Introduction
BRCA1
BRCA2
BRCA1 and BRCA2 Function
Mutations in BRCA1 and BRCA2
Prevalence and Founder Effects
Penetrance of Mutations
Models for Prediction of the Likelihood of a BRCA1 or BRCA2 Mutation
        Population Estimates of the Likelihood of Having a BRCA1 or BRCA2 Mutation
Role of BRCA1 and BRCA2 in Sporadic Cancer
Molecular Correlations
Pathology/Prognosis of Breast Cancer
Pathology/Prognosis of Ovarian Cancer
Li-Fraumeni Syndrome
CHEK2
Cowden’s Syndrome
Ataxia Telangiectasia
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 4 relatives in the same biologic line affected) is not present. In some families, however, inherited factors are clearly the major component of an individual’s cancer risk. We now know that some of these “cancer families” can be explained by specific mutations in single cancer susceptibility genes. The recent isolation of several of these genes associated with a significantly increased risk of breast/ovarian cancer make it possible to identify families who carry mutations in these genes. Mutation carriers who have a risk of developing breast cancer that may exceed 50% comprise no more than 5% to 10% of all breast cancer cases.

Hereditary breast cancer is characterized by early age at onset (on average 5-15 years earlier than sporadic cases), bilaterality, vertical transmission through both maternal and paternal lines, and familial association with tumors of other organs, particularly the ovary and prostate gland.[1-3]

The clinical evidence of an autosomal dominant inherited predisposition to breast cancer has been supported by segregation analysis, a statistical genetics method to determine if a particular trait follows a Mendelian pattern of inheritance. (For more information on criteria of autosomal dominant inheritance, refer to the Introduction section of this summary.)

A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families.[4] When segregation analysis was applied to the Cancer and Steroid Hormone (CASH) data set, goodness-of-fit tests of genetic models provided additional evidence for the existence of a rare autosomal dominant allele associated with increased susceptibility to breast cancer.[5]

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, and PTEN/MMAC1.

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.[6] 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.[1] The BRCA1 gene was subsequently identified by positional cloning methods, and has been found to contain 24 exons that encode a protein of 1,863 amino acids. BRCA1 appears 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.[7]

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 are thought to account for approximately 35% of multiple case breast cancer families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.[8,9] BRCA2 is also a large gene with 27 exons that encode a protein of 3,418 amino acids.[10] 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, with loss of the unmutated allele found in tumor specimens.

Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on 1 copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome. However, in most breast and ovarian cancers that have been studied from mutation carriers, 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.[11,12]

Additional evidence that BRCA1 is a tumor suppressor gene is that overexpression of the BRCA1 protein leads to tumor growth suppression in vitro and in a mouse model, in a fashion similar to the tumor suppressor gene TP53 and the retinoblastoma (RB) gene.[13] While this provides a conceptual framework for understanding the role of mutations in cancer progression, it does little to indicate how these genes normally function to prevent cancer.

However, a variety of evidence now points to BRCA1 and BRCA2 being directly involved in the DNA repair process. Several strategies are used to evaluate gene function. These include comparing the sequence and structure of the protein product to other known genes; determining the tissues, cell types, and stages of the cell cycle in which the protein is expressed; and identifying other proteins with which the protein interacts. Animal models also provide an important tool; in particular, knockout mice provide a way to study the effects of different gene mutations. In this approach, the normal mouse gene coding for the analogous function has been removed, and normal or mutated human genes are then inserted to assess their biological effects. Epidemiological studies can provide important evidence for other factors, both genetic and nongenetic, that modify the effect of BRCA1 and BRCA2 gene mutations. New technical tools for study of gene function are now being developed; for example, microarray techniques that permit the assessment of gene variants or gene expression at multiple gene sites may allow the identification of other gene proteins that interact with or modify the effect of the BRCA1 and BRCA2 protein products.

Taken together, current data suggest that the BRCA1 and BRCA2 protein products interact with each other and with RAD51 and other proteins known to be involved in DNA repair. Loss of DNA repair function is assumed to lead to the accumulation of additional mutations and ultimately to carcinogenesis. Several review articles are available in the literature on BRCA1 and BRCA2 gene function.[14,15]

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described.[16] 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-strand conformational polymorphism (SSCP) analysis and conformation sensitive gel electrophoresis (CSGE), miss nearly a third of the mutations that are detected by DNA sequencing.[17] In addition, large genomic rearrangements are missed by most of the techniques, including direct DNA sequencing, currently used for clinical testing. Such rearrangements are believed to be responsible for 10% to 15% of BRCA1 inactivating mutations.[18]

Approximately 1 in 800 individuals in the general population may carry a pathogenic mutation in BRCA1. The frequency of carriers in selected groups has been measured. 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 3 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%).[19] In a second study, 263 women with familial breast cancer were analyzed.[20] 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.[21]

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, 2 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.[22-25] Altogether, the frequency of these 3 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.[26,27] Additional founder mutations have been described in the Netherlands (BRCA1 2804delAA and several large deletion mutations), Iceland (BRCA2, 995del5), and Sweden (BRCA1, 3171ins5).[28-31]

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 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.[32]

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.[7,21,24,33-49] 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.[7,33,34] 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.[33,34] 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 4 affected relatives in the same biologic lineage). Thus, the penetrance figures derived from the BCLC may not provide a high level of accuracy for individual patients seeking genetic counseling and testing.

In addition to the estimates from multiple-case families and patients from high-risk genetics clinics,[7,33,34,36,38,42,49,50] 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.[24,37,39,40,21,41-48] 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,[24,35,37,40,43,44,46] compared with complete sequencing of the 2 genes required in most populations. The first study of a community-based series was carried out in the Washington, DC, area. Blood samples and family medical histories were collected from more than 5,000 Ashkenazi Jewish individuals.[24] Study participants were tested for 3 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 2-fold increased risk of prostate cancer in BRCA2 mutation carriers.[40,51,52] .

Many subsequent studies, whether in founder or predominantly outbred populations, have estimated breast cancer risks by age 70 years of ~60% or lower and ovarian cancer risks of ~40% or lower, although often with large confidence limits because, even in studies of founder populations, the number of identified mutation carriers is relatively small. Most studies have done molecular testing on the proband only and have done no,[21,24,35,37,40-44,46,47] or limited,[39,49] 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.[48] 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.[47] 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 ovarian 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.

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.[47,48,53-55] While the average breast and ovarian cancer penetrances may not be as high as initially estimated, they are very high, 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 frequent 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.

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.[20,56-61] 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 1 or more male family members.[20,56-58,61]

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 2 primary cancers.
• Ashkenazi Jewish background.[20,56-58]

The likelihood of having a BRCA mutation can vary from one individual to the next based on their country of origin, ethnicity, and family history of cancer. The models outlined in the table titled Characteristics of Common Models for Estimating the Likelihood of a BRCA Mutation take these factors into account and assist in providing tailored risk assessments.

Statistics regarding the percentage of women found to be BRCA mutation carriers among samples of women 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 (.002%).[63]
• Women with breast cancer (all ages): 1 in 50 (2%).[64]
• Women with breast cancer (younger than 40 years): 1 in 11 (9%).[65]
• Men with breast cancer (regardless of age): 1 in 20 (5%).[66]
• Women with ovarian cancer (all ages): 1 in 10 (10%).[21,67]

Among Ashkenazi Jewish individuals (likelihood of having one of 3 founder mutations):

• General Ashkenazi Jewish population: 1 in 40 (2.5%).[24]
• Women with breast cancer (all ages): 1 in 10 (10%).[48]
• Women with breast cancer (younger than 40 years): 1 in 3 (30%-35%).[48,68,69]
• Men with breast cancer (regardless of age): 1 in 5 (19%).[70]
• Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%-41%).[43,71,72]

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 with which to estimate an individual patient’s risk of carrying a mutation. 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. To date, only weak connections have been made between these genes and sporadic breast and ovarian cancer. Studies of tumor tissue from sporadic breast cancers have detected no somatic BRCA1 mutations and a very low frequency of BRCA2 mutations.[73-77] In ovarian cancer tumor tissue, however, BRCA1 mutations appear to occur with some frequency. In an unselected series of 103 ovarian cancers, 7 disease-causing mutations in BRCA1 were found that were not present in normal tissue of these patients.[78] Another series of 221 ovarian cancers analyzed for mutations in BRCA1 identified 15 somatic mutations and 18 tumors with evidence of BRCA1 dysfunction due to hypermethylation.[79]

Since few somatic BRCA1 and BRCA2 mutations are seen in sporadic breast tumors, other mechanisms for the inactivation of these tumor suppressor genes have been investigated. In particular, decreased expression of wild-type BRCA1 may occur on an epigenetic basis, i.e., as a result of DNA methylation or other physiological change that results in loss of gene expression, an event that in turn leads to cancer. In support of this hypothesis, artificially decreasing expression of BRCA1 using antisense oligonucleotides resulted in accelerated growth of mammary epithelial cells in culture.[80] Compared with normal breast epithelium, many breast cancers have low levels of the BRCA1 mRNA, which may result from hypermethylation of the gene promoter.[80-84] Similar findings have not been reported for BRCA2, although the BRCA2 locus on chromosome 13q is the target of frequent loss of heterozygosity (LOH) in breast cancer.[85,86]

Taken together, current pathologic, cytogenetic, and gene expression data suggest not only that inactivation of BRCA1 and BRCA2 plays a role in sporadic cancer, but also that there are biologic differences between BRCA1-related, BRCA2-related, and sporadic breast cancers. A clear understanding of these differences (and similarities) has not yet been reached.[87-91]

Mutations in BRCA1 and BRCA2 confer a highly increased susceptibility to breast and ovarian cancer, but these mutations do not lead to cancer by themselves. The current consensus is that these are “gatekeeper” genes that, when removed, allow other genetic defects to accumulate. The nature of these other molecular events may define the pathway through which BRCA1 and BRCA2 function.

A number of studies have looked at steroid hormone receptor levels in tumors containing BRCA1 and BRCA2 mutations. In most of these studies, BRCA1 cancers were shown to be more often estrogen receptor negative than nonhereditary cancers.[92-96] Some discrepancies exist in these studies that may be attributable to the relatively small sample sizes and the geographically or ethnically defined populations that may all carry the same mutation. This raises the issue of whether specific founder mutations in BRCA1 or BRCA2 such as the Ashkenazi or Icelandic mutations have specifically associated phenotypes.

One such genotype-phenotype correlation that appears significant is with families carrying BRCA2 mutations in a specific region of the gene. From 25 families with BRCA2 mutations, an “ovarian cancer cluster region” was identified in exon 11 bordered by nucleotide 3,035 and 6,629.[9,36] 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.[45] 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.[97] These observations have generally been confirmed in subsequent studies;[47,49,98] however, none of the studies has 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.

Additional evidence exists that this region of BRCA2 contains a specific functional domain. Of the 5 different homozygous BRCA2 knockout mice constructed by independent laboratories, 3 lead to embryonic lethality during the first 10 days of gestation.[99-101] The other 2 knockouts yield viable full-term mice that can survive to adulthood.[102,103] The dramatic difference in phenotype correlates with the position of the BRCA2 mutation. The mice that die in utero contain a truncation in the BRCA2 gene before a series of repeated sequences in the large exon 11, while in those mice that can come to term, some copies of these repeats are retained. The repeats themselves have been shown to be the site of interaction of the Rad51 protein, suggesting that Rad51 binding is critical in determining the function of BRCA2 both during development and neoplasia.[104]

Genetic changes associated with BRCA1- and BRCA2-related cancers are just beginning to be examined. Mutations in TP53 seem to be much more frequent in BRCA1 breast cancers (20/26) and somewhat more frequent in BRCA2-associated breast cancers (10/22) than in grade-matched sporadic cancers (7/20).[105] BRCA mutation-associated cancers contain TP53 mutations not typically found in sporadic breast cancer, and 12 individual hereditary breast cancers were shown to contain more than a single TP53 mutation. This raised the issue that mutations of BRCA1 and BRCA2 may confer a “mutator” phenotype allowing the general accumulation of a high rate of genetic abnormalities. Analysis of the coding sequence from the I-ran and Pancho oncogenes and the a-globin gene revealed no increase in mutations in BRCA mutation-associated breast cancers. In addition, no evidence was seen of the microsatellite instability characteristic of HNPCC associated cancers. Therefore, TP53 inactivation (or perhaps gain of function mutations) may be specifically selected for during BRCA1 and BRCA2 tumor progression.

A genome-wide screening for chromosomal gains or losses was performed on BRCA1 and BRCA2 breast cancers to determine the presence of other associated genetic “hot-spots.”[88] On the whole, BRCA-associated cancers had more regions that were amplified or deleted compared with controls (not stage matched and grade matched), suggesting a generalized increase in large-scale genomic instability. Specifically, chromosomes 5q, 4q, and 4p had very frequent LOH in BRCA1 tumors, while BRCA2 tumors were characterized by losses at 13q (near the BRCA2 locus itself) and 6q and chromosomal gains at 17q (outside of the HER2/neu locus) and 20q. LOH of both chromosomes 13 and 17 have been found simultaneously in a series of sporadic ovarian cancers, suggesting a synergistic mechanism.[106] In addition, the oncogene MYC on chromosome 8q24 was found to be amplified in 48% of 60 BRCA1-related breast cancers versus 14% of non-BRCA1 tumors.[107]

The identification of a histologic pattern characterizing hereditary breast cancer has been elusive, although historically, medullary, tubular, and lobular histologies and improved survival have been associated with familial breast cancer.[108] Others have noted an excess of medullary histology in multicase families.[109,110] Medullary histology was significantly more common (19% versus 0%) in a series of BRCA1-associated breast cancers compared with sporadic cases in a study from France,[111] in carriers from the Breast Cancer Linkage Consortium,[112] and among women with early-onset breast cancer in a population-based study,[113] suggesting that medullary histology itself is an indication for BRCA1 testing.

The phenotype for BRCA2-related tumors appears to be more heterogeneous and is less well characterized than that of BRCA1 to date.[114] A report from Iceland, where a founder effect has been observed in the BRCA2 999del5 mutation, found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2-related tumors compared with sporadic controls.[115] Other reports suggest that BRCA2-related tumors may include an excess of lobular and tubulolobular histology.[113,116] To date, studies of the prognosis of BRCA2-associated breast cancer have not shown substantial differences in comparison with sporadic breast cancer.[117]

The mutation's phenotypic expression of BRCA1-related breast cancer indicates distinctive prognostic features. The Breast Cancer Linkage Consortium examined histopathologic features of breast cancer in women with BRCA1 mutations and, when compared with controls, showed an excess of high-grade tumors in BRCA1 carriers, and a relative lack of in situ component adjacent to invasive lesions. High mitotic rates and high total grade, as well as higher rates of aneuploidy and high proliferative fractions, were also reported for BRCA1 carriers in kindreds being followed. Also noted were higher rates of medullary histology.[118] A Norwegian study also reported that breast cancers occurring in BRCA1 mutation carriers were phenotypically distinct, with invasive, high-grade, estrogen receptor-negative breast cancers.[119] The Breast Cancer Linkage Consortium also found an increased frequency of high-intensity immunostaining for p53 in tumors among BRCA1 mutation carriers.[120] In a separate study, immunohistochemical analysis of BRCA1 and BRCA2 tumors (all Ashkenazi Jewish individuals with one of the 3 founder mutations) 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 with a control group of cancers.[93] Another study used tissue microarray technology to compare BRCA1, BRCA2, and sporadic breast tumors. In addition to the above findings, BRCA1 tumors were more likely to be BCL2 negative and express high levels of P-cadherin. BRCA2 tumors were intermediate between BRCA1 and sporadic tumors.[96]

Another case-control study among women of Jewish descent found that BRCA1-associated tumors were significantly more likely to be grade III and estrogen receptor negative.[121] A population-based study confirmed an 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.[113] A study of 76 ER-negative/erbB-2 negative breast cancers found that those occurring in BRCA1 mutation carriers were significantly more likely to have a basal epithelial phenotype as determined by cytokeratin 5/6 expression.[122] Breast cancers derived from the basal epithelial layer of cells characteristically exhibit higher grade features and frequent TP53 mutations. In accordance with the poor prognostic features noted histologically for BRCA1-related breast cancer, 2 European studies reported survival rates that were similar to or worse than sporadic cases, with a significantly increased risk of contralateral breast cancer.[95,123,124] Encouraging, however, was a report that failed to find a higher rate of local, regional, or distant failure among young women treated with breast-conserving surgery and radiation therapy whose family history was suggestive of hereditary breast cancer compared with a group without a significant family history.[125] On the other hand, a case series report found higher rates of both ipsilateral and contralateral breast cancers among BRCA1/2 mutation carriers compared with mutation negative cases.[126]

Breast cancer is also a component of the rare Li-Fraumeni syndrome (LFS), in which germline mutations of the TP53 gene on chromosome 17p have been documented.[127] This syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[128,129] 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.[130] Brain and adrenal gland tumors were associated with specific sites of missense mutations. Age of 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.[131] 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.[129] 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.

Mutations in TP53 are thought to account for fewer than 1% of breast cancer cases.[132] Because many of the cancers associated with germline TP53 mutations do not lend themselves to early detection, predictive testing of LFS family members has so far been limited and primarily confined to the research setting.

Based on numerous studies, a mutation in the CHEK2 gene appears to be a rare low-penetrance susceptibility allele. The 1100delC mutation was initially identified in a patient with LFS.[133] While other mutations in CHEK2 have been identified in LFS patients, the 1100delC mutation does not appear to be a common cause of this syndrome.[134-140] The deletion was present in 1.2% of the European controls, 4.2% of the European BRCA1/2-negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases. In both Europe and the United States (where the mutation appears to be slightly less common), additional studies have detected the mutation in 4% to 11% of familial cases of breast cancer and overall have found an approximately 1.5-fold to 2-fold increased risk of female breast cancer.[141-144] Because of its low frequency, however, no single study has had sufficient power to detect a statistically significant risk among unselected breast cancer cases. A multicenter combined analysis/reanalysis of nearly 20,000 subjects from 10 case-control studies, however, has verified a significant, 2.3-fold excess of breast cancer among mutation carriers.[145] At least one study has also suggested that the mutation may be associated with both breast and colorectal cancer.[142] Although the initial report suggested that male mutation carriers were at a significantly increased risk of breast cancer,[140] several follow-up studies have failed to confirm the association.[146-149] Additional, larger studies will be required to more precisely define the absolute risk of female breast and other cancers in individuals who carry germline CHEK2 variants.

One of the more than 50 cancer-related genodermatoses, Cowden’s syndrome is characterized by an excess of breast cancer, gastrointestinal malignancies, and thyroid disease, both benign and malignant.[148] Lifetime estimates for breast cancer among women with Cowden’s syndrome range from 25% to 50%. As in other forms of hereditary breast cancer, onset is often at young ages and may be bilateral.[149] 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’s syndrome. Germline mutations in PTEN, 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.[150] Disruption of PTEN appears to occur late in tumorigenesis and may act as a regulatory molecule of cytoskeletal function. Although PTEN accounts 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.[151]

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygote carriers of the ATM gene, which has been localized to chromosome 11q22-23.[152] More than 200 mutations in the gene have been identified to date, most of which are truncating mutations.[153] ATM proteins have been shown to play a role in cell cycle control.[154] In vitro, AT cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.[155]

It is well known that individuals homozygous for ATM are at increased risk of malignancies, especially hematologic. A number of epidemiologic studies have also suggested a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated relative risk of 3.9 to 6.4.[156-158] Studies searching for an excess of ATM mutations among breast cancer patients have provided conflicting results.[159-166] If an association between the heterozygous carrier status and breast cancer is established, it could account for a significant proportion of hereditary breast cancer, given the high heterozygote carrier rate in the population, and could pose a potential risk related to screening-related radiation exposure in these individuals.

Peutz-Jeghers syndrome (PJS) 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.[167-169] Mutations in the STK11 gene at chromosome 19p13.3, which appears to function as a tumor suppressor gene,[170] have been identified as one cause of PJS.[171,172] Germline mutations in STK11, also known as LKB1, have been reported and appear to be responsible for about 50% of the cases of PJS.[171-176] A meta-analysis performed on available reports from the literature concluded that patients with this syndrome have a very high risk of developing breast, gastrointestinal, and other malignancies. Of 210 patients with PJS in this overview, it was estimated that the risk of developing noncutaneous cancer between the ages of 15 years and 64 years is 93%. The highest cumulative risk in these patients was for breast (54%), colon (39%), pancreatic (36%), stomach (29%), and ovarian (21%) cancer. The risk estimates for breast and ovarian cancer are similar to those observed in women carrying BRCA1 or BRCA2 mutations.[177] Multiple case reports have suggested most ovarian cancer cases associated with this syndrome are sex cord stromal tumors, which have a variable behavior, ranging from benign to highly malignant.[178-181]

The identification and location of breast cancer genes permit further investigation of the precise role they play in cancer progression, and will allow us to determine the percentage of total breast cancer caused by the inheritance of mutant genes. This in turn will ultimately enrich our understanding of all breast cancer, sporadic as well as hereditary, and will facilitate the identification of high-risk individuals.

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