Novel BRCA1 gene mutations in breast cancer patients from St. Petersburg

Screening of patients with familial breast cancer from St. Petersburg for BRCA1 gene mutations resulted in identification of three mutations (414del3, 276delA, and A622V) and two polymorphisms (P871L and S1436S). Mutations 4146del3 and 276delA are novel, never previously described elsewhere. Deletion 2761delA produces a reading frame shift, premature protein synthesis termination and can cause predisposition for breast cancer. Deletion 414de13 does not cause a frame shift, but can result both in the disappearance of amino acid residue (D1343del) in the BRCA1 protein and in alteration of folding of the protein, entailing loss of its functional activity. Two variants of nucleotide sequence observed in the number of patients were classified as DNA polymorphisms (P871L and S1436S) rather than mutations as they were not tightly associated with the increased risk of breast cancer.     

Prevalence of widespread <Emphasis Type="Italic">BRCA1</Emphasis> gene mutations in patients with familial breast cancer from St. Petersburg

Ten variants different from the canonical nucleotide sequence (GenBank, U14680) has been identified when studying the mutation spectrum in gene BRCA1. Six of them (5382insC, 2963del10, 3819del5, 3875del4, 2274insA, and R1203X) cause premature termination of protein synthesis, thus predisposing to breast cancer. A missense mutation E1250K is presumed to be a factor of predisposition to cancer. We classified three variants of nucleotide sequence found in a number patients as DNA polymorphisms S694S, L771L, and E1038G. The 5382insC and 3819del5 mutations have been recorded in four and two families, respectively. Five of the mutations detected have not been found in Russia before. However, all mutations except for 2963del10 have been found in other populations of the world, which indicates their long evolutionary history. Two mutations found in patients from St. Petersburg (5382insC and 3875del4) have also been found in oncological patients from other regions of the Russian Federation.Translated from Genetika, Vol. 41, No. 3, 2005, pp. 405–410.Original Russian Text Copyright © 2005 by Grudinina, Golubkov, Tikhomirova, Brezhneva, Hanson, Vasilyev, Mandelshtam.     

Novel <Emphasis Type="Italic">BRCA1</Emphasis> gene mutations in breast cancer patients from St. Petersburg

Screening of patients with familial breast cancer from St. Petersburg for BRCA1 gene mutations resulted in identification of three mutations (4146del3, 2761delA, and A622V) and two polymorphisms (P871L and S1436S). Mutations 4146del3 and 2761delA are novel, never previously described elsewhere. Deletion 2761delA produces a reading frame shift, premature protein synthesis termination and can cause predisposition for breast cancer. Deletion 4146del3 does not cause a frame shift, but can result not only in the disappearance of amino acid residue (D1343del) in the BRCA1 protein but also in alteration of folding of the protein, entailing loss of its functional activity. Two variants of nucleotide sequence observed in the number of patients were classified as DNA polymorphisms (P871L and S1436S) rather than mutations as they were not tightly associated with the increased risk of breast cancer.     

Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer.

Previous studies of high-risk breast cancer families have proposed that two major breast cancer-susceptibility genes, BRCA1 and BRCA2, may account for at least two-thirds of all hereditary breast cancer. We have screened index cases from 106 Scandinavian (mainly southern Swedish) breast cancer and breast-ovarian cancer families for germ-line mutations in all coding exons of the BRCA1 and BRCA2 genes, using the protein-truncation test, SSCP analysis, or direct sequencing. A total of 24 families exhibited 11 different BRCA1 mutations, whereas 11 different BRCA2 mutations were detected in 12 families, of which 3 contained cases of male breast cancer. One BRCA2 mutation, 4486delG, was found in two families of the present study and, in a separate study, also in breast tumors from three unrelated males with unknown family history, suggesting that at least one BRCA2 founder mutation exists in the Scandinavian population. We report 1 novel BRCA1 mutation, eight additional cases of 4 BRCA1 mutations described elsewhere, and 11 novel BRCA2 mutations (9 frameshift deletions and 2 nonsense mutations), of which all are predicted to cause premature truncation of the translated products. The relatively low frequency of BRCA1 and BRCA2 mutations in the present study could be explained by insufficient screening sensitivity to the location of mutations in uncharacterized regulatory regions, the analysis of phenocopies, or, most likely, within predisposed families, additional uncharacterized BRCA genes.     

BRCA2 gene mutations in Slovenian male breast cancer patients

Male breast cancer (MBC) is a rare disease, comprising less than 1% of breast cancer patients in Slovenia. Some inherited cases are due to the mutations of BRCA1 or BRCA2 genes. There is no information available about the frequency of BRCA gene mutations in Slovenian MBC population. The purpose of this study was to characterize BRCA germline mutations in Slovenian MBC patients. Forty-one patients who were diagnosed with breast cancer at the Institute of Oncology Ljubljana between 1970 and 2006 were proposed to take part in this study. Of them, 27 agreed to follow a genetic counseling session and 25 patients agreed to provide a blood sample for genetic testing. The BRCA1 and BRCA2 genes from the MBC patients were screened for four highly recurrent mutations in the Slovenian population. When an additional breast cancer case or an ovarian cancer was present in the family, a more extended analysis was performed. No BRCA1 mutations were found. A BRCA2 gene mutation was identified in four MBC patients. Three of them carried the Slovenian founder mutation IVS16-2A>G. All four mutations were confined to the patients with a family history of breast cancer. Among the MBC patients with a family history of breast cancer in the first- or second-degree relatives, the frequency of BRCA2 gene mutation was 50%. The median age of the patients with a BRCA2 gene mutation was 60 years, not significantly different from those without a mutation. The BRCA2 mutations were diagnosed in 16% of our MBC patients.     

Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients.

Based on breast cancer families with multiple and/or early-onset cases, estimates of the lifetime risk of breast cancer in carriers of BRCA1 or BRCA2 mutations may be as high as 85%. The risk for individuals not selected for family history or other risk factors is uncertain. We determined the frequency of the common BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) mutations in a series of 268 anonymous Ashkenazi Jewish women with breast cancer, regardless of family history or age at onset. DNA was analyzed for the three mutations by allele-specific oligonucleotide hybridization. Eight patients (3.0%, 95% confidence interval [CI] 1.5%-5.8%) were heterozygous for the 185delAG mutation, two (0.75%, 95% CI 0.20-2.7) for the 5382insC mutation, and eight (3.0%, 95% CI 1.5-5.8) for the 6174delT mutation. The lifetime risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was calculated to be 36%, approximately three times the overall risk for the general population (relative risk 2.9, 95% CI 1.5-5.8). For the 5382insC mutation, because of the low number of carriers found, further studies are necessary. The results differ markedly from previous estimates based on high-risk breast cancer families and are consistent with lower estimates derived from a recent population-based study in the Baltimore area. Thus, presymptomatic screening and counseling for these common mutations in Ashkenazi Jewish women not selected for family history of breast cancer should be reconsidered until the risk associated with these mutations is firmly established, especially since early diagnostic and preventive-treatment modalities are limited.     

Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families.

We have identified four mutations in each of the breast cancer-susceptibility genes, BRCA1 and BRCA2, in French Canadian breast cancer and breast/ovarian cancer families from Quebec. To identify founder effects, we examined independently ascertained French Canadian cancer families for the distribution of these eight mutations. Mutations were found in 41 of 97 families. Six of eight mutations were observed at least twice. The BRCA1 C4446T mutation was the most common mutation found, followed by the BRCA2 8765delAG mutation. Together, these mutations were found in 28 of 41 families identified to have a mutation. The odds of detection of any of the four BRCA1 mutations was 18.7x greater if one or more cases of ovarian cancer were also present in the family. The odds of detection of any of the four BRCA2 mutations was 5.3x greater if there were at least five cases of breast cancer in the family. Interestingly, the presence of a breast cancer case <36 years of age was strongly predictive of the presence of any of the eight 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 will facilitate carrier detection in French Canadian breast cancer and breast/ovarian cancer families.     

Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: results from three U.S. population-based case-control studies of ovarian cancer.

We investigate the familial risks of cancers of the breast and ovary, using data pooled from three population-based case-control studies of ovarian cancer that were conducted in the United States. We base estimates of the frequency of mutations of BRCA1 (and possibly other genes) on the reported occurrence of breast cancer and ovarian cancer in the mothers and sisters of 922 women with incident ovarian cancer (cases) and in 922 women with no history of ovarian cancer (controls). Segregation analysis and goodness-of-fit testing of genetic models suggest that rare mutations (frequency .0014; 95% confidence interval .0002-.011) account for all the observed aggregation of breast cancer and ovarian cancer in these families. The estimated risk of breast cancer by age 80 years is 73.5% in mutation carriers and 6.8% in noncarriers. The corresponding estimates for ovarian cancer are 27.8% in carriers and 1.8% in noncarriers. For cancer risk in carriers, these estimates are lower than those obtained from families selected for high cancer prevalence. The estimated proportion of all U.S. cancer diagnoses, by age 80 years, that are due to germ-line BRCA1 mutations is 3.0% for breast cancer and 4.4% for ovarian cancer. Aggregation of breast cancer and ovarian cancer was less evident in the families of 169 cases with borderline ovarian cancers than in the families of cases with invasive cancers. Familial aggregation did not differ by the ethnicity of the probands, although the number of non-White and Hispanic cases (N = 99) was sparse.     

Lack of germ-line promoter methylation in BRCA1-negative families with familial breast cancer

Hereditary breast cancer accounts for about 10% of breast cancer in the United States, but high-penetrance, germ-line mutations in BRCA1 and BRCA2 are responsible for less than half of these high-risk families. Epigenetic modification of DNA by promoter methylation can result in a potentially heritable epimutation that silences the gene. Using a highly sensitive technique, we assayed the BRCA1 gene for promoter methylation among 41 BRCA1- and BRCA2-negative women whose personal and family histories indicated a high risk of BRCA mutations (median prior likelihood = 60%) using the BRCAPro model. DNA from 19 women who were "true negatives" for BRCA mutations served as controls. We found no evidence for promoter methylation among the high-risk women who tested negative for germ-line BRCA mutations. Thus, epimutation is an unlikely explanation for hereditary breast cancer in women who test negative for BRCA mutations.     

A clinical case of diagnosis of breast cancer in patients with family history of BRCA mutations 1

BackgroundThe incidence of breast cancer is growing rapidly worldwide (1.7 million new cases and 600,000 deaths per year). Moreover, about 10% of breast cancer cases occur in young women under the age of 45. The aim of the study was to report a rare case of BRCA 1-mutated breast cancer in a young patient with multiple affected relatives. Breast cancer is due to a genetic predisposition with BRCA1 and BRCA2 representing a significant proportion of families with a very high risk of developing the disease over a lifetime of up to 50–80%.Case presentationIn this paper we report a case of a 29-year-old woman with a confirmed diagnosis of left breast carcinoma.ConclusionsMutations of the BRCA1 gene were revealed in the patient, in two of her sisters, brother and brother’s daughter.     

Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer.

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. 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.