermutability leaves cells susceptible to the accumulation of pathogenic mutations that ultimately lead to neoplasia. Clinical criteria to make the diagnosis of Lynch syndrome were developed in 1991 and are called the Amsterdam criteria60 (Table 44.1). The diagnosis relies on an accurate and complete family history. However, these criteria were found to be too restrictive, and they decreased the sensitivity of identifying affected families. The criteria were, therefore, liberalized and these more inclusive crite-ria are called the Bethesda criteria (Table 44.2). A subset of HNPCC families have HNPCC-associated cancers and seba-ceous gland tumors (adenomas, epitheliomas, and carcino-mas) and keratoacanthomas and are called the Muir–Torre variant due to mutations in MSH2.61,62 Once a clinical diag-nosis has been made, genetic testing can be used for risk assessment of unaffected members of the family. Screening for HNPCC can also be directly performed on the tumor for testing for MSI or lack of immunohistochemistry (IHC) for MHS2, MLH1, and MSH6. The most sensitive and efficient method to identify symptomatic HNPCC mutation carriers would be to screen all colon cancers by immunohistochem-istry63 followed by DNA mutation analysis on patients with tumors that fail to stain. Some IHC tumors will be negative due to epigenetic changes rather than germline mutations, so IHC should be considered only a screening test.

Expressivity of HNPCC is sex-dependent. Men with HNPCC mutations are most likely to develop colon cancer, whereas women with HNPCC mutations are most likely to develop endometrial cancer. The lifetime risk of endome-trial cancer has been estimated at 61% and 42% for MSH2 and MLH1 mutations, respectively64 compared with the population risk of 3%. The median age of endometrial can-cer diagnosis is 46 years.57 The relative risk for other extra-colonic HNPCC-associated cancers is 4.1–4.4 for stomach, 6.4–8.0 for ovarian, 103–292 for small intestinal, and 75.3 for renal and ureteral.64 The relative risk varies somewhat

taBle 44.1 amsterdam criteria for hereditary nonpolyposis colorectal cancer

• At least three affected relatives with colorectal cancer• At least one is a first-degree relative of the other two• Familial adenomatous polyposis has been excluded• At least two successive generations are affected• One colon cancer occurs before the age of 50

depending on the specific gene implicated. Identification of patients with HNPCC is important because of the high prob-ability of a metachronous cancer after successful treatment of the first neoplasm. Prognosis of colon cancer is, how-ever, no worse and may be somewhat better with HNPCC-associated colon cancer. Surgical treatment of colon cancer should be total colon resection. Presymptomatic mutation carriers should follow a cancer surveillance protocol con-sisting of colorectal cancer surveillance and endometrial carcinoma screening starting at the age of 25–35. There is no consensus about the optimal method of endometrial car-cinoma screening, but ultrasound and endometrial biopsy are usually done on an annual basis. Ovarian cancer screen-ing consists of annual CA-125 and transvaginal ultrasound but is not associated with decreased mortality. Therefore, mutation carriers may consider prophylactic total hysterec-tomy to maximally reduce their cancer risk once childbear-ing is complete. Screening methods and frequency for other HNPCC-associated cancers has not yet been standardized.

testiCular CanCer

Testicular cancer composes only 2% of all malignancies, but it is the most common type of cancer in men between the ages of 20 to 40.65 Several risk factors for testicular cancer have been identified including cryptorchidism, tes-ticular dysgenesis, Klinefelter syndrome, prior history of a germ cell tumor, and a family history of an affected first-degree relative. There is a 6- to 10-fold relative risk of tes-ticular cancer with an affected first-degree relative,66,67 and approximately 2% of all men with germ cell tumors have

taBle 44.2 Betheseda criteria for hereditary nonpolyposis colorectal cancer (hnpCC)

• Families that meet Amsterdam criteria• Individuals with two HNPCC-related cancers including

synchronous or metachronous colorectal cancer or extracolonic cancers including endometrial, ovarian, gastric, hepatobiliary, small bowel, or transitional cell carcinoma of the renal pelvis or ureter

• Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or a colorectal adenoma; one of the cancers diagnosed at age younger than 45, the adenoma at age younger than 40

• Individuals with colorectal cancer or endometrial cancer diagnosed at age younger than 45

• Individuals with right-sided colorectal cancer with an undifferentiated pattern on histopathology diagnosed at age younger than 45

• Individuals with signet ring cell type colorectal cancer diagnosed at age younger than 45

• Individuals with adenomas diagnosed at age younger than 40


an affected family member.68 The familial aggregation of testicular cancer is stronger with a history of an affected sibling rather than an affected father, which suggests that shared environmental contributions in addition to shared genetic factors are important. The International Testicular Cancer Linkage Consortium is working to identify genomic regions of linkage with testicular cancer, but the data to date have demonstrated only suggestive linkages with sev-eral chromosomal regions including Xq27-28, 18q22-qter, and 16p13 without clear identification of a major testicular cancer susceptibility locus.68 Because no genes have been identified that confer high risk of testicular cancer, no clini-cal genetic testing is currently available for risk assessment.

multiPle endOCrine neOPlasia tyPe 2 (men2)

Multiple endocrine neoplasia type 2 is a rare cancer syn-drome associated with medullary thyroid cancer, pheo-chromocytomas, and parathyroid hyperplasia or adenomas affecting 1 in 30 000 individuals resulting from autosomal dominant inheritance of activating mutations in the onco-gene rearranged in transfection (RET), a receptor tyrosine kinase. MEN2 families are characterized by one or more of these MEN2 endocrine tumors either in the same indi-vidual or in close relatives. Several subtypes of MEN2 have been identified, including MEN2A with the clinical fea-tures described previously, which accounts for at least 65% of MEN2 families.69 MEN2B is characterized by an earlier age of onset and more aggressive medullary thyroid cancer; pheochromocytomas; hyperplasia of the intestinal auto-nomic nerve plexuses; and disorganized growth of periph-eral nerve axons in the lips, oral mucosa, and conjunctiva. MEN2B is also autosomal dominantly inherited resulting from mutations in RET. Familial medullary thyroid can-cer is associated in some cases with mutations in the same RET gene. The location of mutations in RET tend to be specific to the phenotypes of MEN2A, MEN2B, or famil-ial medullary thyroid cancer. The penetrance of MEN2A is approximately 70%, with an initial presentation usually of medullary thyroid cancer.70 Approximately 50% of patients with MEN2A develop pheochromocytoma and 5–10% develop hyperparathyroidism. MEN2B is characterized by an earlier mean age of onset of medullary thyroid cancer (18 years) and pheochromocytoma (24 years).71

Genetic testing of at-risk individuals is clinically availa-ble and considered the standard of care. It is imperative that at-risk individuals receive genetic testing before the age of 5 in MEN2A and before the age of 1 in MEN2B to prevent medullary thyroid cancer. Prophylactic total thyroidectomy is performed after the genetic diagnosis is made.72 Pre-symptomatic mutation carriers are also followed by annual monitoring of blood pressure, urinary catecholamines, and

serum metanephrine for pheochromocytomas and monitor-ing of serum calcium for evidence of hyperparathyroidism. In addition to testing those families with classic features of MEN2, some have advocated that all patients with medul-lary thyroid cancer regardless of family history be tested for inherited RET mutations because 10% of these patients have RET mutations that would predispose them to pheo-chromocytomas or hyperparathyroidism.

PrOstate CanCer

Prostate cancer is the most common noncutaneous cancer and is the second leading cause of cancer death among men.73 Evidence of an underlying genetic contribution to prostate cancer includes familial clustering and differing prevalence by ethnicity and country of origin.74 Twenty-five percent of men with prostate cancer report a positive family history. The concordance rate of prostate cancer in monozygotic twins is 0.11–0.21 compared with dizygotic twins of only 0.03–0.06,75–77 indicating that prostate cancer is likely a result of interactions of genetic and environmental factors. Prostate cancer is more common in black men, and among black men there is a higher proportion who present with metastases at diagnosis and a higher cancer-specific mortal-ity.78 Men with a single first-degree relative (father, brother, or son) with prostate cancer are twice as likely to develop prostate cancer as those without affected close relatives. As the number of affected relatives increases to two and three first-degree relatives, the risk of prostate cancer increases 5- and 11-fold, respectively.79 Epidemiologic studies suggest that 5–10% of all prostate cancers are attributable to highly penetrant susceptibility genes.80

Although there is clear evidence of a genetic contribu-tion to prostate cancer, identifying those genes conferring increased susceptibility to prostate cancer has been dif-ficult because of the multifactorial nature of the disease. Genetic models assuming a dominant mode of inheritance suggest that 9% of all prostate cancer and 43% of prostate cancer diagnosed before the age of 55 years could be attrib-utable to a single gene with a mutant allele frequency of 0.36–1.67%.80,81 There is evidence of locus heterogeneity for inherited factors with linkage of prostate cancer with several different chromosomal regions. Despite multiple studies, no prostate cancer genes have been definitively identified by linkage analysis.82 Genome-wide association studies have begun to identify several loci associated with increased pros-tate cancer risk, and some of them such as the 8q24 locus have susceptibility allele frequencies that are particularly high, specifically in the black population.83–86 However, none of these susceptibility alleles is associated with high risk.

Prostate cancer is seen at low frequency with some inher-ited cancer syndromes. Although BRCA1 and BRCA2 con-fer the majority of their cancer risk for breast and ovarian


cancer, there is an increased frequency of prostate cancer in men who carry mutations in either of these tumor suppressor genes,7,87,88 with an approximately three-fold higher lifetime relative risk of developing prostate cancer in mutation- positive males6 who have an earlier age of onset of prostate cancer. However, on a population-wide basis, the number of cases of prostate cancer attributable to mutations in either BRCA1 or BRCA2 is low. Currently, the only clinical genetic testing that is available for inherited prostate cancer is BRCA1 and BRCA2 testing, although this should change as additional genes are identified.

CanCer risk assessment, COunseling, and testing

With the recent identification of genes for a variety of hereditary cancer syndromes, risk assessment based on individual genetic test results is now feasible. When used appropriately, genetic testing for hereditary cancer facili-tates the development of individualized surveillance and prevention strategies for at-risk individuals. However, care must be taken not to misinterpret negative test results to falsely reassure patients regarding risks for cancer in cases in which a familial mutation has not been identified. Currently, most research on the impact of testing for cancer predisposition has focused on hereditary breast/ovarian cancer (HBOC) families and hereditary nonpolyposis colon cancer (HNPCC) families. The following section focuses on these two well-described cancer syndromes in relation to the process of genetic counseling. They serve as important models for understanding the medical, sociodemographic, psychological, and family variables that arise in counseling individuals about increased cancer risks. Although limited research has been done on gender differences in genetic counseling for cancer-predisposing mutations, some pre-liminary information is available.

genetic Counseling

Genetic counseling translates basic scientific advances into clinically practical and understandable information for patients. Accurate cancer risk assessment requires collec-tion of accurate medical and family history and recognition of patterns of inheritance and clinical characteristics of can-cer syndromes. The National Society of Genetic Counselors has developed practice principles for genetic counseling including respect for autonomy and privacy of the individ-ual, the need for confidentiality and informed consent, and the provision of information to the patient in a nondirective manner.89–91 In oncogenetics, cancer prevention education is the central goal. Oncogenetic testing should include both pre-test and post-test genetic counseling, informed consent, and careful interpretation and explanation of the results.

Specialized programs have been developed to provide com-prehensive services in cancer genetics (www.cancer.gov).

importance of the Family History

The patient’s personal history of cancer and a carefully ascertained three-generation family history of cancer remain the key components for identification of heredi-tary cancer syndromes. Based on this information, one can determine who in the family should be tested, which genes should be tested, and what is the best surveillance and management strategy is. For all relatives it is important to document whether they have had any cancer, the primary cancer site(s), the age at diagnosis, the presence of bilater-ality or multiple primary tumors, the tumor histology/stage, current age, history of chronic diseases that predispose to cancer (particularly Crohn’s disease and ulcerative colitis for colon cancer risk), potential occupational and environ-mental exposures, age at and cause of death, and ethnic background. To accurately assess the family history often requires contacting multiple family members and obtaining medical records on deceased individuals. It is also impor-tant to note pieces of the family history that are unknown and to appreciate the limitations of self-reported family his-tory. It is important to consider factors that may confound the pedigree interpretation, such as small family size, pre-mature death because of trauma or war, prophylactic sur-gery that may mask the presence of a genetic susceptibility, and nonpaternity. Finally, family history is dynamic and changes over time and should be kept current.

The main features of a pedigree that suggest a hereditary cancer syndrome are the following:

n Autosomal dominant pattern of inheritance of cancern A pattern of cancer types associated with a known cancer

syndromen Early onset cancern Multiple relatives with the same or associated cancersn Bilateral, synchronous, or metachronous cancers or mul-

tiple primary cancers in the same individualn Rare cancers, such as male breast cancer.

In addition to assessing the family risk, the pedigree can also be important in identifying unaffected members who would benefit from enhanced cancer surveillance.

Before the advent of genetic testing, the diagnosis of a hereditary cancer syndrome was made on the basis of established clinical criteria and all at-risk relatives would be advised to have screening for the development of the cancers associated with the cancer syndrome. Now when a mutation is identified within a family, genetic testing allows accurate, relatively inexpensive risk stratification by differ-entiating presymptomatic genetic carriers from noncarriers who have no increased risk of cancer. It is important to note, however, that some families that meet the clinical criteria of a cancer syndrome may not have a detectable mutation

http://www.cancer.gov


because their cancer syndrome is caused by a mutation in an undiscovered gene or because the current testing method is not able to detect all mutations.

genetic testing

Several medical organizations have offered guidelines that support genetic testing for cancer risk. Some of these include the American Society of Clinical Oncology,92 the American College of Medical Genetics,93 the American Society of Human Genetics.93 and the American Gastroenterological Association.55 Genetic testing offers many benefits, but, because of the inherent challenges, the following critical recommendations should be followed:

n Pretest genetic counseling and written informed consent should proceed genetic testing

n An affected individual should be the first in the family to be tested, whenever possible

n Genetic testing should be offered to families with a sub-stantial pretest probability of carrying a mutation and used only when the results will influence the clinical management of the patient or family member

n The test must be interpretable.

informed Consent

The American Society of Clinical Oncology has identi-fied essential elements to be discussed in conjunction with written informed consent for genetic testing.92 First, infor-mation should be provided about the specific test being per-formed and the implications of a positive, a negative, and an uninformative result. Second, education about the medi-cal aspects of the disorder, the mode of inheritance, cancer risks associated with a positive genetic test result, and the options and limitations of medical surveillance and screen-ing should be provided. Third, the risks of genetic testing should be discussed, including short- and long-term psycho-logical effects of having a positive genetic test, the risk of discrimination, and patient confidentiality. With the passage of the Genetic Information Non-discrimination Act (GINA), there is now federal legislation protecting again discrimina-tion in health insurance regardless of provider and employ-ment discrimination. GINA does not however protect against differential rates for life insurance or long-term dis-ability based upon genetic test results. Fourth, the technical accuracy of the test and the cost of genetic counseling and genetic testing should be explained. In addition, the Cancer Genetics Studies Consortium stresses that genetic profes-sionals should assist patients in exploring their beliefs, val-ues, and experiences with the disorder in the family.

Hereditary Breast–Ovarian Cancer syndrome

Although it is clear that genetic testing for cancer risk has potential benefits for carefully selected and counseled

patients and family members, it also has the potential to increase anxiety or depression and negatively affect fam-ily relationships.94 Much of initial understanding of interest and use of predictive genetic testing comes from research studies that have offered BRCA1 and BRCA2 testing to members of HBOC families. Studying HBOC families, Biesceker et al.52 reported that 55% of eligible relatives contacted by letter and telephone chose to participate in the education and counseling and to have BRCA1 and BRCA2 testing. Most studies suggest that individuals seeking pre-dictive genetic testing for BRCA1 and BRCA2 are female and in their early to mid 40s.95,96

In general, studies have shown that both unaffected women with a family history of breast or ovarian cancer and women affected with these cancers greatly overestimate their risk for breast cancer.97–99 Young unaffected women experience more psychological burden. Perception of per-sonal breast cancer risk was nearly twice as high for unaf-fected women as compared with perceived risk before the diagnosis for the affected women (59% vs. 31%), even with similar family histories.100 Not surprisingly, a higher per-ception of risk is related to the expectation of being a gene carrier, which is overestimated before counseling. However, following genetic counseling the perception of cancer risk is markedly reduced.101 Men usually seek genetic testing for HBOC for the sake of their children and are often referred by a family member, whereas females more often seek test-ing to manage their own clinical care and to reduce anxi-ety. Most men believe that they were at increased risk of development of cancer (prostate, breast, colorectal, and skin cancer), and, similar to their female counterparts, more than half (55%) had intrusive thoughts about their cancer risk.102

Hereditary nonpolyposis Colon Cancer

Analogous to benefits in families with BRCA1 and BRCA2, the absence or presence of a HNPCC mutation is of consid-erable medical and psychological significance. Importantly, patients with a predisposing mutation can benefit from a medical surveillance program that has been shown to reduce the risk of developing colorectal cancer and decrease the overall mortality by 65%.103,104 In contrast to cancer risks in BRCA1 and BRCA2 that predominately affect female mutation carriers, HNPCC-associated cancer risks affect both male and female mutation carriers. A recent study of 18 clinically ascertained HNPCC families (523 subjects) with identified mutations showed that slightly more women than men (62% vs. 51%) sought genetic testing, which may reflect the additional risk for endometrial cancer in female mutation carriers.105

Psychological issues

The potential adverse psychological impact of genetic test-ing for hereditary cancer susceptibility is of great concern;


however, there are scarce data to address this issue. Members of families with hereditary cancer syndromes often have been faced with close relatives who have died of cancer, sometimes at a young age. Knowledge of being at high risk of cancer has been associated with anxiety or depression106 and the possibility of predisposition testing may add further psychological burden. To date, studies per-formed worldwide on ethnically diverse populations show that genetic counseling and testing for BRCA1 and BRCA2 can be performed without a significant increase in anxiety and distress.99,107–11 There were some initial concerns that genetic test results might negatively affect insurability, but there is now federal and state legislation in place to protect Americans from having individually assessed health insur-ance rates or coverage determined on the basis of genetic predisposition.

COnClusiOn

During the past decade there have been major advances in clinical oncogenetics, and genetic testing for several hereditary cancer syndromes is now the standard of care. Recognizing the clues of hereditary cancer susceptibil-ity can have lifesaving potential for the patient and at-risk relatives by developing an enhanced surveillance and/or preventive or therapeutic interventions based on the under-lying genetic cancer predisposition. Additional cancer sus-ceptibility genes including those that account for the less penetrant but more common familial cancer susceptibility are likely to be identified allowing for more accurate risk assessment and cancer prevention in the years to come.

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