Major Genes

Introduction
BRCA1
BRCA2
BRCA1 and BRCA2 Function
Mutations in BRCA1 and BRCA2
        Variants of uncertain significance
Population Estimates of the Likelihood of Having a BRCA1 or BRCA2 Mutation
Clinical Criteria and Models for Prediction of the Likelihood of a BRCA1 or BRCA2 Mutation
        Clinical criteria for identifying individuals who may have a BRCA1 or BRCA2 mutation
        Models for prediction of the likelihood of a BRCA1 or BRCA2 mutation
Penetrance of Mutations
        Cancers other than female breast/ovarian
        Cancer risk in individuals who test negative for a known familial BRCA1/BRCA2 mutation
        Breast and ovarian cancer risk in breast cancer families without detectable BRCA1/BRCA2 mutations
Role of BRCA1 and BRCA2 in Sporadic Cancer
Genotype-Phenotype Correlations
Pathology of Breast Cancer
        BRCA1 pathology
        BRCA2 pathology
Pathology of Ovarian Cancer
Other Rare Breast and Ovarian Cancer–Associated Syndromes
        Hereditary non-polyposis colorectal cancer (HNPCC)
        Li-Fraumeni syndrome
        Cowden syndrome
        Peutz-Jeghers syndrome (PJS)

Epidemiologic studies have clearly established the role of family history as an important risk factor for both breast and ovarian cancer. After gender and age, a positive family history is the strongest known predictive risk factor for breast cancer. In most cases an extensive family history (more than four affected relatives in the same biologic line) is not present. However, it has long been recognized that in some families, there is hereditary breast cancer, which is characterized by an early age of onset, bilaterality, and the presence of breast cancer in multiple generations in an apparent autosomal dominant pattern of transmission (through either the maternal or paternal lineage), sometimes including tumors of other organs, particularly the ovary and prostate gland.[1,2] It is now known that some of these “cancer families” can be explained by specific mutations in single cancer susceptibility genes. The isolation of several of these genes, which when mutated are associated with a significantly increased risk of breast/ovarian cancer, makes it possible to identify individuals at risk. Although such cancer susceptibility genes are very important, highly penetrant germline mutations are estimated to account for only 5% to 10% of breast cancers overall.

A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families.[3] The search for genes associated with hereditary susceptibility to breast cancer has been facilitated by studies of large kindreds with multiple affected individuals, and has led to the identification of several susceptibility genes, including BRCA1, BRCA2, TP53, PTEN/MMAC1, and STK11. Other genes, such as the mismatch repair genes MLH1, MSH2, MSH6, and PMS2, have been associated with an increased risk of ovarian cancer, but have not been consistently associated with breast cancer.

In 1990, a susceptibility gene for breast cancer was mapped by genetic linkage to the long arm of chromosome 17, in the interval 17q12-21.[4] The linkage between breast cancer and genetic markers on chromosome 17q was soon confirmed by others, and evidence for the coincident transmission of both breast and ovarian cancer susceptibility in linked families was observed.[5] The BRCA1 gene (OMIM) was subsequently identified by positional cloning methods and has been found to contain 24 exons that encode a protein of 1,863 amino acids. Germline mutations in BRCA1 are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance of Mutations section of this summary for more information.) Male breast cancer, pancreatic cancer, testicular cancer, and early-onset prostate cancer may also be associated with mutations in BRCA1;[6-9] however, male breast cancer, pancreatic cancer, and prostate cancer are more strongly associated with mutations in BRCA2.

A second breast cancer susceptibility gene, BRCA2, was localized to the long arm of chromosome 13 through linkage studies of 15 families with multiple cases of breast cancer that were not linked to BRCA1. Mutations in BRCA2 (OMIM) are associated with multiple cases of breast cancer in families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, melanoma, and pancreatic cancer.[8-14] (Refer to the Penetrance of Mutations section of this summary for more information.) BRCA2 is a large gene with 27 exons that encode a protein of 3,418 amino acids.[15] While not homologous genes, both BRCA1 and BRCA2 have an unusually large exon 11 and translational start sites in exon 2. Like BRCA1, BRCA2 appears to behave like a tumor suppressor gene. In tumors associated with both BRCA1 and BRCA2 mutations, there is often loss of the wild-type (nonmutated) allele.

Mutations in BRCA1 and BRCA2 appear to be responsible for disease in 45% of families with multiple cases of breast cancer only and in up to 90% of families with both breast and ovarian cancer.[16]

Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function, although some missense mutations cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on one copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome. In most breast and ovarian cancers that have been studied from mutation carriers, deletion of the normal allele results in loss of all function, leading to the classification of BRCA1 and BRCA2 as tumor suppressor genes. In addition to, and as part of, their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in myriad functions within cells, including homologous DNA repair, genomic stability, transcriptional regulation, protein ubiquitination, chromatin remodeling, and cell cycle control.[17,18]

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described.[19] Approximately one in 400 to 800 individuals in the general population may carry a pathogenic germline mutation in BRCA1 or BRCA2.[20,21] The mutations that have been associated with increased risk of cancer result in missing or nonfunctional proteins, supporting the hypothesis that BRCA1 and BRCA2 are tumor suppressor genes. While a small number of these mutations have been found repeatedly in unrelated families, most have not been reported in more than a few families.

Mutation-screening methods vary in their sensitivity. Methods widely used in research laboratories, such as single-stranded conformational polymorphism (SSCP) analysis and conformation-sensitive gel electrophoresis (CSGE), miss nearly a third of the mutations that are detected by DNA sequencing.[22] In addition, large genomic alterations such as translocations, inversions, or large deletions or insertions are missed by most of the techniques, including direct DNA sequencing, but testing for these are commercially available. Such rearrangements are believed to be responsible for 12% to 18% of BRCA1 inactivating mutations but are less frequently seen in BRCA2 and in individuals of Ashkenazi Jewish descent.[23-26]

Germline deleterious mutations in the BRCA1/BRCA2 genes are associated with an approximately 60% lifetime risk of breast cancer and a 15% to 40% lifetime risk of ovarian cancer. There are no definitive functional tests for BRCA1 or BRCA2; therefore, the classification of nucleotide changes to predict their functional impact as deleterious or benign relies on imperfect data. The majority of accepted deleterious mutations result in protein truncation and/or loss of important functional domains. However, 10% to 15% of all individuals undergoing genetic testing with full sequencing of BRCA1 and BRCA2 will not have a clearly deleterious mutation detected but will have a variant of uncertain (or unknown) significance (VUS). Variants of uncertain significance may cause substantial challenges in counseling, particularly in terms of cancer risk estimates and risk management. Clinical management of such patients needs to be highly individualized and must take into consideration factors such as the patient’s personal and family cancer history, in addition to sources of information to help characterize the VUS as benign or deleterious. Thus an improved classification and reporting system may be of clinical utility.[27]

African Americans appear to have a higher rate of VUS.[28] A comprehensive analysis examined the results of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratories, Inc., over a 3-year period.[29] Among subjects who had no clearly deleterious mutation, 13% had VUS defined as “missense mutations and mutations that occur in analyzed intronic regions whose clinical significance has not yet been determined, chain-terminating mutations that truncate BRCA1 and BRCA2 distal to amino acid positions 1853 and 3308, respectively, and mutations that eliminate the normal stop codons for these proteins.” The classification of a sequence variant as a VUS is a moving target. An additional 6.8% of subjects with no clear deleterious mutations had sequence alterations that were once considered VUS, but were reclassified as a polymorphism, or occasionally as a deleterious mutation. In a 2009 study of data from Myriad, 16.5% of individuals of African ancestry had VUS, the highest rate among all ethnicities. Over time, the rate of changes classified as VUS has decreased in all ethnicities, largely due to improved mutation classification algorithms.[30] VUS continue to be reclassified as additional information is accumulated. Such information may impact the continuing care of affected individuals.

A number of methods for discriminating deleterious from neutral VUS exist and others are in development [31-34] including integrated methods (see below).[35] Interpretation of VUS is greatly aided by efforts to track VUS in the family to determine if there is cosegregation of the VUS with the cancer in the family. In general, a VUS observed in individuals who also have a deleterious mutation, especially when the same VUS has been identified in conjunction with different deleterious mutations, is less likely to be in itself deleterious, although there are rare exceptions. As an adjunct to the clinical information, models to interpret VUS have been developed, based on sequence conservation, biochemical properties of amino acid changes,[31,36-40] incorporation of information on pathologic characteristics of BRCA1- and BRCA2-related tumors (e.g., BRCA1-related breast cancers are usually estrogen receptor [ER]–negative),[41] and functional studies to measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 proteins.[42,43] When attempting to interpret a VUS, all available information should be examined.

Statistics regarding the percentage of individuals found to be BRCA mutation carriers among samples of women and men with a variety of personal cancer histories regardless of family history are provided below. These data can help determine who might best benefit from a referral for cancer genetic counseling and consideration of genetic testing but cannot replace a personalized risk assessment, which might indicate a higher or lower mutation likelihood based on additional personal and family history characteristics.

In some cases, the same mutation has been found in multiple apparently unrelated families. This observation is consistent with a founder effect, wherein a mutation identified in a contemporary population can be traced back to a small group of founders isolated by geographic, cultural, or other factors. Most notably, two specific BRCA1 mutations (185delAG and 5382insC) and a BRCA2 mutation (6174delT) have been reported to be common in Ashkenazi Jews. However, other founder mutations have been identified in African Americans and Hispanics.[44-46] The presence of these founder mutations has practical implications for genetic testing. Many laboratories offer directed testing specifically for ethnic-specific alleles. This greatly simplifies the technical aspects of the test but is not without limitations. For example, it is estimated that up to 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.[29]

Among the general population, the likelihood of having any BRCA mutation is as follows:

• General population (excluding Ashkenazim): about 1 in 400 (~0.25%).[21,47]
• Women with breast cancer (any age): 1 in 50 (2%).[48]
• Women with breast cancer (younger than 40 years): 1 in 10 (10%).[49-51]
• Men with breast cancer (any age): 1 in 20 (5%).[52]
• Women with ovarian cancer (any age): 1 in 8 to 1 in 10 (10%–15%).[53-55]

Among Ashkenazi Jewish individuals, the likelihood of having any BRCA mutation is as follows:

• General Ashkenazi Jewish population: 1 in 40 (2.5%).[56]
• Women with breast cancer (any age): 1 in 10 (10%).[57]
• Women with breast cancer (younger than 40 years): 1 in 3 (30%–35%).[57-59]
• Men with breast cancer (any age): 1 in 5 (19%).[60]
• Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%–41%).[61-63]

Two large U.S. population-based studies of breast cancer patients younger than age 65 years examined the prevalence of BRCA1 [50,64] and BRCA2 [50] mutations in various ethnic groups. The prevalence of BRCA1 mutations in breast cancer patients by ethnic group was 3.5% in Hispanics, 1.3% to 1.4% in African Americans, 0.5% in Asian Americans, 2.2% to 2.9% in non-Ashkenazi Caucasians, and 8.3% to 10.2% in Ashkenazi Jewish individuals.[50,64] The prevalence of BRCA2 mutations by ethnic group was 2.6% in African Americans and 2.1% in Caucasians.[50]

A retrospective review of 29 Ashkenazi Jewish patients with primary fallopian tube tumors identified germline BRCA mutations in 17%.[63] Another study of 108 women with fallopian tube cancer identified mutations in 55.6% of the Jewish women and 26.4% of non-Jewish women (30.6% overall).[65]

Several studies have assessed the frequency of BRCA1 or BRCA2 mutations in women with breast or ovarian cancer.[50,51,64,66-74] Personal characteristics associated with an increased likelihood of a BRCA1 and/or BRCA2 mutation include the following:

• Breast cancer diagnosed at an early age. (Some studies use age 40 years, while others use age 50 years as a cutoff.)
• Ovarian cancer.
• Bilateral breast cancer.
• A history of both breast and ovarian cancer.
• Breast cancer diagnosed in a male at any age.[66-69,72]
• Triple-negative breast cancer diagnosed in women younger than 50 years.[75-77]
• Ashkenazi Jewish background.[66,67,69]

Family history characteristics associated with an increased likelihood of carrying a BRCA1 and/or BRCA2 mutation include the following:

• Multiple cases of breast cancer.
• Both breast and ovarian cancer.
• One or more breast cancers in male family members.
• Ashkenazi Jewish background.[66-69]

Several professional organizations and expert panels, including the American Society of Clinical Oncology,[78] the National Comprehensive Cancer Network,[79] the American Society of Human Genetics,[80] the American College of Medical Genetics, the U.S. Preventive Services Task Force,[81] and the Society of Gynecologic Oncologists,[82] have developed clinical criteria that can be helpful to health care providers in identifying individuals who may have a BRCA1 or BRCA2 mutation.

Many models have been developed to predict the probability of identifying germline BRCA1/BRCA2 mutations in individuals or families. These models include those using logistic regression,[29,66,67,69,72,83,84] genetic models using Bayesian analysis (BRCAPRO and BOADICEA),[72,85] and empiric observations,[47,50,53,86-88] including the Myriad prevalence tables. Two of the earliest models predicted only for BRCA1 mutations and are not clinically useful at this time.[66,67] More recently, using complex segregation analysis, a polygenetic model (BOADICEA) examining both breast cancer risk and the probability of having a BRCA1 or BRCA2 mutation has been published.[85] Even among experienced providers, the use of prediction models has been shown to increase the power to discriminate which patients are most likely to be identified as BRCA1/BRCA2 mutation carriers.[89,90] The power of several of the models has been compared in different studies, and currently there is no one model that is consistently superior to others.[91-94] Most models do not include other cancers seen in the BRCA1 and BRCA2 spectrum such as pancreatic cancer and prostate cancer. Interventions that decrease the likelihood that an individual will develop cancer (such as oophorectomy and mastectomy) may influence the ability to predict BRCA1 and BRCA2 mutation status.[95] One study has shown that the risk models are sensitive to the amount of family history data available and do not perform as well with limited family information.[96]

The performance of the models can vary in specific ethnic groups. The BRCAPRO model appeared to best fit a series of French Canadian families.[97] There have been variable results in the performance of the BRCAPRO model among Hispanics,[98,99] and both the BRCAPRO model and Myriad tables underestimated the proportion of mutation carriers in an Asian American population.[100] Further information is needed to determine which model performs best in each ethnic group.

Genetic testing for BRCA1 and BRCA2 mutations has been available to the public since 1996. As more individuals have undergone testing, risk assessment models have improved. This, in turn, gives providers better data to estimate an individual patient’s risk of carrying a mutation. There remains an art to risk assessment. There are factors that might limit the ability to provide an accurate risk assessment (i.e., small family size, paucity of women, or ethnicity) including the specific circumstances of the individual patient (such as history of disease or prophylactic surgeries).

The proportion of individuals carrying a mutation who will manifest the disease is referred to as penetrance. For adult-onset diseases, penetrance is usually dependent upon the individual carrier's age and sex. For example, the penetrance for breast cancer in female BRCA1/BRCA2 mutation carriers is often quoted by age 50 years (generally premenopausal) and by age 70 years. Of the numerous methods for estimating penetrance, none are without potential biases, and determining an individual mutation carrier's risk of cancer involves some level of imprecision.

Numerous studies have estimated breast and ovarian cancer penetrance in BRCA1 and BRCA2 mutation carriers. Risk of both breast and ovarian cancer is consistently estimated to be higher in BRCA1 than in BRCA2 mutation carriers. Results from two large meta-analyses are shown in Table 3.[104,105] One study [104] analyzed pooled pedigree data from 22 studies involving 289 BRCA1 and 221 BRCA2 mutation–positive individuals. Index cases from these studies had female breast cancer, male breast cancer, or ovarian cancer but were unselected for family history. A subsequent study [105] combined penetrance estimates from the previous study and nine others that included an additional 734 BRCA1 and 400 BRCA2 mutation–positive families. The estimated cumulative risks of breast cancer by age 70 years in these two meta-analyses were 55% to 65% for BRCA1 and 45% to 47% for BRCA2 mutation carriers. Ovarian cancer risks were 39% for BRCA1 and 11% to 17% for BRCA2 mutation carriers.

While the cumulative risks of cancer by age 70 years are higher for BRCA1 than BRCA2 mutation carriers, the relative risks (RR) of breast cancer decline with age more in BRCA1 mutation carriers.[104] Studies of penetrance for carriers of specific individual mutations are not usually large enough to provide stable estimates, but numerous studies of the Ashkenazi founder mutations have been conducted. One group of researchers analyzed the subset of families with one of the Ashkenazi founder mutations from their larger meta-analyses and found that the estimated penetrance for the individual mutations was very similar to the corresponding estimates among all mutation carriers.[106]

One study provided prospective 10-year risks of developing cancer among asymptomatic carriers at various ages.[105] Nonetheless, making precise penetrance estimates in an individual carrier is difficult.

Risk-reducing salpingo-oophorectomy and/or use of oral contraceptives have been shown to alter risk.[57,104,107-112] (Refer to the Risk-reducing salpingo-oophorectomy section and the Oral contraceptives section of this summary for more information.) Other environmental factors being studied include reproductive and hormonal factors.[113-118] Genetic modifiers of penetrance of breast cancer and ovarian cancer are increasingly under study but are not clinically useful at this time.[119-121] While the average breast cancer and ovarian cancer penetrances may not be as high as initially estimated, they are substantial, both in relative and absolute terms, particularly in women born after 1940. A higher risk before age 50 years has been consistently seen in more recent birth cohorts,[57,122] and additional studies will be required to further characterize potential modifying factors to arrive at more precise individual risk projections. Precise penetrance estimates for less common cancers, such as pancreatic cancer, are lacking.

Female breast and ovarian cancers are clearly the dominant cancers associated with BRCA1 and BRCA2. BRCA mutations also confer an increased risk of fallopian tube and primary peritoneal carcinomas. One large study from a familial registry of BRCA1 mutation carriers has found a 120-fold relative risk of tubal cancer among BRCA1 mutation carriers compared with the general population.[6] The risk of primary peritoneal cancer among BRCA mutation carriers with intact ovaries is increased but remains poorly quantified, despite a residual risk of 3% to 4% in the 20 years following risk-reducing salpingo-oophorectomy.[123,124] (Refer to the Risk-reducing salpingo-oophorectomy section in the Ovarian cancer section of this summary for more information.)

Pancreatic, male breast, and prostate cancers have also been consistently associated with BRCA mutations, particularly with BRCA2. Other cancers have been associated in some studies. The strength of the association of these cancers with BRCA mutations has been more difficult to estimate because of the lower numbers of these cancers observed in mutation carriers.

Men with BRCA2 mutations, and to a lesser extent BRCA1 mutations, are at increased risk of breast cancer with lifetime risks estimated at 5% to 10% and 1% to 2%, respectively.[6,8,9,125] Men carrying BRCA2 mutations, and to a lesser extent BRCA1 mutations, have an approximately threefold to sevenfold increased risk of prostate cancer.[7,8,12,88,126-128] BRCA2-associated prostate cancer also appears to be more aggressive.[129-134] (Refer to the BRCA1 and BRCA2 section in the PDQ summary on Genetics of Prostate Cancer summary for more information.)

Studies of familial pancreatic cancer (FPC) [135-139] and unselected series of pancreatic cancer [140-142] have also supported an association with BRCA2, and to a lesser extent, BRCA1.[7] Overall, it appears that between 3% to 15% of families with FPC may have germline BRCA2 mutations, with risks increasing with more affected relatives.[135-137] Similarly, studies of unselected pancreatic cancers have reported BRCA2 mutation frequencies between 3% to 7%, with these numbers approaching 10% in those of Ashkenazi Jewish descent.[140,141,143] The lifetime risk of pancreatic cancer in BRCA2 carriers is estimated to be 3% to 5% [8,12] compared with an estimated lifetime risk of 0.5% by age 70 years in the general population.[144] Other cancers associated with BRCA2 mutations in some, but not all, studies include melanoma, biliary cancers, and head and neck cancers, but these risks appear modest (<5% lifetime) and are less well studied.[12]

The first Breast Cancer Linkage Consortium study investigating cancer risks reported an excess of colorectal cancer in BRCA1 carriers (RR, 4.1; 95% CI, 2.4–7.2).[145] This finding was supported by some,[6,7,146] but not all,[8,56,62,88,147-149] family-based studies. However, unselected series of colorectal cancer that have been exclusively performed in the Ashkenazi Jewish population have not shown elevated rates of BRCA1 or BRCA2 mutations.[150-152] Taken together, the data suggest little, if any, increased risk of colorectal cancer, and possibly only in specific population groups. Therefore, at this time, BRCA1 mutation carriers should adhere to population-screening recommendations for colorectal cancer.

No increased prevalence of hereditary BRCA mutations was found among 200 Jewish women with endometrial carcinoma or 56 unselected women with uterine papillary serous carcinoma.[153,154] (Refer to the Risk-reducing salpingo-oophorectomy section in the Ovarian cancer section of this summary for more information.)

There is conflicting evidence as to the residual familial risk among women who test negative for the BRCA1/BRCA2 mutation segregating in the family. An initial study based on prospective evaluation of 353 women who tested negative for the BRCA1 mutation segregating in the family found that five incident breast cancers occurred during more than 6,000 person-years of observation, for a lifetime risk of 6.8%, a rate similar to the general population.[110] A report that the risk may be as high as fivefold in women who tested negative for the BRCA1 or BRCA2 mutation in the family [155] was followed by numerous letters to the editor suggesting that ascertainment biases account for much of this observed excess risk.[156-161] Three additional analyses have suggested an approximate 1.5-fold to 2-fold excess risk.[160,162,163] Several studies have involved retrospective analyses; all studies have been based on small observed numbers of cases and have been of uncertain statistical and clinical significance. No cases of ovarian cancer have been reported in these studies.[160]

Results from numerous other prospective studies have found no increased risk. A study of 375 women who tested negative for a known familial mutation in BRCA1 or BRCA2 reported two invasive breast cancers, two in situ breast cancers, and no ovarian cancers diagnosed, with a mean follow-up of 4.9 years. Four invasive breast cancers were expected, whereas two were observed.[164] Another study of similar size but longer follow-up (395 women and 7,008 person-years of follow-up) also found no statistically significant overall increase in breast cancer risk among mutation-negative women (observed/expected [O/E], 0.82; 95% CI, 0.39–1.51), although women who had at least one first-degree relative with breast cancer had a nonsignificant increased risk (O/E, 1.33; 95% CI, 0.41–2.91).[165] A study of 160 BRCA1 and 132 BRCA2 mutation–positive families from the Breast Cancer Family Registry found no evidence for increased risk among noncarriers in these families.[166] Based on the currently available data, it appears that women testing negative for known familial BRCA1/BRCA2 mutations can adhere to general population screening guidelines unless they have sufficient additional risk factors, such as a personal history of atypical hyperplasia of the breast or family history of breast cancer in relatives who do not carry the familial mutation.

The majority of families with site-specific breast cancer test negative for BRCA1/BRCA2 and have no features consistent with Cowden syndrome or Li-Fraumeni syndrome.[29] Three studies using population-based and clinic-based approaches have demonstrated no increased risk of ovarian cancer in such families. Although ovarian cancer risk was not increased, breast cancer risk remained elevated.[167-169]

Given that germline mutations in BRCA1 or BRCA2 lead to a very high probability of developing breast and/or ovarian cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease. Although somatic mutations in BRCA1 and BRCA2 are not common in sporadic breast and ovarian cancer tumors,[170-173] there is increasing evidence that downregulation of BRCA1 protein expression may play a role in these tumor types. Compared with normal breast epithelium, many breast cancers have low levels of the BRCA1 mRNA, which may result from hypermethylation of the gene promoter.[174-176] Similar findings have not been reported for BRCA2 mutations, although the BRCA2 locus on chromosome 13q is the target of frequent loss of heterozygosity (LOH) in breast cancer.[177,178] Approximately 10% to 15% of sporadic breast cancers appear to have BRCA1 promoter hypermethylation, and even more have downregulation of BRCA1 by other mechanisms. Basal-type breast cancers (ER negative, progesterone receptor negative, human epidermal growth factor receptor 2 [HER2] negative, cytokeratin 5/6 positive), more commonly have BRCA1 dysregulation than other tumor types.[179-181] BRCA1-related tumor characteristics have also been associated with constitutional methylation of the BRCA1 promoter. In a study of 255 breast cancers diagnosed before age 40 years in women without germline BRCA1 mutations, methylation of BRCA1 in peripheral blood was observed in 31% of women whose tumors had multiple BRCA1-associated pathological characteristics (e.g., high mitotic index, growth pattern including multinucleated cells) compared with less than 4% methylation in controls.[182] (Refer to the BRCA1 pathology section for more information.) Loss of BRCA1 or BRCA2 protein expression is more common in ovarian cancer than in breast cancer,[183] and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease.[184,185] Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.[186]

Some genotype-phenotype correlations have been identified in both BRCA1 and BRCA2 mutation families. None of the studies have had sufficient numbers of mutation-positive individuals to make definitive conclusions, and the findings are probably not sufficiently established to use in individual risk assessment and management. In 25 families with BRCA2 mutations, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3,035 and 6,629.[11,187] This is the region of the gene containing the BRCA1 C-terminal (BRCT) repeat,[188] which has been shown to specifically interact with RAD51. A study of 164 families with BRCA2 mutations collected by the Breast Cancer Linkage Consortium confirmed the initial finding. Mutations within the ovarian cancer cluster region were associated with an increased risk of ovarian cancer and a decreased risk of breast cancer in comparison to families with mutations on either side of this region.[189] In addition, a study of 356 families with protein-truncating BRCA1 mutations collected by the Breast Cancer Linkage Consortium reported breast cancer risk to be lower with mutations in the central region (nucleotides 2,401–4,190) compared with surrounding regions. Ovarian cancer risk was significantly reduced with mutations 3’ to nucleotide 4,191.[190] These observations have generally been confirmed in subsequent studies.[104,191,192] Studies in Ashkenazim, in whom substantial numbers of families with the same mutation can be studied, have also found higher rates of ovarian cancer in carriers of the BRCA1:185delAG mutation, in the 5' end of BRCA1, compared with carriers of the BRCA1:5382insC mutation in the 3' end of the gene.[193,194] The risk of breast cancer, particularly bilateral breast cancer, and the occurrence of both breast and ovarian cancer in the same individual, however, appear to be higher in BRCA1:5382insC mutation carriers compared with carriers of BRCA1:185delAG and BRCA2:6174delT mutations. Ovarian cancer risk is considerably higher in BRCA1 mutation carriers, and it is uncommon before age 45 years in BRCA2:6174delT mutation carriers.[193,194]

Several studies evaluating pathologic patterns seen in BRCA1-associated breast cancers have suggested an association with adverse pathologic and biologic features. These findings include higher than expected frequencies of medullary histology, high histologic grade, areas of necrosis, trabecular growth pattern, aneuploidy, high S-phase fraction, high mitotic index, and frequent TP53 mutations.[195-205] Additionally, the triple-negative breast cancer phenotype (i.e., negative for ER, progesterone receptor [PR], and HER2), which also carries an adverse prognosis, accounts for 80% to 90% of BRCA1-associated breast cancers.[75,199,206,207]

There is considerable, but not complete, overlap between the triple-negative and basal-like subtype cancers, both of which are common in BRCA1-associated breast cancer,[208,209] particularly in women diagnosed before age 50 years.[75-77] A small proportion of BRCA1-related breast cancers are ER-positive, which are associated with later age of onset.[210,211] These ER-positive cancers have clinical behavior features that are "intermediate" between ER-negative BRCA1 cancers and ER-positive sporadic breast cancers, raising the possibility that there may be a unique mechanism by which they develop.

The prevalence of germline BRCA1 mutations in women with triple-negative breast cancer is significant, both in women undergoing clinical genetic testing (and thus selected in large part for family history) and in unselected triple-negative patients, with mutations reported in 11% to 35%.[77,199,206,212-217] The highest rate reported was in a clinic-based series in women younger than 30 years with high-grade triple-negative breast cancer. In this small, highly selected population, 35% had BRCA1 mutations. Notably, studies have demonstrated a high rate of BRCA1 mutations in unselected women with triple-negative breast cancer, particularly in those diagnosed before age 50 years. One study examined 308 individuals with triple-negative breast cancer; BRCA1 mutations were present in 45. Mutations were seen both in women unselected for family history (11 of 58; 19%) and in those with family history (26 of 111; 23%).[218] A group of researchers reported results of BRCA1/2 testing in 77 unselected patients with triple-negative breast cancer. Of these, 15 (19.5%) had either a germline BRCA1 (n = 11; 14%) or BRCA2 (n = 3; 4%) mutation or a somatic BRCA1 (n = 1) mutation. The median age at cancer diagnosis was 45 years in BRCA1 mutation carriers and 53 years in noncarriers (P = .005). Interestingly, this study also demonstrated a lower risk of relapse in those with BRCA1 mutation–associated triple-negative breast cancer than in those with nonmutated triple-negative breast cancer, although this study was limited by its size.[215] A second study examining clinical outcomes in BRCA1-associated versus non-BRCA1-associated triple-negative breast cancer showed no difference, although there was a trend toward more brain metastases in those with BRCA1-associated breast cancer. In both of these studies, all but one BRCA1 mutation carrier received chemotherapy.[216]

It has been hypothesized that many BRCA1 tumors are derived from the basal epithelial layer of cells of the normal mammary gland, which account for 3% to 15% of unselected invasive ductal cancers. If the basal epithelial cells of the breast represent the breast stem cells, the regulatory role suggested for wild-type BRCA1 may partly explain the aggressive phenotype of BRCA1-associated breast cancer when BRCA1 function is damaged.[219] Further studies are needed to fully appreciate the significance of this subtype of breast cancer within the hereditary syndromes.

The most accurate method for identifying basal-like breast cancers is through gene expression studies, which have been used to classify breast cancers into biologically- and clinically-meaningful groups.[207,220,221] This technology has also been shown to correctly differentiate BRCA1- and BRCA2-associated tumors from sporadic tumors in a high proportion of cases.[222-224] Notably, among a set of breast tumors studied by gene expression array to determine molecular phenotype, all tumors with BRCA1 alterations fell within the basal tumor subtype;[207] however, this technology is not in routine use due to its high cost. Instead, immunohistochemical markers of basal epithelium have been proposed to identify basal-like breast cancers, which are typically negative for ER, progesterone receptor, and HER2, and stain positive for cytokeratin 5/6, or epidermal growth factor receptor.[225-228] Based on these methods to measure protein expression, a number of studies have shown that the majority of BRCA1-associated breast cancers are positive for basal epithelial markers.[75,199,227]

There is growing evidence that preinvasive lesions are a component of the BRCA phenotype. The Breast Cancer Linkage Consortium initially reported a relative lack of an in situ component in BRCA1-associated breast cancers,[196] also seen in two subsequent studies of BRCA1/BRCA2 carriers.[229,230] However, in a study of 369 ductal carcinoma in situ (DCIS) cases, BRCA1 and BRCA2 mutations were detected in 0.8% and 2.4%, respectively, which is only slightly lower than previously reported prevalence in studies of invasive breast cancer patients.[231] A retrospective study of breast cancer cases in a high-risk clinic found similar rates of preinvasive lesions, particularly DCIS, among 73 BRCA-associated breast cancers and 146 mutation-negative cases.[232,233] A study of Ashkenazi Jewish women, stratified by whether they were referred to a high-risk clinic or were unselected, showed similar prevalence of DCIS and invasive breast cancers in referred patients compared with one-third lower DCIS cases among unselected subjects.[234] Similarly, data about the prevalence of hyperplastic lesions have been inconsistent, with reports of increased[235,236] and decreased prevalence.[230] Similar to invasive breast cancer, DCIS diagnosed at an early age and/or with a family history of breast and/or ovarian cancer is more likely to be associated with a BRCA1/BRCA2 mutation.[237]

Overall evidence suggests DCIS is part of the BRCA1/BRCA2 spectrum, particularly BRCA2; however, the prevalence of mutations in DCIS patients, unselected for family history, is less than 5%.[231,234]

The phenotype for BRCA2-related tumors appears to be more heterogeneous and is less well-characterized than that of BRCA1, although they are generally positive for ER and PR.[196,200,238] A report from Iceland found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2-related tumors compared with sporadic controls; however, a single BRCA2 founder mutation (999del5) accounts for nearly all hereditary breast cancer in this population, thus limiting the generalizability of this observation.[239] A large case series from North America and Europe described a greater proportion of BRCA2-associated tumors with continuous pushing margins, fewer tubules and lower mitotic counts.[240] Other reports suggest that BRCA2 related tumors include an excess of lobular and tubulolobular histology.[198,200] In summary, histologic characteristics associated with BRCA2 mutations have been inconsistent.

Ovarian cancer arising in women with BRCA1 and BRCA2 mutations is more likely to be invasive serous adenocarcinoma and less likely to be mucinous or borderline.[241-244] Fallopian tube cancer and papillary serous carcinoma of the peritoneum are also part of the spectrum of BRCA-associated disease.[63,245] Approximately 60% of sporadic ovarian cancers have serous histology, but a survey of all published data shows that 94% of BRCA1-related ovarian cancers have this type of histology.[174] Serous carcinoma was also found to be the predominant histologic subtype of intraperitoneal carcinoma among BRCA1/BRCA2 carriers in a Dutch case-control study.[246] In contrast to high-grade serous ovarian cancer, low-grade serous ovarian cancer is not likely to be part of the spectrum of BRCA1- or BRCA2-related ovarian cancer.[247] Both primary ovarian carcinomas and primary peritoneal carcinomas have a higher incidence of somatic TP53 mutations and exhibit relatively aggressive features, including higher grade and p53 overexpression.[241,248] The histopathologic profile of BRCA2-related ovarian cancer has not been well defined. The finding of differential expression of genes in BRCA1, BRCA2, and sporadic ovarian cancer, using DNA microarray technology, suggests distinct molecular pathways of carcinogenesis that may ultimately distinguish them histologically.[249] Furthermore, there have been data to suggest that BRCA-related ovarian cancers that relapse frequently metastasize to viscera, while relapsed sporadic ovarian cancers commonly remain confined to the peritoneum.[250]

Histopathologic examinations of fallopian tubes removed prophylactically from women with a hereditary predisposition to ovarian cancer show dysplastic and hyperplastic lesions that are accompanied by changes in cell-cycle and apoptosis-related proteins, suggesting a premalignant phenotype.[251,252] Occult carcinomas have been reported in 2% to 11% of the adnexa removed at the time of risk-reducing surgery from BRCA mutation carriers. The majority of these occult carcinomas are seen within the fallopian tube, which has led to the hypothesis that many BRCA-associated ovarian cancers may actually have originated in the fallopian tube. Specifically, the distal segment of the fallopian tube (fimbriae) has been implicated as a common origin for the high-grade serous cancers seen in BRCA mutation carriers based on its close proximity to the ovarian surface and peritoneal cavity and its large surface area.[253]

HNPCC is characterized by autosomal dominant inheritance of susceptibility to predominantly right-sided colon cancer, endometrial cancer, ovarian cancer, and other extracolonic cancers (including cancer of the renal pelvis, ureter, small bowel, and pancreas), multiple primary cancers, and a young age of onset of cancer.[254] The condition is due to germline mutations in the mismatch repair (MMR) genes, which are involved in repair of DNA mismatch mutations.[255] The MLH1 and MSH2 genes are the most common susceptibility genes for HNPCC, accounting for 80% to 90% of observed mutations,[256,257] followed by MSH6 and PMS2.[258-263] (Refer to the Lynch syndrome (LS) section in the PDQ summary on Genetics of Colorectal Cancer for more information about this syndrome.)

The lifetime risk of ovarian carcinoma in females with HNPCC is estimated to be up to 12%, and the reported RR of ovarian cancer has ranged from 3.6 to 13, based on families ascertained from high-risk clinics with known or suspected HNPCC.[264-269] Characteristics of HNPCC-associated ovarian cancers may include over-representation of the International Federation of Gynecology and Obstetrics stages 1 and 2 at diagnosis (reported as 81.5%), under-representation of serous subtypes (reported as 22.9%), and a better 10-year survival (reported as 80.6%) than reported both in population-based series and in BRCA mutation carriers.[270,271]

Prior studies suggest breast cancer risk in individuals with HNPCC is not elevated.[272,273] However, in approximately 50% of individuals with HNPCC who develop breast cancer, there is loss of MMR protein expression, which corresponds with the MMR gene mutation segregating in the family.[273]

Breast cancer is also a component of the rare Li-Fraumeni syndrome (LFS) (OMIM), in which germline mutations of the TP53 gene (OMIM) on chromosome 17p have been documented.[274] This syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[275,276] Tumors in LFS families tend to occur in childhood and early adulthood, and often present as multiple primaries in the same individual. Evidence supports a genotype-phenotype correlation, with an association of the location of the mutation, the kind of cancer that develops, and the age of onset.[277] Brain and adrenal gland tumors were associated with specific sites of missense mutations. Age at onset of breast cancer was 34.6 years in families with a TP53 mutation compared with 42.5 years in those families without a mutation. A germline mutation in the TP53 gene has been identified in more than 50% of families exhibiting this syndrome, and inheritance is autosomal dominant, with a penetrance of at least 50% by age 50 years.

Germline TP53 mutations were identified in 17% (n = 91) of 525 samples submitted to City of Hope laboratories for clinical TP53 testing. All families with a TP53 mutation had at least one family member with a sarcoma, breast cancer, brain cancer, or adrenocortical cancer (core cancers). In addition, all eight individuals with a choroid plexus tumor had a TP53 mutation, as did 14 of the 21 individuals with childhood adrenocortical cancer. In women aged 30 to 49 years who had breast cancer but no family history of other core cancers, no TP53 mutations were found. TP53 mutations are uncommon in women with breast cancer before age 30 years with no other indications for TP53 screening (e.g., a family history of sarcoma). In three studies, the numbers of women with TP53 mutations were 0 (of 95), 1 (of 14), and 2 (of 52).[278-280]

Located on chromosome 17p, TP53 encodes a 53kd nuclear phosphoprotein that binds DNA sequences and functions as a negative regulator of cell growth and proliferation in the setting of DNA damage. It is also an active component of programmed cell death.[281] Inactivation of the TP53 gene or disruption of the protein product is thought to allow the persistence of damaged DNA and the possible development of malignant cells.[276] Evidence also exists that patients treated for a TP53-related tumor with chemotherapy or radiation therapy may be at risk of a treatment-related second malignancy. Germline mutations in TP53 are thought to account for fewer than 1% of breast cancer cases.[282] HER2 overexpression may be common in Li-Fraumeni-associated breast cancer.[283]

Screening for breast cancer with annual magnetic resonance imaging is recommended;[79] additional screening for other cancers has been studied and is evolving.[284,285]

One of the more than 50 cancer-related genodermatoses, Cowden syndrome (OMIM) is characterized by multiple hamartomas, an excess of breast cancer, gastrointestinal malignancies, endometrial cancer, and thyroid disease, both benign and malignant.[286,287] Lifetime estimates for breast cancer among women with Cowden syndrome range from 25% to 50%. As in other forms of hereditary breast cancer, onset is often at a young age and may be bilateral.[288] Skin manifestations include multiple trichilemmomas, oral fibromas and papillomas, and acral, palmar, and plantar keratoses. History or observation of the characteristic skin features raises a suspicion of Cowden syndrome. Central nervous system manifestations include macrocephaly, developmental delay, and dysplastic gangliocytomas of the cerebellum.[289,290] Germline mutations in the PTEN gene (OMIM), which is located on chromosome 10q23 and encodes a tyrosine phosphatase protein with homology to tensin, are responsible for Cowden syndrome. Loss of heterozygosity at the PTEN locus observed in a high proportion of related cancers suggests that PTEN functions as a tumor suppressor gene. Its defined enzymatic function indicates a role in maintenance of the control of cell proliferation.[291] Disruption of PTEN appears to occur late in tumorigenesis and may act as a regulatory molecule of cytoskeletal function. Although PTEN mutations, which are estimated to occur in 1 in 200,000 individuals,[287] account for a small fraction of hereditary breast cancer, the characterization of PTEN function will provide valuable insights into the signal pathway and the maintenance of normal cell physiology.[287,292] (Refer to the Major Genes section in the PDQ summary on Genetics of Colorectal Cancer for more information about Cowden syndrome.)

PJS is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, and the perioral and buccal regions, and multiple gastrointestinal polyps, both hamartomatous and adenomatous.[293-295] Germline mutations in the STK11 gene at chromosome 19p13.3 have been identified in the vast majority of PJS families.[296-300] (Refer to the Peutz-Jeghers Gene(s) section in the PDQ summary on Genetics of Colorectal Cancer for more information.) The most common cancers in PJS are gastrointestinal. However, other organs are at increased risk of developing malignancy. A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93% in patients with PJS.[301] Table 5 shows the cumulative risk of these tumors. The high cumulative risk of cancers in PJS has led to the various screening recommendations summarized in the table of Clinical Practice Guidelines for the Diagnosis of Cancer in Peutz-Jeghers Syndrome in the PDQ summary on Genetics of Colorectal Cancer.

Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in over-estimates of these risks should be considered.

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