Introduction
BRCA1
BRCA2
BRCA1 and BRCA2 Function
Mutations in BRCA1 and BRCA2
        Variants of uncertain significance
Prevalence and Founder Effects
Penetrance of Mutations
Population Estimates of the Likelihood of Having a BRCA1 or BRCA2 Mutation
Models for Prediction of the Likelihood of a BRCA1 or BRCA2 Mutation
Role of BRCA1 and BRCA2 in Sporadic Cancer
Genotype-Phenotype Correlations
Pathology/Prognosis of Breast Cancer
        BRCA1
        BRCA2
Pathology/Prognosis of Ovarian Cancer
        Pathology
        Prognosis
Other Rare Breast and Ovarian Cancer Associated Syndromes
        Li-Fraumeni syndrome
        Cowden syndrome
        Peutz-Jeghers syndrome

Introduction

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 relatives in the same biologic line affected) 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 through either the maternal or paternal lines in an apparent autosomal dominant pattern of transmission and familial association with tumors of other organs, particularly the ovary and prostate gland.[1,2] We now know 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, only 5% to10% of individuals who develop breast cancer are known to carry highly penetrant gene mutations.

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 the study 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 and MSH2, 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. Mutations in BRCA1 are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance section 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.[8-13] (Refer to the Penetrance section for more information.) BRCA2 is also a large gene with 27 exons that encode a protein of 3,418 amino acids.[14] 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 (unmutated) 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.[15]

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, however, the normal allele is deleted, resulting in loss of all function. This finding strongly suggests that BRCA1 and BRCA2 are in the class of tumor suppressor genes, i.e., genes whose loss of function can result in neoplastic growth.[16,17]

In addition to, and as part of, their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in a myriad of functions within cells including homologous DNA repair, genomic stability, transcriptional regulation and cell cycle control.[18,19]

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described.[20] Approximately one in 400 to 800 individuals in the general population may carry a pathogenic mutation in BRCA1 and BRCA2.[21,22] 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.[23] In addition, large genomic rearrangements are missed by most of the techniques, including direct DNA sequencing. Such rearrangements are believed to be responsible for 10% to 15% of BRCA1 inactivating mutations.[24-26]

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, classifying deleterious nucleotide changes to predict their functional impact 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 problems 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, as well as the likelihood that the VUS is significant.

African Americans appear to have a higher rate of VUS.[27] A comprehensive analysis examined the results of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratory over a 3-year period.[28] 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 individuals had sequence alterations that were once considered VUS, but were reclassified, usually as a polymorphism though occasionally as a deleterious mutation. As additional information is accumulated, VUS are reclassified and 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.[29,30] 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. Variant tracking is accomplished by testing parents and all affected family members (these costs are generally covered by Myriad Genetic Laboratory). The Myriad Genetic Laboratory typically provides additional information when a VUS is reported, including available data on cosegregation and whether the VUS has been seen in conjunction with a known deleterious mutation. In general, a VUS observed in subjects who also have a deleterious mutation, especially when it occurs with different mutations, is not felt to be in itself deleterious, although there are rare exceptions. Models based on sequence conservation and the biochemical properties of amino acid changes exist [29,31-34] and are an adjunct to the clinical information. An attempt at further refining such models has also incorporated information on pathologic characteristics of BRCA1- and BRCA2- related tumors (such as the fact that BRCA1-related breast cancers are usually estrogen receptor negative).[35] Functional studies that measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 have been employed as well.[36,37] When attempting to interpret a VUS, all available information should be examined.

Two large U.S. population-based studies of breast cancer patients younger than age 65 years examined the prevalence of BRCA1[38,39] and BRCA2[39] mutations in various ethnic groups. The prevalence of mutations by ethnic group was as follows:

BRCA1

• 3.5% Hispanic,
• 1.3% to 1.4% African American,
• 0.5% Asian American,
• 2.2% to 2.9% non-Ashkenazi Caucasian, and
• 8.3 % to 10.2% Ashkenazi Jewish.[38,39]

BRCA2

• 2.6% African American and
• 2.1% Caucasian.[39]

Among cases identified from the Cancer Surveillance System of Western Washington, the frequency of BRCA1 mutations was highest in cases diagnosed before age 30 years (23% carriers, 95% confidence interval [CI], 5.0-53.8), and in those with more than three relatives with breast cancer (20%, 95% CI, 6%-44%). A family history of ovarian cancer in a first-degree relative was also associated with an increased prevalence of BRCA1 mutations (25%, 95% CI, 3.2%-65.1%).[40] In a second study, 263 women with familial breast cancer were analyzed.[41] BRCA1 mutations were found in 7% (95% CI, 0.3%-39%) of families with site-specific breast cancer, 18% of families with bilateral breast cancer, and 40% (95% CI, 1.7%-80.0%) of families with both breast and ovarian cancer. In a population-based series of incident cases of ovarian cancer in Canada, the overall prevalence of BRCA1/2 mutations was 11.7%; among women with a first-degree relative with breast or ovarian cancer, it was 19%. Of note, 6.5% of women with no affected first-degree relative carried a mutation, suggesting a higher overall prevalence of mutations in women with a diagnosis of ovarian cancer than in those with breast cancer.[39,42,43]

In some cases the same mutation has been found in multiple apparently unrelated families. This observation is consistent with a founder effect. This occurs when a contemporary population can be traced back to a small, isolated group of founders. Most notably, two specific BRCA1 mutations (185delAG and 5382insC) and a BRCA2 mutation (6174delT) have been reported to be common in Ashkenazi Jews (those tracing their roots to Central and Eastern Europe). Carrier frequencies for these mutations have been determined in the general Jewish population: 0.9% (95% CI, 0.7%-1.1%) for the 185delAG mutation, 0.3% (95% CI, 0.2%-0.4%) for the 5382insC mutation, and 1.3% (95% CI, 1.0%-1.5%) for the BRCA2 6174delT mutation.[44-47] Altogether, the frequency of these three mutations approximates 1 in 40 among Ashkenazi Jews; they account for 25% of early-onset breast cancer, and up to 90% of families with multiple cases of both breast and ovarian cancer in this population.[48,49] Additional founder mutations have been described in multiple non–Ashkenazi Jewish populations including the Netherlands (BRCA1 2804delAA and several large deletion mutations), Iceland (BRCA2, 999del5), Portugal (BRCA2, exon 3 Alu insertion),[50] and Sweden (BRCA1, 3171ins5).[51-54]

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 pitfalls. It is estimated that up to 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.[28]

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 BRCA1/2 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.

Estimates of penetrance by age 70 years for BRCA1 and BRCA2 mutations show a large range, from 14% to 87% for breast cancer and 10% to 68% for ovarian cancer.[12,15,42,43,46,55-70] Initial penetrance estimates for BRCA1 and BRCA2 mutations were derived from multiple-case families from the Breast Cancer Linkage Consortium (BCLC), families studied to localize and clone the genes.[15,55,56] For breast cancer, the estimates ranged from 50% to 73% by age 50 years and 65% to 87% by age 70 years for BRCA1, and 59% and 82% at ages 50 years and 70 years, respectively, for BRCA2. For ovarian cancer, the estimates were as high as 29% by age 50 years and 63% by age 70 years.[55,56] For many patients currently seeking genetic testing for BRCA1 and BRCA2, the family history will not be as strong as this study by the BCLC (e.g., more than four affected relatives in the same biologic lineage) and therefore, these estimates may not apply.

There are now several lines of evidence indicating that primary fallopian tube cancer should be considered a part of the BRCA1/2 phenotype. Epidemiologic evidence points to an increased risk of early-onset breast and/or ovarian cancer among first-degree relatives of women with fallopian tube cancers.[71] Histopathologic examination 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.[72,73] A retrospective review of 29 Ashkenazi Jewish patients with primary fallopian tube tumors identified germline BRCA mutations in 17%.[74] While the true incidence of fallopian tube tumors in BRCA carriers is not known, there is a growing consensus that risk-reducing oophorectomy should be accompanied by removal of the fallopian tubes.

In addition to the estimates from multiple-case families and patients from high-risk genetics clinics,[12,15,55,56,58,63,69,75] at least 13 studies have estimated penetrance by studying the families of mutation carriers who were not specifically recruited and studied because of a positive family history.[42,43,46,59-68] Often these studies have concentrated on founder populations in which testing of larger, more population-based subjects are possible owing to a reduced number of mutations that require testing,[46,57,59,61,64,65,67] compared with complete sequencing of the two genes required in most populations. The first study of a community-based series was carried out in the Washington, D.C., area. Blood samples and family medical histories were collected from more than 5,000 Ashkenazi Jewish individuals.[46] Study participants were tested for three founder mutations: 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. The prevalence of breast cancer in the relatives of carriers was compared with that reported by mutation-negative individuals. The risk of breast cancer in carriers of these mutations was estimated to be 56% (95% CI, 40%-73%) by age 70 years. Ovarian cancer risk was estimated to be 16% (95% CI, 6%-28%). These values were lower than most prior risk estimates. Men carrying BRCA1 and BRCA2 mutations were at modestly increased risk of prostate cancer, reaching 16% by age 70 years. Subsequent studies have provided additional support for an approximately twofold increased risk of prostate cancer in BRCA2 mutation carriers.[61,76,77].

Many subsequent studies, whether in founder or predominantly outbred populations, have estimated breast cancer risks by age 70 years of approximately 60% or lower and ovarian cancer risks of approximately 40% or lower, though often with large confidence limits because, even in studies of founder populations, the number of identified mutation carriers is relatively small. A meta-analysis of ten studies estimates risks among BRCA1 and BRCA2 mutation carriers of 57% and 49% for breast cancer and 40% and 18% for ovarian cancer.[78] Most studies have done molecular testing on the proband only and have done no,[42,46,57,59,61-65,67,68] or limited,[60,69] testing among relatives. Instead, the mutation status of relatives is modeled on simple Mendelian principles that on average, one-half of first-degree relatives of mutation carriers will themselves be carriers. Such modeling may lead to imprecision in the penetrance estimates; by chance, more than or less than half the relatives of some families will be carriers. In the New York Breast Cancer Study of 104 mutation-positive Ashkenazi Jews with breast cancer, penetrance estimates were based only on relatives whose mutation status was known.[43] These estimates were 69% and 74% for breast cancer by age 70 years for BRCA1 and BRCA2 mutation carriers, respectively, and 46% and 12% for ovarian cancer for BRCA1 and BRCA2, respectively.

The largest study to date to estimate penetrance involved a pooled analysis of 22 studies of over 8,000 breast and ovarian cancer cases unselected for family history.[68] Subjects were from 12 different countries and had a broad spectrum of mutations. Using modified segregation analysis on the families of the nearly 500 cases found to carry a BRCA1/2 mutation, the cumulative risk of breast cancer by age 70 years was 65% (95% CI, 44%-78%) for BRCA1 and 45% (95% CI, 31%-56%) for BRCA2. The penetrances for cancer are somewhat higher for BRCA1 mutation carriers, especially for ovarian cancer and early-onset breast cancer. These estimates are average risks of cancer among mutation carriers, assuming there is at least one family member with breast cancer or ovarian cancer (since all probands had these cancers), the situation likely to be encountered in clinical genetics situations. A case series of 491 women with stage I or stage II breast cancer and a known or suspected deleterious BRCA1/2 mutation was reviewed for incidence of ovarian cancer. The actuarial risk of developing ovarian cancer at 10 years following diagnosis of breast cancer was 12.7% for BRCA1 mutation carriers and 6.8% for BRCA2 mutation carriers. Eight of 83 cancer deaths (9.6%) in this series were because of ovarian cancer. Systemic treatment for the primary breast cancer did not alter these findings.[79] Several studies have suggested that cancer risks in BRCA1/BRCA2 mutation carriers are affected by the type of cancer of the index case. Relatives of breast cancer index cases were more likely to develop breast cancer, and relatives of ovarian cancer index cases were more likely to develop ovarian cancer.[68,80-82] Risk of breast cancer appears increased in more recent birth cohorts.[43,80]

The continuing uncertainty as to the exact penetrance for breast and ovarian cancer among BRCA1/2 mutation carriers may be due to several factors, including differences owing to study design, allelic heterogeneity (differing risks for different mutations within either of the genes), and to modifying genetic and/or environmental factors, such as differing rates of oophorectomy.[43,68,83-87] A large population-based family study found that the risk of breast cancer for relatives of probands with deleterious BRCA1/2 mutations demonstrated significant interfamilial variation, even when controlling for age at diagnosis of the proband and the presence of contralateral breast cancer.[88] While the average breast and ovarian cancer penetrances may not be as high as initially estimated, they are substantial, both in relative and absolute terms, and additional studies will be required to further characterize potential modifying factors in order to arrive at more precise individual risk projections. Precise penetrance estimates for less common cancers, such as pancreatic cancer, are lacking.

The tables titled “ Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Breast Cancer ” and “ Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Ovarian Cancer ” review the incidence of breast and ovarian cancer among BRCA1 and BRCA2 mutation carriers.

There is conflicting evidence as to the residual familial risk among women who themselves test negative for the BRCA1/BRCA2 mutation segregating in their family. Based on prospective evaluation of 353 women who tested negative for the BRCA1 mutation segregating in the family, five incident breast cancers occurred during more than 6,000 person-years of observation, for a lifetime risk of 6.8%.[86] A report that the risk may be as high as fivefold in women who have tested negative for the BRCA1 or BRCA2 mutation in the family[89] was followed by numerous letters suggesting that ascertainment biases account for much of this observed excess risk.[90-93] Two additional analyses have suggested an approximately twofold excess risk.[94,95] All studies have been based on small observed numbers of cases and most have involved retrospective analyses. Additional prospective analyses will be required to determine whether women from BRCA1/BRCA2 families who test negative in families are at the general population risk for breast cancer.[96] No information has been published regarding ovarian cancer risk in this setting.

Statistics regarding the percentage of women 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 family history characteristics.

Among non-Ashkenazi Jewish individuals (likelihood of having any BRCA mutation):

• General non-Ashkenazi Jewish population: 1 in 500 (.2%).[97]
• Women with breast cancer (all ages): 1 in 50 (2%).[98]
• Women with breast cancer (younger than 40 years): 1 in 11 (9%).[99]
• Men with breast cancer (regardless of age): 1 in 20 (5%).[100]
• Women with ovarian cancer (all ages): 1 in 10 (10%).[42,101]

Among Ashkenazi Jewish individuals (likelihood of having one of three founder mutations):

• General Ashkenazi Jewish population: 1 in 40 (2.5%).[46]
• Women with breast cancer (all ages): 1 in 10 (10%).[43]
• Women with breast cancer (younger than 40 years): 1 in 3 (30%-35%).[43,102,103]
• Men with breast cancer (regardless of age): 1 in 5 (19%).[104]
• Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%-41%).[64,74,105]

Several studies have assessed the frequency of BRCA1 or BRCA2 mutations in women with breast or ovarian cancer. These studies have used populations derived from clinical referral centers.[41,106-111] Personal characteristics associated with an increased likelihood of a BRCA1 or BRCA2 mutation include the following:

• Breast cancer diagnosed at an early age.
• Bilateral breast cancer.
• A history of both breast and ovarian cancer.
• The presence of breast cancer in one or more male family members.[41,106-108,111]

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

• Multiple cases of breast cancer in the family.
• Both breast and ovarian cancer in the family.
• One or more family members with two primary cancers.
• Ashkenazi Jewish background.[41,106-108]

Many models have been developed to predict the probability of identifying germline BRCA1/2 mutations in individuals or families. These models include those using logistic regression,[28,41,106,108,111-113], “genetic” models using Bayesian analysis (BRCAPRO and BOADICEA),[111,114] and empiric observations,[39,42,44,45,61,62] including the Myriad prevalence tables. Two of the earliest models predicted only for BRCA1 mutations and are not clinically useful at this time.[41,106] 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.[114] Prediction models have been shown to increase the discrimination power of even experienced providers in identifying patients in whom BRCA1/2 mutations are likely to be found.[115,116] Many of the models have been compared with each other in different studies and currently there is no one model that is clearly superior to others.[117-119] 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.[120]

Genetic testing for BRCA1 and BRCA2 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. One study has shown that the risk models are sensitive to the amount of family history data available and perform less well with limited family information.[122] There remains an art to risk assessment in practitioners’ selection of the best model to fit their individual patient’s circumstances and consideration of factors that might limit the ability to provide an accurate risk assessment (i.e., small family size or paucity of women).

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,[123-126] 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.[127-129] 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.[130,131] 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 (estrogen receptor negative, progesterone receptor negative, HER2 negative, cytokeratin 5/6 positive), more commonly have BRCA1 dysregulation than other tumor types.[132-134] Loss of BRCA1 or BRCA2 protein expression is more common in ovarian cancer than in breast cancer,[135] and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease.[136,137] Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.[138]

Some genotype-phenotype correlations have been identified in both BRCA1 and BRCA2 mutation families. In 25 families with BRCA2 mutations, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3,035 and 6,629.[11,58] This is the region of the gene containing the BRC repeats, which have 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.[66] 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.[139] These observations have generally been confirmed in subsequent studies.[68,69,140] 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.[67,141] 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 in BRCA2:6174delT mutation carriers.[67,141] 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.

The identification of a histologic pattern characterizing hereditary breast cancer has been elusive, though historically, medullary, tubular, and lobular histologies have been associated with familial breast cancer.[142] Other studies have noted an excess of medullary histology in multicase families.[143,144] Since the identification of the BRCA1 and BRCA2 genes, several studies have evaluated the distinct pathologic patterns seen in known hereditary breast cancers. Medullary histology was significantly more common (19% vs. 0%) in a series of BRCA1-associated breast cancer compared with sporadic cases in a study from France,[145] in carriers from the Breast Cancer Linkage Consortium,[146], in a Swedish population-based study of breast cancer cases from high-risk families,[147] and among women with early-onset breast cancer in a population-based study,[148] suggesting that medullary histology itself may be an indication for BRCA1 testing.

The prevalence of high-risk, preinvasive lesions in BRCA mutation carriers is controversial. The Breast Cancer Linkage Consortium reported a relative lack of an in situ component in BRCA1-associated breast cancers.[146] Data from the Mayo Clinic cohort of women undergoing mastectomy found a significantly lower prevalence of hyperplastic lesions among BRCA1/2 mutation carriers, but no difference in the prevalence of in situ lesions.[149] In contrast, one study from the United States and one study from the Netherlands reported a high rate of hyperplastic lesions in BRCA carriers.[150,151] A population-based case-control study of ductal carcinoma in situ (DCIS) patients found the prevalence of BRCA mutations to be similar, as previously reported in studies of invasive breast cancer patients.[152] A study of 199 Ashkenazi Jewish women with DCIS and 2,248 women with invasive cancers compared BRCA1/2 mutation prevalence, stratified by whether they were referred to a high-risk clinic or were unselected. The prevalence of founder mutations in DCIS cases was similar to that of invasive cases among referred patients, but was about one-third lower among unselected subjects.[153] A retrospective cohort study found that DCIS was equally common among patients with BRCA1/2 mutations as among women with a familial risk who were not mutation carriers.[154] Overall evidence suggests DCIS is part of the BRCA1/BRCA2 spectrum, however, the prevalence of mutations in DCIS patients, unselected for family history, is less than 5%.[152,153]

The development of gene-expression technology has created the potential to increase the specificity of the classification of breast cancer at the molecular level. Global gene expression profiles of tumors with BRCA1 and BRCA2 mutations and sporadic tumors differed significantly from each other in one small series.[155] Using comparative genomic hybridization (CGH), investigators from the Netherlands were able to develop a profile of distinct somatic genetic alterations, which can identify BRCA1-associated tumors with an accuracy of 84%.[156] Another study using tissue microarray technology to compare BRCA1, BRCA2, and sporadic tumors found that BRCA1 tumors were more likely to be BCL2-negative and to express high levels of P-cadherin.[157]

One potentially unifying hypothesis is 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. These tumors characteristically exhibit higher-grade features, areas of necrosis, and frequent TP53 mutations.[158] They are typically estrogen receptor–negative, are HER2-negative, and they stain positive for cytokeratin 5/6, 14, or 17, which are markers of basal epithelium.[159-161] A study of 76 estrogen receptor–negative breast cancers found that those occurring in BRCA1 mutation carriers were significantly more likely (88% vs. 45% in BRCA1-negative subjects) to have a basal epithelial phenotype as determined by cytokeratin 5/6 expression.[158] Two additional studies of invasive breast cancers occurring in BRCA1 mutation carriers not selected for estrogen receptor status found that 78% of 27 tumors [161] and 61% of 182 tumors [162] were positive for basal epithelial markers. 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.[163] If, in fact, the basal epithelial cells of the breast represent the breast stem cells, the suggested regulatory role for wild-type BRCA1, it may partly explain the aggressive phenotype of BRCA1-associated breast cancer when BRCA1 function is damaged.[164] Further studies are needed to fully appreciate the significance of this subtype of breast cancer within the hereditary syndromes.

The phenotypic expression of BRCA1-related breast cancer indicates distinctive prognostic features. A large study of 1,555 women with invasive breast cancer in ten North American centers failed to find the expected correlation of tumor size with lymph node status among carriers of a deleterious BRCA1 mutation, suggesting that these tumors are characterized by an accelerated growth rate.[165] Investigators from the Mayo Clinic reached similar conclusions based on the risk-reducing mastectomy cohort, in whom both in situ and invasive lesions from BRCA1/2 carriers had higher-grade tumors and higher proliferation indices.[149] A Norwegian study reported that breast cancers occurring in BRCA1 mutation carriers were more likely to be invasive, high grade, and estrogen receptor negative.[166] A case-control study among women of Jewish descent also found that BRCA1-associated tumors were significantly more likely to be grade III and estrogen receptor negative.[167] Analysis of tumors from a North American study indicated that the estrogen receptor–negative status of the BRCA1 tumors is an intrinsic feature and not simply a correlate of younger age or higher grade.[168] The Breast Cancer Linkage Consortium compared the histopathologic features of breast cancer in women with BRCA1 mutations to a control group and found an excess of high-grade tumors, high mitotic rates, high proliferative fractions, and increased aneuploidy.[146] They also found an increased frequency of high-intensity immunostaining for p53 in tumors from BRCA1 mutation carriers.[169] A population-based study confirmed the excess of high-grade tumors with high mitotic rates in BRCA1 carriers, but did not find a relative absence of in situ cancers in this group.[148] In a separate study of tumors from women with one of the three Ashkenazi founder mutations, immunohistochemical analysis demonstrated a relatively low rate of HER2/neu positivity and no differences in p53, epidermal growth factor receptor, cathepsin D, bcl-2, or cyclin D staining compared to a control group.[170] A population-based study of incident cases of breast cancer among women in Israel failed to find a difference in prognosis for carriers of BRCA founder mutations compared with noncarriers.[171] Similar findings were seen in a European cohort with no differences in disease-free survival in BRCA1- or BRCA2-associated breast cancers.[172]

In accordance with the poor prognostic features noted histologically for BRCA1-related breast cancer, two European studies reported survival rates that were similar to or worse than sporadic cases, with a significantly increased risk of contralateral breast cancer.[173-175] A case series report found higher rates of both ipsilateral and contralateral breast cancers among BRCA1/2 mutation carriers than among mutation-negative cases.[176] Higher rates of ipsilateral and contralateral breast cancers were also seen in the cohort of Ashkenazi women with founder mutations.[177] That study failed, however, to show a significantly different event-free or overall survival at 5 years compared with nonmutation carriers. A retrospective cohort study of 496 Ashkenazi breast cancer patients from two centers compared the relative survival among the 56 BRCA1/2 mutation carriers followed for a median 116 months. BRCA1 mutations were independently associated with worse disease-specific survival; there was no effect for BRCA2. The poorer prognosis associated with BRCA1 was not observed in women who received chemotherapy.[178]

In summary, there is a growing consensus that BRCA1-related breast cancer presents with clinical, histopathologic, and molecular features, suggesting a more aggressive phenotype. Most clinical outcome studies are consistent with there being a somewhat worse prognosis, especially among women who do not receive chemotherapy. There is no consensus about whether these differences should alter the approach to treating women with BRCA1-related breast tumors.

The phenotype for BRCA2-related tumors appears to be more heterogeneous and is less well-characterized than that of BRCA1. A report from Iceland, where a BRCA2 founder mutation (999del5) accounts for nearly all hereditary breast cancer, found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2-related tumors compared with sporadic controls.[179] 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.[180] Other reports suggest that BRCA2 related tumors include an excess of lobular and tubulolobular histology.[148,181]

Studies of the prognosis of BRCA2 associated breast cancer have not shown substantial differences in comparison with sporadic breast cancer.[182]

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.[183-185] Fallopian tube cancer and papillary serous carcinoma of the peritoneum are also part of the spectrum of BRCA-associated disease.[74,186] 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.[127] Serous carcinoma was also found to be the predominant histologic subtype of intraperitoneal carcinoma among BRCA1/2 carriers in a Dutch case-control study.[187] 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.[183,188] 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, which may ultimately distinguish them histologically.[189]

Despite generally poor prognostic factors, several studies have found an improved survival among ovarian cancer patients with BRCA mutations.[189-194] A nationwide, population-based case-control study in Israel found 3-year survival rates to be significantly better for ovarian cancer patients with BRCA founder mutations, compared with controls.[191] In a retrospective, U.S., hospital-based study (n = 71), BRCA Ashkenazi heterozygotes had a better response to platinum-based chemotherapy, as measured by response to primary therapy, disease-free survival, and overall survival, compared with sporadic cases.[192] A similar study in Japanese patients also found a survival advantage in stage III BRCA1-associated ovarian cancers treated with cisplatin regimens compared with nonhereditary cancers treated in a similar manner.[193] In a U.S. study of Ashkenazi Jewish women with ovarian cancer, those with BRCA mutations had a longer median time to recurrence and an overall improved survival as compared with Ashkenazi Jewish women with ovarian cancer who did not have a BRCA mutation as well as two large groups of advanced stage ovarian cancer clinical trial patients.[194] A U.S. population–based study showed improvement in overall survival in BRCA2, but not in BRCA1, carriers.[195]

In contrast, several studies have not found improved overall survival among ovarian cancer patients with BRCA mutations.[174,196-198] A population-based study from Sweden noted an initial survival advantage in BRCA1-associated cases, but this advantage did not persist after 3 or 4 years.[174] Similarly, a case-control study from the Netherlands found an improvement in short-term (up to 5 years) survival among women with familial ovarian cancer compared to sporadic controls, but no difference in longer-term survival.[196] A study from the United Kingdom found a worse survival rate in ovarian cancer patients with a family history of ovarian cancer, whether or not they had a BRCA mutation, compared with sporadic controls.[197] Finally, a case-control study at the University of Iowa failed to find any survival advantage for women with BRCA1 inactivation, whether by germline mutation, somatic mutation, or BRCA1 promoter silencing.[198] In this study, however, cases (women with BRCA1 inactivation) were matched to controls on several variables, including tumor grade and p53 status, thus possibly minimizing any differences between the two groups.

Further large studies with appropriate control populations will be required to determine whether there is a survival advantage in either BRCA1- or BRCA2-related ovarian cancers.

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.[199] This syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[200,201] 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.[202] 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.

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. In response to DNA damage, p53 protein arrests cells in the G1 phase of the cell cycle, allowing DNA repair mechanisms to proceed before DNA synthesis. The p53 protein is also an active component of programmed cell death.[203] 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.[201] 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.[204]

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.[205,206] 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.[207] 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.[208,209] Germline mutations in PTEN (OMIM), a protein tyrosine phosphatase with homology to tensin, located on chromosome 10q23, are responsible for this 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.[210] 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,[206] 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.[206,211] (Refer to the PDQ summary Genetics of Colorectal Cancer Major Genes section for more information on Cowden syndrome.)

Peutz-Jeghers syndrome (PJS) (OMIM) is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, perioral, and buccal regions, and multiple gastrointestinal polyps, both hamartomatous and adenomatous.[212-214] Mutations in the STK11 gene (OMIM) at chromosome 19p13.3, which appears to function as a tumor suppressor gene,[215] have been identified as one cause of PJS.[216,217] Germline mutations in STK11, also known as LKB1, have been reported and appear to be responsible for about 50% of the cases of PJS.[216-221] A large series of 419 patients had a cumulative incidence of cancer of 85% by age 70 years, commonly affecting the GI tract. In addition, the cumulative risk of breast cancer was 31% by age 60 years; only two ovarian cancers were seen in this series.[222] Elevated cancer risks have also been seen in smaller series and a meta-analysis, including a higher risk of sex cord stromal tumors of the ovary.[223-227]

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