Low incidence of BRCA2 mutations in breast carcinoma and other cancers

Teng, Da; Bogden, Robert; Mitchell, Jeffrey T.; Baumgard, Michelle; Bell, Russell; Berry, Simin; Davis, Thaylon; Ha, Phuong C.; Kehrer, Robert; Jammulapati, Srikanth; Chen, Qian; Offit, Kenneth; Skolnick, Mark H.; Tavtigian, Sean V.; Jhanwar, Suresh C.; Swedlund, Brad; Wong, Alexander; Kamb, Alexander

doi:10.1038/ng0696-241

Cited by 145 publications

(80 citation statements)

References 16 publications

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“…LOHs in 13q are relatively frequent in HCCs (up to 49%) and additionally sequence abnormalities in the RB-1 gene have been detected in up to 25% of HCCs (Murakami et al, 1991). Loss of function of the BRCA-2 gene has so far not been described in HCCs, but beside its well-documented role in breast cancer (Wooster et al, 1994(Wooster et al, , 1995, it also occurs in sporadic cancer of the exocrine pancreas (Schutte et al, 1995;Teng et al, 1996), an organ with its cellular origin embryologically closely related to hepatic tissue.…”

Section: Discussionmentioning

confidence: 99%

Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis

Niketeghad

Decker²,

Caselmann

et al. 2001

Br J Cancer

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Summary Hepatocellular carcinoma (HCC) is one of the most frequent-occurring malignant tumours worldwide, but molecular changes of tumour DNA, with the exception of viral integrations and p53 mutations, are poorly understood. In order to search for common macroimbalances of genomic tumour DNA, 21 HCCs and 3 HCC-cell lines were characterized by comparative genomic hybridization (CGH), subsequent database analyses and in selected cases by fluorescence in situ hybridization (FISH). Chromosomal subregions of 1q, 8q, 17q and 20q showed frequent gains of genomic material, while losses were most prevalent in subregions of 4q, 6q, 13q and 16q. Deleted regions encompass tumour suppressor genes, like RB-1 and the cadherin gene cluster, some of them previously identified as potential target genes in HCC development. Several potential growth-or transformation-promoting genes located in chromosomal subregions showed frequent gains of genomic material. The present study provides a basis for further genomic and expression analyses in HCCs and in addition suggests chromosome 4q to carry a so far unidentified tumour suppressor gene relevant for HCC development.

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Section: Discussionmentioning

confidence: 99%

Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis

Niketeghad

Decker²,

Caselmann

et al. 2001

Br J Cancer

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“…However, no consistent pattern of mutation of these genes has been found in sporadic tumor samples (Futreal et al, 1994;Merajver et al, 1995;Miki et al, 1996;Teng et al, 1996;Lancaster et al, 1996). In contrast, the expression of the BRCA1 gene has been reported to be decreased in a variety of sporadic breast tumors, and appears to be correlated with tumor progression (Thompson et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

GA-binding protein α/β is a critical regulator of the BRCA1 promoter

et al. 2000

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Decreased expression of BRCA1 may play a role in the etiology of sporadic breast cancer. Deletion and point mutant analysis of proximal promoter elements in the BRCA1 1a promoter revealed a 22 bp region which was critical for the expression of the promoter in MCF-7 cells, but had a much reduced e ect in T47D cells. The main transcription factor interacting with this site was identi®ed as GABPa/b, and a discrete DNA binding complex was only observed in nuclear extracts from MCF-7 cells. Cotransfection experiments with GABPa and b1 expression vectors produced transactivation of this element in both lines. These results suggest that GABPa/b is a critical activator of BRCA1 expression, and that its activity may di er in human breast cell lines.

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“…18,19 Similarly, only 3 somatic BRCA2 mutations have been detected in 270 primary sporadic breast tumors, 1 frameshift and 2 missense variants with unknown functional significance. 6,8,20,21 One missense and 3 frameshift somatic BRCA2 mutations have been detected in 230 sporadic ovarian cancers. 6,8,15,16 One of the frameshift mutations, 605insA, occurred in a poly(A) microsatellite tract in the BRCA2 region in ovarian tumor that exhibited genome-wide microsatellite instability due to somatic mutation in the hMSH2 gene.…”

mentioning

confidence: 99%

“…6,8,20,21 One missense and 3 frameshift somatic BRCA2 mutations have been detected in 230 sporadic ovarian cancers. 6,8,15,16 One of the frameshift mutations, 605insA, occurred in a poly(A) microsatellite tract in the BRCA2 region in ovarian tumor that exhibited genome-wide microsatellite instability due to somatic mutation in the hMSH2 gene. 16 Somatic BRCA2 mutations have been also detected in 50% of RERϩ (mismatch repair deficiency and replication errors) endometrial carcinomas.…”

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confidence: 99%

Somatic mutations in the BRCA2 gene and high frequency of allelic loss of BRCA2 in sporadic male breast cancer

Kwiatkowska

Teresiak

Breborowicz

et al. 2002

Intl Journal of Cancer

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Breast cancer occurs rarely in men and risk factors for the disease include germline mutations of the BRCA2 gene. High frequency of allelic loss at the BRCA2 locus has been reported in sporadic breast tumors, but somatic mutations of BRCA2 are very rare. Here we report the first case of somatic BRCA2 mutation in male breast cancer with demonstrated loss of heterozygosity. We analyzed a series of 27 archival samples from male breast cancer patients for BRCA2 mutations and loss of heterozygosity at BRCA2 locus. The mutation analysis of BRCA2 gene was performed using SSCA-HA and sequencing methods. PCR was used to detect LOH at 3 highly polymorphic microsatellite markers spanning BRCA2 region on 13q by comparing the allelic pattern in matched tumor and blood DNA samples. In this study LOH at the BRCA2 locus was observed in 82.6% of informative cases, confirming previous observations on high frequency of LOH affecting the BRCA2 region in male breast cancer. We identified 5 somatic BRCA2 mutations in a set of 23 sporadic male breast cancers (21%). Two silent and 1 missense alterations were novel BRCA2 variants. Here we also report first somatic frameshift BRCA2 mutation in male breast cancer 8138del5. In 3 tumors with somatic BRCA2 alterations, 1 missense, 1 silent and frameshift LOH at chromosome 13q12-13 were detected and losses involved a wild-type allele of BRCA2 gene. © 2002 Wiley-Liss, Inc. Key words: male breast cancer; BRCA2; germline mutations; somatic mutations; loss of heterozygosity Carcinoma of the male breast is an uncommon disease, accounting for less than 1% of all malignancies detected in men. The most important risk factor for the disease in both male and female breast cancer seems to be inherited predisposition. Two genes, BRCA1 and BRCA2 account for the disease in large majority of breast cancer families. 1 Unlike BRCA1 mutations, germline mutations of BRCA2 are involved in the development of a considerable number of male breast cancer. [2][3][4][5] LOH on chromosome 13q12-13 was reported in 20-60% of sporadic breast tumors. 6 -8 Such high frequency of allelic loss at BRCA2 locus points to an important role of this gene in the development and progression of sporadic breast cancer. However, in sporadic breast cancers somatic mutations of BRCA2, like BRCA1, are very rare. Here we report the first case of somatic BRCA2 mutation in male breast cancer with demonstrated loss of heterozygosity.We analyzed a series of 27 archival samples from male breast cancer patients for BRCA2 mutations and loss of heterozygosity at BRCA2 locus. Four patients were previously identified as BRCA2 mutation carriers (4T, 8T, 37T and 38T), whereas the other 23 tumors studied were considered sporadic since no germline BRCA2 mutations were found in these male breast cancer patients. 9 Family history data were obtained from each patient. Two mutation carriers (4T and 38T) and 2 patients with sporadic breast cancer (13T and 22T) had a family history of breast cancer in one first-(38T, 13T, 22T) or second-degree (4T) relative...

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Low incidence of BRCA2 mutations in breast carcinoma and other cancers

Cited by 145 publications

References 16 publications

Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis

Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis

GA-binding protein α/β is a critical regulator of the BRCA1 promoter

Somatic mutations in the BRCA2 gene and high frequency of allelic loss of BRCA2 in sporadic male breast cancer

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