Significant Contribution of Germline BRCA2 Rearrangements in Male Breast Cancer Families

Centre Léon Bérard, Lyons, Rhône-Alpes, France
Cancer Research (Impact Factor: 9.33). 12/2004; 64(22):8143-7. DOI: 10.1158/0008-5472.CAN-04-2467
Source: PubMed


Although screening for large deletions or duplications of the BRCA1 gene is becoming a routine component of the molecular diagnosis of familial breast cancer, little is known about the occurrence of such rearrangements in the BRCA2 gene. Because of the high frequency of BRCA2 mutations in breast cancer families with at least one case of male breast cancer, we selected a cohort of 39 such families, tested negative for mutations in the coding regions of BRCA1 and BRCA2, and developed an assay for BRCA2 rearrangements, based on quantitative multiplex PCR of short fluorescent fragments (QMPSF). We found three rearrangements: (1) a deletion of exons 12 and 13; (2) a duplication of exons 1 and 2; and (3) a complete deletion of BRCA2. We determined the boundaries of the deletion of exons 12 and 13, showing that it resulted from an unequal recombination between Alu sequences. We mapped the complete BRCA2 deletion, which extends over at least 298 kb and showed that it does not affect APRIN/AS3, previously characterized as a tumor suppressor gene, but it comprises several loci corresponding to proven or putative transcripts of unknown functional significance. These data suggest that screening for BRCA2 rearrangements should be done, especially in male breast cancer families tested negative for BRCA1 and BRCA2 mutations.

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Available from: Isabelle Tournier
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    • "APC Colon cancer L1 Germline [26] APC L1 Somatic [27] BRCA1, breast cancer 1 gene Breast/ovarian cancer Alu Germline [31] BRCA2, breast cancer 2 gene Breast/ovarian cancer Alu Germline [30] [31] MYC, c-myc proto-oncogene Breast carcinoma L1 Somatic [24] NF1, neurofibromatosis 1 gene Neurofibroma Alu Germline [29] Chromosomal deletions VHL, von Hippel Lindau gene von Hippel Lindau disease Alu Germline [43] [44] BRCA1 Breast/ovarian cancers Alu Germline [32] [33] BRCA2 Breast/ovarian cancers Alu Germline [33] [35] CDH1, cadherin 1 gene Hereditary diffuse gastric cancer Alu Germline [45] CAD, caspase activated DNase gene Hepatoma Alu Somatic [46] Chromosomal duplication MLL1, myeloid/lymphoid mixed lineage leukemia gene Acute myeloid leukemia Alu Somatic [37] [38] MYB, myb transcription factor gene T-acute lymphoblastic lymphoma Alu Somatic [41] BRCA1 Breast/ovarian cancers Alu Germline [33] [34] Chromosomal translocation EWSR1-ETV, t(5q23q31)(18q12) Ewing sarcoma Alu Somatic [42] BCR-ABL, t(9;22)(q34;q11) Chronic myeloid leukemia Alu Somatic [36] Author's personal copy between the flanking Alu elements on sister chromatids in T cell acute lymphoblastic leukemia [41]. Finally, recombination between Alu elements, which causes a translocation involving the Tre-2 oncogene (TRE-USP6, ubiquitin-specific protease-6), has been shown to play an important role in Ewing sarcoma development [42]. "
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    • "Similarly, large rearrangements in other breast cancer predisposition genes seem to be infrequent. A few BRCA2 deletions have been previously reported in families with male breast cancer [26], and contribute to inactivate this gene in breast cancer families [21,27]. Rearrangements affecting the BRCA2 gene have also been reported in breast/sarcoma families, causing a Li–Fraumeni type of cancer pattern [16]. "
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    • "Large genomic rearrangements may account for 3%–15% of all BRCA1 and BRCA2 mutations.38 The higher density of Alu repeat sequences in BRCA1 and both Alu and non-Alu repetitive DNA in BRCA2 are thought to contribute to the large number of deletions and duplications observed in these genes.37,40–43 The frequency of large BRCA1 genomic rearrangements in families with a strong family history of breast and/or ovarian cancer, varies greatly (0%–36%) in different populations.37–39 "
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