Low-Penetrance Predisposition to Breast and Ovarian Cancer

Background
Breast Cancer Susceptibility Genes Identified Through Candidate Gene Approaches
        CHEK2
        ATM
        BRIP1
        PALB2
        CASP8 and TGFB1
        RAD51C
Genome-Wide Searches

Mutations in BRCA1, BRCA2, and the genes involved in other rare syndromes discussed in the Major Genes section of this summary account for less than 25% of the familial risk of breast cancer.[1] Despite intensive genetic linkage studies, there do not appear to be other BRCA1/BRCA2-like high-penetrance genes that account for a significant fraction of the remaining multiple-case familial clusters.[2] These observations suggest that the remaining breast cancer susceptibility is polygenic in nature, meaning that a relatively large number of low-penetrance genes are involved.[3] On its own, each low-penetrance locus would be expected to have a relatively small effect on breast cancer risk and would not produce dramatic familial aggregation or influence patient management. However in combination with other genetic loci and/or environmental factors, particularly given how common these can be, variants of this kind might significantly alter breast cancer risk. These types of genetic variations are sometimes referred to as “polymorphisms,” meaning that the gene or locus occurs in several “forms” within the population (and more formally defined as polymorphic when a specific variation in a given locus occurs in more than 1% of the population). Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed “disease-associated polymorphisms” or “functionally relevant polymorphisms.” This polygenic model of susceptibility is consistent with the observed patterns of familial aggregation of breast cancer.[4] Although the clinical significance and causality of associations with breast cancer are often difficult to evaluate and establish, genetic polymorphisms may account for why some individuals are more sensitive than others to environmental carcinogens.[5]

Polymorphisms underlying polygenic susceptibility to breast cancer are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to “high-penetrance” variants or alleles that are typically associated with more severe phenotypes, for example those BRCA1/BRCA2 mutations leading to an autosomal dominant inheritance patterns in a family. The definition of a “moderate” risk of cancer is arbitrary, but it is usually considered to be in the range of a relative risk of 1.5 to 2.0. Because these types of sequence variants (also called low-penetrance genes, alleles, mutations, and polymorphisms) are relatively common in the general population, their contribution to cancer risk overall is estimated to be much greater than the attributable risk in the population from mutations in BRCA1 and BRCA2. For example, it is estimated by segregation analysis that half of all breast cancer occurs in 12% of the population that is deemed most susceptible.[3] There are no known low-penetrance variants in BRCA1/BRCA2. The N372H variation in BRCA2, initially thought to be a low-penetrance allele, was not verified in a large combined analysis.[6]

Two strategies have been taken to identify low-penetrance polymorphisms leading to breast cancer susceptibility: candidate gene and genome-wide searches. Both involve the epidemiologic case-control study design. The candidate gene approach involves selecting genes based on their known or presumed biological function, relevance to carcinogenesis or organ physiology, and searching for or testing known genetic variants for an association with cancer risk. This strategy relies on imperfect and incomplete biological knowledge, and, despite some confirmed associations (described below), has been relatively disappointing [6,7] The candidate gene approach has largely been replaced by the genome-wide association studies (GWAS) in which a very large number of single nucleotide polymorphisms (SNPs) (potentially 1 million or more) are chosen within the genome and tested, mostly without regard to their possible biological function, but instead to capture all genetic variation throughout the genome more uniformly.

There is a very large literature of genetic epidemiology studies describing associations between various loci and breast cancer risk. Many of these studies suffer from significant design limitations. Perhaps as a consequence, most reported associations do not replicate in follow-up studies. This section is not a comprehensive review of all reported associations. This section describes associations that are believed by the editors to be clinically valid, in that they have been described in several different studies or are supported by robust meta-analyses. The clinical utility of these observations remains unclear, however, as the risks associated with these variations usually fall below a threshold that would justify a clinical response.

CHEK2 (OMIM) is a gene involved in the DNA damage repair response pathway. Based on numerous studies, a polymorphism, 1100delC, appears to be a rare, moderate-penetrance cancer susceptibility allele.[8-13] One study identified the mutation in 1.2% of the European controls, 4.2% of the European BRCA1/BRCA2-negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases.[8] In a group of 1,479 Dutch women younger than 50 years with invasive breast cancer, 3.7% were found to have the CHEK2 1100delC mutation.[14] In additional European and U.S. (where the mutation appears to be slightly less common) studies, including a large prospective study,[15] the frequency of CHEK2 mutations detected in familial breast or ovarian cancer cases has ranged from 0% [16] to 11%; overall, these studies have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer.[15,17-20] A multicenter combined analysis and reanalysis of nearly 20,000 subjects from ten case-control studies, however, has verified a significant 2.3-fold excess of breast cancer among mutation carriers.[21]

Two studies have suggested that the risk associated with a CHEK2 1100delC mutation was stronger in the families of probands ascertained because of bilateral breast cancer.[22,23] Furthermore, a meta-analysis of 1100delC mutation carriers estimated the risk of breast cancer to be 42% by age 70 years in women with a family history of breast cancer.[24] Similarly, a Polish study reported that CHEK2 truncating mutations confer breast cancer risks based on a family history of breast cancer as follows: no family history: 20%; one second-degree relative: 28%; one first-degree relative: 34%; and both first- and second-degree relatives: 44%.[25] Although there have been conflicting reports regarding cancers other than breast cancer associated with CHEK2 mutations, this may be dependent on mutation type (i.e., missense vs. truncating) or population studied and is not currently of clinical utility.[13,18,26-31] The contribution of CHEK2 mutations to breast cancer may depend on the population studied, with a potentially higher mutation prevalence in Poland.[32] CHEK2 mutation carriers in Poland may be more susceptible to ER-positive breast cancer.[33]

Currently, the clinical applicability of CHEK mutations remains uncertain because of low mutation prevalence and lack of guidelines for clinical management.[34]

Ataxia telangiectasia (AT) (OMIM) 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 ATM mutations (OMIM).[35] More than 300 mutations in the gene have been identified to date, most of which are truncating mutations.[36] ATM proteins have been shown to play a role in cell cycle control.[37-39] In vitro, AT-deficient cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.[40]

Initial studies searching for an excess of ATM mutations among breast cancer patients provided conflicting results, perhaps due to study design and mutation testing strategies.[41-51] However, two large epidemiologic studies have demonstrated a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated relative risk of approximately 2.0.[51,52] Despite this convincing epidemiologic association, the clinical application of testing for ATM mutations is unclear due to the wide mutational spectrum and the logistics of testing. Because the presence of a mutation could pose a risk in screening-related radiation exposure, further investigation is needed.

BRIP1 (also known as BACH1) encodes a helicase that interacts with the BRCT domain of BRCA1. This gene also has a role in BRCA1-dependent DNA repair and cell cycle checkpoint function. Biallelic mutations in BRIP1 are a cause of Fanconi anemia,[53-55] much like such mutations in BRCA2. Inactivating mutations of BRIP1 are associated with an increased risk of breast cancer. In one study, more than 3,000 individuals from BRCA1/BRCA2 mutation negative families were examined for BRIP1 mutations. Mutations were identified in 9 of 1,212 individuals with breast cancer but in only 2 of 2,081 controls (P = .003). The relative risk of breast cancer was estimated to be 2.0 (95% confidence interval [CI], 1.2–3.2; P = .012). Of note, in families with BRIP1 mutations and multiple cases of breast cancer, there was incomplete segregation of the mutation with breast cancer, consistent with a low penetrance allele and similar to that seen with CHEK2.[56]

PALB2 (partner and localizer of BRCA2) interacts with the BRCA2 protein and plays a role in homologous recombination and double-stranded DNA repair. Similar to BRIP1 and BRCA2, biallelic mutations in PALB2 have also been shown to cause Fanconi anemia.[57] PALB2 mutations have been screened for in multiple small studies of familial and early-onset breast cancer in multiple populations.[58-68] Mutation prevalence has ranged from 0.4% to 3.4%. Similar to BRIP1 and CHEK2, there was incomplete segregation of PALB2 mutations in families with hereditary breast cancer.[59] A Finnish PALB2 founder mutation (c.1592delT) has been reported to confer a 40% risk of breast cancer to age 70 years [60] and is associated with a high incidence (54%) of triple-negative disease and lower survival.[61] Mutations have been observed in early-onset and familial breast cancer in many populations.[62,63]

Male breast cancer has been observed in PALB2 mutation–positive breast cancer families.[58,64] In a study of 115 male breast cancer cases in which 18 men had BRCA2 mutations, an additional two men had either a pathogenic or predicted pathogenic PALB2 mutation (accounting for about 10% of germline mutations in the study and 1%–2% of the total sample).[58] Following the identification of PALB2 mutations in pancreatic tumors and the detection of germline mutations in 3% of 96 familial pancreatic patients,[69] numerous studies have pointed to a role for PALB2 in pancreatic cancer. A sixfold increase in pancreatic cancer was observed in the relatives of 33 BRCA1/2-negative, PALB2 mutation–positive breast cancer probands.[64] PALB2 mutations were detected in 3.7% of 81 familial pancreatic cancer families [70] and in 2.1% of 94 BRCA1/2 mutation–negative breast cancer patients who had either a personal or family history of pancreatic cancer.[71] Two relatively small studies, one of 77 BRCA1/2 mutation–negative probands with a personal or family history of pancreatic cancer, one-half of whom were of Ashkenazi Jewish descent, and another study of 29 Italian pancreatic cancer patients with a personal or family history of breast or ovarian cancer, failed to detect any PALB2 mutations.[72,73]

The observed prevalence of PALB2 mutations in familial breast cancer varied depending on ascertainment relative to personal and family history of pancreatic and ovarian cancers, but in all studies, the observed mutation rate was less than 4%. The relative risk of breast cancer appears moderate, and the risk of other cancers (e.g., pancreatic) is poorly defined; therefore, the clinical utility of testing is not clear. There is insufficient evidence to support routine screening of PALB2 when tests of the more common genes, namely BRCA1/2, are negative.

The Breast Cancer Association Consortium (BCAC) investigated single nucleotide polymorphisms identified in previous studies as possibly associated with excess breast cancer risk in 15,000 to 20,000 cases and 15,000 to 20,000 controls. Two SNPs, CASP8 D302H and TGFB1 L10P, were associated with invasive breast cancer with relative risks of 0.88 (95% CI, 0.84–0.92) and 1.08 (95% CI, 1.04–1.11) respectively.[74]

RAD51C is involved in DNA damage repair through homologous recombination and interaction with numerous DNA repair proteins. Like PALB2 and BRCA2, the RAD51C gene has been evaluated as a breast and ovarian cancer susceptibility gene and as one of the causes of Fanconi anemia. Despite a possible role in German breast-ovarian cancer families and a single German family with Fanconi anemia–like features,[75,76] most studies have not found an association between RAD51C and heritable breast and ovarian cancer.[77,78] It is unclear what role this gene may play in breast and ovarian cancer susceptibility.

In contrast to assessing candidate genes and/or alleles, genome wide association studies involve comparing a very large set of genetic variants spread throughout the genome. The current paradigm uses sets of 100,000 to 1 million SNPs that are chosen to capture a large portion of common variation within the genome based on the HapMap project.[79,80] By comparing allele frequencies between a large number of cases and controls, typically 1,000 or more of each, and validating promising signals in replication sets of subjects, very robust statistical signals of association have been obtained.[81-83] The strong correlation between many SNPs that are physically close to each other on the chromosome (linkage disequilibrium) allows one to “scan” the genome for susceptibility alleles even if the biologically relevant variant is not within the tested set of SNPs. While this between-SNP correlation allows one to interrogate the majority of the genome without having to assay every SNP, when a validated association is obtained, it is not usually obvious which of the many correlated variants is causal.

Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases,[84] including breast cancer.[85-88] The first study involved an initial scan in familial breast cancer cases followed by replication in two large sample sets of sporadic breast cancer, the final being a collection of over 20,000 cases and 20,000 controls from the BCAC, an international group of investigators.[85] Five distinct genomic regions were identified that were within or near the FGFR2, TNRC9, MAP3K1, and LSP1 genes or at the chromosome 8q region. The 8q region and others may harbor multiple independent loci associated with risk, but these regions are included only once in Table 6. Subsequent genome-wide studies have replicated these loci and identified additional ones, as summarized in Table 6.[86,87,89,89-94] SNPs identified through large studies of sporadic breast cancer appear to be associated more strongly with estrogen receptor–positive disease;[95] however, some are associated primarily or exclusively with other subtypes, including triple-negative disease.[96,97] An online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs) is available.

Although the statistical evidence for an association between genetic variation at these loci and breast and ovarian cancer risk is overwhelming, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk (typically, odds ratio <1.5), with more risk variants likely to be identified. No interaction between the SNPs and epidemiologic risk factors for breast cancer have been identified.[116,117] At this time, because their individual and collective influences on cancer risk have not been evaluated prospectively, they are not considered clinically relevant. Furthermore, theoretical models have suggested that common moderate-risk SNPs have limited potential to improve models for individualized risk assessment.[118-120] These models used receiver operating characteristic (ROC) curve analysis to calculate the area under the curve (AUC) as a measure of discriminatory accuracy. A more recent study used ROC curve analysis to examine the utility of SNPs in a clinical dataset of greater than 5,500 breast cancer cases and nearly 6,000 controls, using a model with traditional risk factors compared to a model using both standard risk factors and ten previously identified SNPs. The addition of genetic information modestly changed the AUC from 58% to 61.8%, a result that was not felt to be clinically significant. Despite this, 32.5% of patients were in a higher quintile of breast cancer risk when genetic information was included, and 20.4% were in a lower quintile of risk. It remains unclear whether such information has clinical utility.[118,121]

More limited data are available regarding ovarian cancer risk. Three GWAS involving staged analysis of over 10,000 cases and 13,000 controls have been carried out for ovarian cancer.[112,113,115] The seven loci that reached genome-wide significance are shown in Table 7. As in other GWAS, the odds ratios are modest, generally about 1.2 or weaker, but implicate a number of genes with plausible biological ties to ovarian cancer, such as BABAM1, whose protein complexes with and may regulate BRCA1, and TIRAPR, which codes for a poly (ADP-ribose) polymerase (PARP), molecules that may be important in BRCA1/BRCA2-deficient cells.

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