Site-specific Breast Cancer Families Research Articles

RAD51C germline mutations found in Spanish site-specific breast cancer and breast-ovarian cancer families.

BRCA1 and BRCA2 are the most well-known breast and ovarian cancer susceptibility genes. Additional genes involved in DNA repair have been identified as predisposing to breast cancer. Recently, RAD51C, a new Fanconi Anemia gene, essential for homologous recombination repair, has been reported to be a rare hereditary breast and ovarian cancer susceptibility gene. Indeed, several pathogenic mutations have been identified in BRCA1/BRCA2-negative hereditary breast and ovarian cancer families. Here, we present the results of the screening of RAD51C mutations in a large series of 516 BRCA1/BRCA2-negative Spanish patients from breast and/or ovarian cancer families, and the evaluation of these results in the context of all RAD51C carriers. RAD51C mutation screening was performed by DNA analysis for all index cases. All the genetic variants identified were analyzed in silico for splicing and protein predictions. cDNA analysis was performed for three selected variants. All previous RAD51C mutation studies on breast and/or ovarian cancer were reviewed. We identified three inactivating RAD51C mutations. Two mutations were found in breast and ovarian cancer families and one mutation in a site-specific breast cancer family. Based on the mean age of ovarian cancer diagnosis in RAD51C carriers, we would recommend prophylactic bilateral salpingo-ophorectomy in premenopausal RAD51C mutation carriers. Our results support that RAD51C is a rare breast and ovarian cancer susceptibility gene and may contribute to a small fraction of families including breast and ovarian cancer cases and families with only breast cancer. Thus, RAD51C testing should be offered to hereditary breast and/or ovarian cancer families without selecting for specific cancer origin.

BRCA1 and BRCA2 germline mutations in Uruguayan breast and breast–ovarian cancer families. Identification of novel mutations and unclassified variants

The aim of the present study was to analyze BRCA1 and BRCA2 mutations in Uruguayan families with breast and breast/ovarian cancer. Probands from 42 families with at least three cases of female breast cancer (BC) or two cases and subcriteria (paternal transmission, ovarian cancer, bilateral BC, male BC, Ashkenazi Jewish ancestry) in the same lineage, at least one diagnosed before age 50, were screened for germline mutations. PCR amplification of all exons and intron-exon boundaries were performed, followed by protein truncation test, heteroduplex analysis, and direct sequencing. We identified seven different truncating mutations in seven families, five in BRCA2 (three in site-specific BC families and two in breast-ovarian cancer families) and two in BRCA1 (one in a site-specific BC family and the other in a breast-ovarian cancer family). Both BRCA1 mutations (5583insT and 2687T>G) and one of the five BRCA2 mutations (3829insTdel35) were not previously reported. We also detected ten sequence variants of unknown significance, five of them not described before. The low frequency of BRCA1/2 mutations (0.17) is in agreement with that reported in studies which included families with similar selection criteria. However, the observed predominance of BRCA2 (0.12) over BRCA1 mutations (0.05) is in contrast with the higher proportion of BRCA1 mutations communicated for most previous studies, even those with a predominance of site-specific BC families. Meanwhile, it has been described in one Chilean and some Spanish and Italian reports, highlighting the strong dependence between the mutational spectra and the ethnicity of the population analyzed.

No association of miscarriage and BRCA carrier status in Pakistani breast/ovarian cancer patients with a history of parental consanguinity

To the editor About 80% of breast and ovarian cancer families and about 50% of site-specific breast cancer families are due to germ line mutations in either BRCA1 (MIM 113705) or BRCA2 (MIM 600185) [1–3]. Women carrying a pathogenic mutation in BRCA1 or BRCA2 face average lifetime risks of 65% and 45%, respectively, of developing breast cancer, and corresponding ovarian cancer risks of 39% and 11% [4]. In humans, almost all BRCA carriers have been found to be heterozygous [5, 6]. The lack of viable homozygous BRCA mutation carriers in humans suggests that homozygous fetuses may be more susceptible to spontaneous abortions. Further evidence for this hypothesis comes from in vivo animal studies showing that mice homozygous for mutations in the BRCA1 or BRCA2 gene die early in embryogenesis [7, 8]. Two recent studies have explored the impact of BRCA mutation status on the occurrence of miscarriages. One study included BRCA carriers of Ashkenazi Jewish descent [9], and the other included mutation carriers from United States and Canada [10]. Neither study found a significant difference in the rate of miscarriage between BRCA carriers and non-carriers. We conjectured that miscarriages may occur more frequently in BRCA carriers from consanguineous parents since their offspring are more often homozygous by descent compared to those of unrelated parents, and living homozygous BRCA mutation carriers have not been observed. To explore this question, we studied the rates of miscarriages in Pakistani BRCA mutation carriers and non-carriers with a history of parental consanguinity. Pakistan has one of the highest rates of consanguinity in the world (range 60–70%) [11, 12]. Breast and/or ovarian cancer families were recruited at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, between June 2001 and November 2004. Of the 165 female index patients, 30 carried a deleterious BRCA mutation, and 135 were without any identifiable mutation. All families, screening methods and mutations have been described previously [13]. Four additional families carrying a deleterious BRCA mutation identified recently were also included in this study. Relevant information regarding potential breast cancer risk factors including family history of cancer, hormone use, reproductive history, medical history and life style factors was collected by interview-administered questionnaires. Detailed information on the outcome of each pregnancy (year of each pregnancy, number of miscarriages including spontaneous and therapeutic abortions, number of still and live born), and parental consanguinity was collected. Spontaneous abortion was defined as loss of a pregnancy before the completion of 20 gestational weeks from the M. U. Rashid F. Rasheed F. Sultan Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan

Clinical management of BRCA1 and BRCA2 mutation carriers

The cancer susceptibility genes BRCA1 and BRCA2 appear to be responsible for virtually all hereditary breast ovarian families, and a smaller subset of hereditary site-specific breast cancer families. Fortunately, effective strategies have been developed to reduce the risk for the development of breast and ovarian cancer in women with BRCA1/2 mutations, making genetic testing for these mutations an important part of the management at women with a strong family history of these diseases. Here, we review the current evidence for risk reduction strategies and outline future research directions.

Risk of Ovarian Cancer in BRCA1 and BRCA2 Mutation-Negative Hereditary Breast Cancer Families

Women from site-specific hereditary breast cancer families who carry a BRCA1 or BRCA2 mutation are at increased risk for ovarian cancer. It is less clear, however, whether individuals from hereditary breast cancer families who do not carry such a mutation are also at increased ovarian cancer risk. To determine whether women from BRCA mutation-negative hereditary breast cancer families are at increased risk for ovarian cancer, 199 probands from BRCA mutation-negative, site-specific breast cancer kindreds who consented to prospective follow-up at the time of genetic testing were identified. The incidence of new breast and ovarian cancers in probands and their families since receipt of their genetic test results was determined by questionnaire. The expected number of cancers and standardized incidence ratios (SIRs) were determined from age-specific cancer incidence rates from the Surveillance, Epidemiology, and End Results (SEER) program by using the method of Byar. All statistical tests were two-sided. During 2534 women-years of follow-up in 165 kindreds, 19 new cases of breast cancer were diagnosed, whereas only 6.07 were expected (SIR = 3.13, 95% confidence interval [CI] = 1.88 to 4.89; P < .001), and one case of ovarian cancer was diagnosed, whereas only 0.66 was expected (SIR = 1.52, 95% CI = 0.02 to 8.46; P = .48). These results suggest that women from BRCA mutation-negative, site-specific breast cancer families are not at increased risk for ovarian cancer.

Genetic Basis of Familial Endometrial Cancer: Is There More to Learn?

As a result of the reduced incidence of uterine cervical carcinoma associated with screening, carcinoma of the uterine endometrium (EC) has become the most common gynecologic cancer in the United States. As for several other solid tumor types, familial clustering of EC is recognized, although the literature on this topic is relatively sparse and has been slow to materialize. For example, in a 1949 doctoral thesis on the role of heredity in EC, Brobeck concluded that “no hereditary tendency to the development of cancer of the endometrium has ever been observed.” Evidence to counter to this view included case reports of siblings with early-onset EC, now a well-established hallmark of genetic predisposition to cancer generally. Early genetic-based evidence for the potential role of heredity in EC included the observation that blood group A was over-represented in EC patients. More recent epidemiologic studies demonstrated increased relative risks of EC and colorectal cancer in relatives of EC patients. Notably, in the study by Gruber et al, the authors concluded that a family history of EC was an independent risk factor for EC alone, and that 5% of ECs may be attributable to a site-specific EC syndrome. A historic precursor to the seminal advance in our understanding of genetic susceptibility to EC occurred in 1913, when Alfred Warthin, a pathologist at the University of Michigan, described an excess of gastric and uterine cancers in the family of his seamstress, who later died of EC. The ever-expanding pedigree of Warthin’s “cancer family G” was systematically studied during the next six decades by Warthin, his colleagues Hauser and Weller, and finally Henry Lynch et al. The recognition of similar kindreds by Lynch et al in 1966 led to the description of a cancer-prone syndrome that included aggregation of colon, gastric, and notably, endometrial cancers, which they termed the “cancer family syndrome.” In 1984, the terms Lynch syndromes I and II were proposed by Boland and Troncale as corresponding to site-specific familial colorectal cancer and the cancer family syndrome, respectively, without antecedent polyposis. Then, during a 7-year period from 1991 to 1997, a series of advances extraordinary in pace and breadth resulted in the establishment of a clinical definition (the Amsterdam criteria) of what is now known as the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, localization and cloning of the tumor suppressor genes responsible for HNPCC (MSH2, MLH1, and MSH6) all involved in the same pathway of DNA mismatch repair, and characterization at the genetic and biochemical levels of the molecular hallmark of tumors associated with defective mismatch repair, microsatellite instability (MSI). The term HNPCC is now preferable to the historical terms cancer family syndrome and Lynch syndrome(s). Although it remains common to hear health professionals refer to HNPCC as Lynch II, the latter term, although an appropriate tribute to Henry Lynch and his work, propagates confusion and should be avoided because the distinction between Lynch syndromes I and II, as originally proposed, is likely artificial at the genetic level. There is no evidence for a distinct genetic basis for Lynch syndrome I, which likely represents HNPCC with over-representation of colorectal cancers, or in some cases the incomplete or inaccurate ascertainment of family histories. An analogous cancer genetics story evolved over several years after the discovery of the breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2; sitespecific ovarian cancer was soon shown to represent a variant manifestation of the breast and ovarian cancer syndrome, with essentially all such kindreds showing linkage to BRCA1. In contrast, there remains a substantial proportion of site-specific breast cancer families that are apparently not linked to the BRCA1/2 or other known breast cancer susceptibility alleles, and BRCA3 does not appear to be forthcoming. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 21 JULY 2

BRCA1 and BRCA2 mutation analysis of early-onset and familial breast cancer cases in Mexico.

The entire coding regions of BRCA1 and BRCA2 were screened for mutations by heteroduplex analysis in 51 Mexican breast cancer patients. One BRCA1 and one BRCA2 truncating mutation each was identified in the group of 32 (6%) early-onset breast cancer patients (< or =35 years). Besides these two likely deleterious mutations, eight rare variants of unknown significance, mostly in the BRCA2 gene, were detected in six of 32 (19%) early-onset breast cancer cases and in three of 17 (18%) site-specific breast cancer families, one containing a male breast cancer case. No mutations or rare sequence variants have been identified in two additional families including each an early-onset breast cancer case and an ovarian cancer patient. The two truncating mutations (BRCA1 3857delT; BRCA2 2663-2664insA) and six of the rare variants have never been reported before and may be of country-specific origin. The majority of the alterations appeared to be distinct, with only one of them being observed in more than one family.

Absence of evidence for a familial breast cancer susceptibility gene at chromosome 8p12-p22.

Several recent studies indicate that the majority of families with five or fewer cases of breast cancer and no cases of ovarian cancer are not due to BRCA1 or BRCA2. It has been proposed that a further breast cancer susceptibility gene that may account for some of these families is located on chromosome 8p12-p22. We have identified 31 site-specific breast cancer families that have a greater than 80% posterior probability of being due to genes other than BRCA1 or BRCA2. These families have been examined for linkage to 8p12-p22 using markers flanking the putative location of the gene. The overall multi-point LOD score is strongly negative across the whole 44 cM. The individual multi-point LOD score is negative in 23 families and only exceeds 0.5 in a single family (with a multi-point LOD score of 1.22). The maximum heterogeneity LOD score was 0.03 at marker D8S136 with estimated proportion linked (alpha) of 3% (95% CI 0 - 30%). These data do not lend support to the hypothesis that chromosome 8p12-p22 harbours a familial breast cancer susceptibility gene. Oncogene (2000) 19, 4170 - 4173

Frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families.

The purpose of this investigation is to study the frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families. Mutation analysis of BRCA1 and BRCA2 by SSCP was conducted on the 113 breast cancer patients (probands) with at least 1 breast cancer (site-specific breast cancer families, n = 101) or 1 ovarian cancer (breast/ovarian cancer families, n = 12) patient in their first-degree relatives. Fifteen deleterious mutations (13.3%), including 8 nonsense and 7 frameshift mutations, were identified in BRCA1, and 21 deleterious mutations (18.6%), including 8 nonsense, 12 frameshift and 1 splice-site mutations, were identified in BRCA2. In site-specific breast cancer families, mutation frequency of BRCA1 or BRCA2 was high in families with 3 or more breast cancer patients (36%, 9/25), early onset (40 < or = years old) breast cancer patients (38%, 19/50) or bilateral breast cancer patients (40%, 6/15). In breast/ovarian cancer families, mutations of BRCA1 (58.3%, n = 7), but not BRCA2 (0%, n = 0), were observed. BRCA1 codon 63 (TTA to TAA) nonsense mutation and BRCA2 frameshift mutation (5802 del AATT) were observed in 4 and 7 independent families, respectively. Haplotype analysis has suggested that carriers of each of these mutations have common ancestors. These results demonstrate that family profiles are important determinants of risk for carrying a BRCA1 or BRCA2 mutation and that cumulative frequency of BRCA1 and BRCA2 mutations in Japanese breast cancer families (31.9%) is within the range observed in Caucasian breast cancer families. Presence of Japanese founder mutations has also been suggested.

Erratum: Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families

Erratum: Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families

Mutation analysis of the BRCA2 gene in 49 site–specific breast cancer families

The hereditary breast cancer gene BRCA2 was recently cloned and is believed to account for almost half of site-specific breast cancer families and the majority of male breast cancer families. We screened 49 site-specific breast cancer families for mutations in the BRCA2 gene using single strand conformation analysis (SSCA) followed by direct sequencing. We found mutations in eight families, including all four families with male breast cancer. The eight mutations were small deletions with the exception of a single nonsense mutation, an all were predicted to interrupt the BRCA2 coding sequence and to lead to a truncated protein product. Other factors which predicted the presence of a BRCA2 mutation included a case of breast cancer diagnosed at age 35 or below (P = 0.01) and a family history of pancreatic cancer (P = 0.03). Two mutations were seen twice, including a 8535delAG, which was detected in two French Canadian families. Our results suggest the possibility that the proportion of site-specific breast cancer families attributable to BRCA2 may be overestimated.