Wooster et al. (1994) reported a large family from Utah segregating early-onset breast cancer, ovarian cancer, and male breast cancer.
Thorlacius et al. (1995) described a family with multiple cases of male breast cancer but no ... Wooster et al. (1994) reported a large family from Utah segregating early-onset breast cancer, ovarian cancer, and male breast cancer. Thorlacius et al. (1995) described a family with multiple cases of male breast cancer but no increase in female breast cancer. Seven males in 3 generations had breast cancer. Other members of the family had other forms of cancer. Linkage of breast cancer to the BRCA2 region on chromosome 13q was demonstrated and all the affected men shared the same haplotype for BRCA2 markers and loss of the other alleles in their tumors. Early age at first full-term pregnancy and increasing parity are associated with a reduced risk of breast cancer. However, Jernstrom et al. (1999) found that carriers of the BRCA1 and BRCA2 mutations who have children are significantly more likely to develop breast cancer by age 40 than carriers who are nulliparous. Each pregnancy is associated with an increased cancer risk. The authors found that early first pregnancy does not confer protection for carriers of BRCA1 or BRCA2 mutations. Boyd et al. (2000) performed a retrospective cohort study of a consecutive series of 933 ovarian cancers diagnosed and treated at the Sloan-Kettering Cancer Center. This study was restricted to patients of Jewish origin because of the ease of BRCA1 and BRCA2 genotyping in this ethnic group. Of the 189 patients who identified themselves as Jewish, 88 hereditary cases were identified with the presence of a germline founder mutation in BRCA1 or BRCA2. The remaining 101 cases from the same series not associated with a BRCA mutation and 2 additional groups with ovarian cancer from clinical trials were included for comparison. Hereditary cancers were rarely diagnosed before age 40 years and were common after age 60 years, with mean age at diagnosis being significantly younger for BRCA1 versus BRCA2-linked patients (54 vs 62 years). Histology, grade, stage, and success of cytoreductive surgery were similar for hereditary and sporadic cases. The hereditary group had a longer disease-free interval following primary chemotherapy in comparison with the nonhereditary group, with a median time to recurrence of 14 months and 7 months, respectively (P less than 0.001). Those with hereditary cancers had improved survival compared with the nonhereditary group. Boyd et al. (2000) concluded that although BRCA-associated hereditary ovarian cancers in this population have surgical and pathologic characteristics similar to those of sporadic cancers, advanced-stage hereditary cancer patients may survive longer than nonhereditary cancer patients. Age penetrance was greater for BRCA1-linked than for BRCA2-linked cancers in this population.
In families with breast cancer linked to chromosome 13q12, Wooster et al. (1995) identified 6 different germline mutations in the BRCA2 gene (see, e.g., 600185.0001), each causing serious disruption to the open reading frame of the transcriptional unit. ... In families with breast cancer linked to chromosome 13q12, Wooster et al. (1995) identified 6 different germline mutations in the BRCA2 gene (see, e.g., 600185.0001), each causing serious disruption to the open reading frame of the transcriptional unit. In 9 of 18 kindreds with familial breast cancer selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer, Tavtigian et al. (1996) identified potentially deleterious sequence alterations in the BRCA2 gene (see, e.g., 600185.0007). All except 1, a deletion of 3 nucleotides, involved nucleotide deletions that altered the reading frame, leading to truncation of the BRCA2 protein. No missense or nonsense mutations were found. The authors noted that the mutation profile of BRCA2 differs from that of BRCA1: microinsertions and point mutations are about as common in BRCA1 as microdeletions, which predominate in BRCA2. Friedman et al. (1997) analyzed a population-based series of 54 male breast cancer cases from southern California for germline mutations in the BRCA1 and BRCA2 genes. A family history of breast and/or ovarian cancer in at least one first-degree relative was found in 9 patients (17%). A further 7 (13%) reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. The 54 patients showed no germline BRCA1 mutations. On the other hand, 2 of the male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only 1 of the 2 had a family history of cancer, with 1 case of ovarian cancer in a first-degree relative. Casilli et al. (2006) used quantitative multiplex PCR of short fluorescent fragments (QMPSF) to screen for BRCA2 germline rearrangements in 120 families with familial breast cancer who were negative for BRCA1 and BRCA2 mutations. Three novel and distinct BRCA2 deletions were identified in 3 families: deletion of exons 14 through 18, exons 15 and 16, and exons 12 and 13, respectively. Combined with data from the larger cohort of 194 families selected for the study in which 36 BRCA2 mutations were identified, Casilli et al. (2006) estimated that approximately 7.7% of germline BRCA2 mutations are rearrangements, which is similar to the contribution of rearrangements to the mutation spectrum of BRCA1 (approximately 15%). - Modifier Genes In a sample of 10,358 carriers of BRCA1 or BRCA2 gene mutations from 23 studies, Antoniou et al. (2008) observed associations between breast cancer and 2 different SNPs in the FGFR2 (176943) and MAP3K1 (600982) genes in BRCA2 carriers, but not in BRCA1 carriers. A SNP in the TNRC9 gene (TOX3; 611416) showed increased risk in both BRCA2 and BRCA1 carriers. The authors postulated a multiplicative effect for the SNPs on breast cancer risk.
Among 7 large Icelandic breast cancer families, Gudmundsson et al. (1996) found that 5 showed strong evidence of linkage to the BRCA2 region. The maximum 2-point lod scores in the 5 families ranged from 1.06 to 3.19. Furthermore, ... Among 7 large Icelandic breast cancer families, Gudmundsson et al. (1996) found that 5 showed strong evidence of linkage to the BRCA2 region. The maximum 2-point lod scores in the 5 families ranged from 1.06 to 3.19. Furthermore, haplotype analyses revealed a region with identical allele sizes in the families, suggesting to the authors that they inherited the mutation from a common ancestor. Cancer types other than breast cancer occurred in both males and females segregating the affected haplotype in these families. Thorlacius et al. (1996) studied 21 Icelandic families selected on the basis of a high frequency of breast cancer in females or the occurrence of one or more cases of male breast cancer. Strong evidence for linkage to the BRCA2 region was found in 16 families; these families shared a common haplotype in the BRCA2 region, suggesting a founder effect. In all 16 families there was evidence for a 5-bp deletion in exon 9 (999del5; 600185.0010). The authors noted that in the Icelandic population, the 999del5 mutation has been found in individuals with different tumor types including cancer of the prostate, pancreas, ovary, colon, stomach, thyroid, cervix, and endometrium. Barkardottir et al. (2001) constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in 18 Icelandic and 10 Finnish breast and breast-ovarian cancer families with the 999del5 mutation. All the Icelandic families shared a common haplotype covering approximately 0.85 Mb, or 1.7 cM. The common ancestors were estimated to trace back 320 to 1,000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country mainly by Vikings between the years 860 to 1060. Analysis of the Finnish families revealed 2 distinct haplotypes. A rarer haplotype was present in 3 families and shared a core haplotype with the Icelandic haplotype spanning about 200 kb, or 0.5 cM. A more common haplotype was present in 7 Finnish families and shared a region covering about 6 cM. These 7 families originated from 2 geographic regions in Finland: (1) from the same small region as the families segregating the rare haplotype (early settlement region in the southwest of Finland), and (2) from the 'new' settlement region in the most eastern part of the country. The 2 distinct haplotypes in the Finnish families may represent different mutational events. The authors, however, suggested that another possible explanation is a gene conversion (in agreement with the population historical records), and the results may indicate a common ancient origin of the 999del5 mutation in Iceland and Finland. Among 5,318 Jewish subjects, Struewing et al. (1997) found 120 carriers of a BRCA1 or BRCA2 mutation. The BRCA1 mutations studied were 185delAG (113705.0003) and 5382insC (113705.0018); the BRCA2 mutation studied was 6174delT (600185.0009). By the age of 70, the estimated risk of breast cancer among carriers was 56%; of ovarian cancer, 16%; and of prostate cancer, 16%. There were no significant differences in the risk of breast cancer between carriers of BRCA1 mutations and carriers of BRCA2 mutations, and the incidence of colon cancer among the relatives of carriers was not elevated. They concluded that over 2% of Ashkenazi Jews carried mutations in BRCA1 or BRCA2 that conferred increased risks of breast, ovarian, and prostate cancer. Szabo and King (1997) collated information on the population genetics of BRCA1 and BRCA2 in populations from many countries of Europe as well as the U.S., Canada, and Japan. Taillon-Miller et al. (1997) pointed out that complete 46,XX homozygote hydatidiform moles can serve as homozygous controls in the development of single-nucleotide polymorphism (SNP) markers and provide a way to obtain long-range haplotypes and estimate allele frequencies that are useful in population studies. They used 11 diallelic markers in the BRCA2 region of 13q12-q13 to compare polymorphism allele frequencies of Caucasian, Hispanic, and African American populations. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2 mutations, Neuhausen et al. (1998) constructed a haplotype of 10 polymorphic short tandem repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having 1 of 9 recurrent BRCA2 mutations. Six of the individual mutations were estimated to have arisen 400 to 2,000 years ago. In particular, the 6174delT mutation (600185.0009), found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-lod support interval = 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG (113705.0003) mutation, 46 generations, derived from an analogous study of BRCA1 mutations. In general, Neuhausen et al. (1998) found no evidence of multiple origins of identical BRCA2 mutations. Tonin et al. (1998) noted that 4 mutations in BRCA1 and 4 mutations in BRCA2 had been identified in French-Canadian breast cancer and breast/ovarian cancer families from Quebec. To identify founder effects, they examined independently ascertained French-Canadian cancer families for the distribution of these 8 mutations. Mutations were found in 41 of 97 families. Six of 8 mutations were observed at least twice. The BRCA1 4446C-T mutation (113705.0016) was the most common mutation found, followed by the BRCA2 8765delAG mutation (600185.0012). Together, these mutations were found in 28 of 41 families identified as having the mutation. The odds of detection of any of the 4 BRCA1 mutations was 18.7 times greater if one or more cases of ovarian cancer were also present in the family. The odds of detection of any of the 4 BRCA2 mutations was 5.3 times greater if there were at least 5 cases of breast cancer in the family. Interestingly, the presence of a breast cancer case less than 36 years of age was strongly predictive of the presence of any of the 8 mutations screened. Carriers of the same mutation, from different families, shared similar haplotypes, indicating that the mutant alleles were likely to be identical by descent for a mutation in the founder population. The identification of common BRCA1 and BRCA2 mutations could facilitate carrier detection in French-Canadian breast cancer and breast/ovarian cancer families. Wagner et al. (1999) studied the sequence diversity of the BRCA2 gene in 71 breast cancer and breast/ovarian cancer families and 95 control individuals from a wide range of ethnicities. In the 10,257 bp of the coding sequence and the 2,799 bp of the noncoding sequence, 82 sequence variants were identified. Disease-associated mutations were identified in 6 families (8%). Of the 79 sequence variants not obviously associated with disease, 8 were detected only in breast cancer and breast/ovarian cancer families. The 71 remaining variants were identified in both breast cancer and breast/ovarian cancer families and controls. Sixty-three sequence variants (80%) were continent specific; 42% were detected exclusively in Africa, though only 13% of the chromosomes screened were of African origin. Based on the finding of 1 variant in 194 bp in the coding region and 1 variant in 108 bp in the noncoding region, Wagner et al. (1999) concluded that simple sequence variation is a frequent occurrence in the BRCA2 gene. Sarantaus et al. (2001) screened 233 unselected Finnish ovarian carcinoma patients for 12 BRCA1 and 8 BRCA2 mutations identified previously in the Finnish population. Germline mutations of BRCA1/BRCA2 were detected in 13 of the patients (11 in BRCA1 and 2 in BRCA2) and 7 recurrent founder mutations accounted for 12 of the 13 mutations detected (including the 2 BRCA2 mutations). All mutation-positive patients but one had serous or poorly differentiated carcinoma. The presence of breast and ovarian cancer in the same woman and/or early-onset (under 50 years of age) breast cancer was characteristic of the majority (77%) of the mutation carriers. The population of Pakistan has been reported to have the highest rate of breast cancer of any Asian population (excluding Jews in Israel) and one of the highest rates of ovarian cancer worldwide. To explore the contribution of genetic factors to these high rates, Liede et al. (2002) conducted a case-control study of 341 case subjects with breast cancer, 120 case subjects with ovarian cancer, and 200 female control subjects from 2 major cities of Pakistan (Karachi and Lahore). The prevalence of BRCA1 or BRCA2 mutations among case subjects with breast cancer was 6.7%, and that among case subjects with ovarian cancer was 15.8%. Mutations of the BRCA1 gene accounted for 84% of the mutations among case subjects with ovarian cancer and 65% of mutations among case subjects with breast cancer. Most of the detected mutations were unique to Pakistan. Five BRCA1 mutations and 1 BRCA2 mutation were found in multiple case subjects and may represent candidate founder mutations. The penetrance of deleterious mutations in BRCA1 and BRCA2 was comparable to that of Western populations. The cumulative risk of cancer to age 85 years in female first-degree relatives of BRCA1 mutation-positive case subjects was 48%, and it was 37% for first-degree relatives of the BRCA2 mutation-positive case subjects. A higher proportion of case subjects with breast cancer than of control subjects were the progeny of first-cousin marriages (odds ratio = 2.1). The effects of consanguinity were significant for case subjects with early-onset breast cancer (age less than 40 years) (odds ratio = 2.7) and case subjects with ovarian cancer (odds ratio = 2.4). These results suggested that recessively inherited genes may contribute to breast and ovarian cancer risk in Pakistan. Using the population-based Icelandic Cancer Registry database, Tulinius et al. (2002) found that 90 of 887 families (10%) of breast cancer patients had the 999del5 mutation in the BRCA2 gene (600185.0010). Relatives of probands with the mutation had significantly increased relative risk of breast cancer: 7.55, 3.18, and 2.58 for first-, second-, and third-degree relatives, respectively. First- and second-degree relatives of patients with the mutation also had an increased risk for prostate and ovarian cancer. King et al. (2003) determined the risks of breast and ovarian cancer for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. They selected 1,008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%, similar to risks in families with many cases. Risks appeared to be increasing with time: breast cancer risk by 50 years of age among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%. Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers. Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset. Easton et al. (2004) and Wacholder et al. (2004) disputed the conclusions of the report by King et al. (2003) estimating a breast cancer risk by age 70 to be 71%, irrespective of mutation. Both groups suggested bias of ascertainment. King (2004) rebutted these comments, suggesting that their penetrance estimates, at least to age 60, were comparable to those of other reported studies and that only the risk above age 70 was higher in their study, which may reflect a small sample size in that age group. Among 1,098 Ashkenazi Jewish women with breast and/or ovarian cancer, Kadouri et al. (2007) found that those with BRCA1 or BRCA2 founder mutations (329 patients) had a 2.5-fold increased risk of other cancers compared to those without BRCA1/2 mutations. Among specific cancers, BRCA1 carriers had a 3.9-fold increased risk for colon cancer and BRCA2 carriers had an 11.9-fold increased risk for lymphoma, the latter of which may have been related to treatment. Hartikainen et al. (2007) identified 5 different mutations in the BRCA1 or BRCA2 genes in 7 (19.4%) of 36 families with breast/ovarian cancer from eastern Finland. The BRCA2 999del5 mutation was present in 2 families whose ancestry could be traced to a common geographic region in eastern Finland. Another family had the BRCA2 6503delTT mutation (600185.0002). Hall et al. (2009) examined a comprehensive database of BRCA1/BRCA2 testing in the United States compiled over about 10 years (1996 to 2006). Full-sequence testing of the genes was performed in 46,276 women who met eligibility criteria. The largest ethnic subgroup was of Western or Central European ancestry (87.1%), followed by Latin American (4.2%), African (3.8%), Asian (2.6%), Native American (1.3%), and Middle Eastern (1.1%) ancestry. Individuals of Ashkenazi Jewish origin were excluded. Women of non-European descent were younger (mean age of 45.9 years) than European women (mean age of 50 years) at age of testing. Mutations were identified in 12.5% of women overall, but those of African and Latin American ancestries had significantly higher prevalences of deleterious BRCA1 and BRCA2 mutations (15.6% and 14.8%, respectively) compared with women of Western European ancestry (12.1%), primarily because of an increased prevalence of BRCA1 mutations in the former 2 groups. Overall, BRCA1 mutations were more common than BRCA2 mutations for every ethnicity except Asian, in which the frequency was equal (about 6.3% for each gene). The most common recurrent mutation in the BRCA2 gene was 6174delT (600185.0009), accounting for 4.5% of all mutations among Central Europeans.