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Title: Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population

Abstract

A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes, BRCA1 and BRCA2. Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative. A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. No germ-line BRCA1 mutations were found. Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative. The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene. 23 refs., 1 fig., 5 tabs.

Authors:
; ;  [1]
  1. Univ. of Cambridge (United Kingdom) [and others
Publication Date:
OSTI Identifier:
518510
Resource Type:
Journal Article
Resource Relation:
Journal Name: American Journal of Human Genetics; Journal Volume: 60; Journal Issue: 2; Other Information: PBD: Feb 1997
Country of Publication:
United States
Language:
English
Subject:
55 BIOLOGY AND MEDICINE, BASIC STUDIES; GENES; GENE MUTATIONS; MUTATION FREQUENCY; SPLICING; MALES; HEREDITARY DISEASES; MAMMARY GLANDS; NEOPLASMS; DISEASE INCIDENCE; GENETICS; EPIDEMIOLOGY; OVARIES

Citation Formats

Friedman, L.S., Gayther, S.A., and Ponder, B.A.J. Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population. United States: N. p., 1997. Web.
Friedman, L.S., Gayther, S.A., & Ponder, B.A.J. Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population. United States.
Friedman, L.S., Gayther, S.A., and Ponder, B.A.J. 1997. "Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population". United States. doi:.
@article{osti_518510,
title = {Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population},
author = {Friedman, L.S. and Gayther, S.A. and Ponder, B.A.J.},
abstractNote = {A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes, BRCA1 and BRCA2. Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative. A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. No germ-line BRCA1 mutations were found. Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative. The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene. 23 refs., 1 fig., 5 tabs.},
doi = {},
journal = {American Journal of Human Genetics},
number = 2,
volume = 60,
place = {United States},
year = 1997,
month = 2
}
  • To estimate the proportion of breast cancer families due to BRCA1 or BRCA2, we performed mutation screening of the entire coding regions of both genes supplemented with linkage analysis of 31 families, 8 containing male breast cancers and 23 site-specific female breast cancer. A combination of protein-truncation test and SSCP or heteroduplex analyses was used for mutation screening complemented, where possible, by the analysis of expression level of BRCA1 and BRCA2 alleles. Six of the eight families with male breast cancer revealed frameshift mutations, two in BRCA1 and four in BRCA2. Although most families with female site-specific breast cancers weremore » thought to be due to mutations in either BRCA1 or BRCA2, we identified only eight mutations in our series of 23 site-specific female breast cancer families (34%), four in BRCA1 and four in BRCA2. According to the posterior probabilities calculated for mutation-negative families, based on linkage data and mutation screening results, we would expect 8-10 site-specific female breast cancer families of our series to be due to neither BRCA1 nor BRCA2. Thus, our results suggest the existence of at least one more major breast cancer-susceptibility gene. 24 refs., 1 fig., 3 tabs.« less
  • The mutations 185delAG, 188del11, and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene were analyzed in 199 Ashkenazi and 44 non-Ashkenazi Jewish unrelated patients with breast and/or ovarian cancer. Of the Jewish Ashkenazi women with ovarian cancer, 62% (13/21) had one of the target mutations, as did 30% (13/43) of women with breast cancer alone diagnosed before the age 40 years and 10% (15/141) of those with breast cancer diagnosed after the age 40 years. Age at ovarian cancer diagnosis was not associated with carrier status. Of 99 Ashkenazi patients with no family history of breast and/ormore » ovarian cancer, 10% carried one of the mutations; in two of them the mutation was proved to be paternally transmitted. One non-Ashkenazi Jewish ovarian cancer patient from Iraq carried the 185delAG mutation. Individual mutation frequencies among breast cancer Ashkenazi patients were 6.7% for 185delAG, 2.2% for 5382insC, and 4.5% for 6174delT, among ovarian cancer patients; 185delAG and 6174delT were about equally common (33% and 29%, respectively), but no ovarian cancer patient carried the 5382insC. More mutations responsible for inherited breast and ovarian cancer probably remain to be found in this population, since 79% of high-incidence breast cancer families and 35% of high-incidence breast/ovarian cancer families had none of the three known founder mutations. 25 refs., 3 figs., 6 tabs.« less
  • The common hereditary forms of breast cancer have been largely attributed to the inheritance of mutations in the BRCA1 or BRCA2 genes. However, it is not yet clear what proportion of hereditary breast cancer is explained by BRCA1 and BRCA2 or by some other unidentified susceptibility gene(s). We describe the proportion of hereditary breast cancer explained by BRCA1 or BRCA2 in a sample of North American hereditary breast cancers and assess the evidence for additional susceptibility genes that may confer hereditary breast or ovarian cancer risk. Twenty-three families were identified through two high-risk breast cancer research programs. Genetic analysis wasmore » undertaken to establish linkage between the breast or ovarian cancer cases and markers on chromosomes 17q (BRCA1) and 13q (BRCA2). Mutation analysis in the BRCA1 and BRCA2 genes was also undertaken in all families. The pattern of hereditary cancer in 14 (61%) of the 23 families studied was attributed to BRCA1 by a combination of linkage and mutation analyses. No families were attributed to BRCA2. Five families (22%) provided evidence against linkage to both BRCA1 and BRCA2. No BRCA1 or BRCA2 mutations were detected in these five families. The BRCA1 or BRCA2 status of four families (17%) could not be determined. BRCA1 and BRCA2 probably explain the majority of hereditary breast cancer that exists in the North American population. However, one or more additional genes may yet be found that explain some proportion of hereditary breast cancer. 19 refs., 1 fig., 3 tabs.« less
  • Genetic epidemiological evidence suggests that mutations in BRCA1 may be responsible for approximately one half of early onset familial breast cancer and the majority of familial breast/ovarian cancer. The recent cloning of BRCA1 allows for the direct detection of mutations, but the feasibility of presymptomatic screening for cancer susceptibility is unknown. We analyzed genomic DNA from one affected individual from each of 24 families with at least three cases of ovarian or breast cancer, using SSCP assays. Variant SSCP bands were subcloned and sequenced. Allele-specific oligonucleotide hybridization was used to verify sequence changes and to screen DNA from control individuals.more » Six frameshift and two missense mutations were detected in 10 different families. A frameshift mutation was detected in a male proband affected with both breast and prostate cancer. A 40-bp deletion was detected in a patient who developed intra-abdominal carcinomatosis 1 year after prophylactic oophorectomy. Mutations were detected throughout the gene, and only one was detected in more than a single family. These results provide further evidence that inherited breast and ovarian cancer can occur as a consequence of a wide array of BRCA1 mutations. These results suggests that development of a screening test for BRCA1 mutations will be technically challenging. The finding of a mutation in a family with male breast cancer, not previously thought to be related to BRCA1, also illustrates the potential difficulties of genetic counseling for individuals known to carry mutations. 37 refs., 1 fig., 1 tab.« less
  • We screened 163 women from breast-ovarian cancer-prone families, as well as 178 individuals affected with breast and/or ovarian cancer but unselected for family history, for germ-line mutations in exon 2 of BRCA1, by SSCP analysis and direct sequencing. A total of 25 mutations were detected. Thirteen of 64 Jewish Ashkenazi women and 2 non-Jewish individuals were found to possess the 185delAG mutation. Haplotype data for all 15 individuals, with markers intragenic to BRCA1, suggest that the Jewish Ashkenazi individuals share a common ancestry that is distinct from the lineage shared by the other two women. These data provide the firstmore » evidence of two distinct lines of transmission for the 185delAG mutation, only one of which has its origins in the Jewish Ashkenazi population. Our screening also uncovered 10 affected individuals with an 11-bp deletion at nucleotide 188 of BRCA1 (188del11), 4 of whom are Ashkenazi Jews. This is only the third reported mutation detected within the Jewish Ashkenazi population and may represent the second most common alteration in BRCA1 found in Ashkenazi Jews in the United States. The observed overrepresentation of specific mutations within a subgroup of the general population may eventually contribute to the development of inexpensive and routine tests for BRCA1 mutations, as well as to the elucidation of other contributory factors (e.g., diet, environment, and chemical exposures) that may play a key role in cancer initiation and development. The implications of the mutational data, as well as the role that founder effect, demographic history, and penetrance play in the resulting observed phenomena, are discussed. 32 refs., 3 figs., 2 tabs.« less