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

ABSTRACT 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, Sep 29, 2015
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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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    ABSTRACT: Transposable elements are present in almost all genomes including that of humans. These mobile DNA sequences are capable of invading genomes and their impact on genome evolution is substantial as they contribute to the genetic diversity of organisms. The mobility of transposable elements can cause deleterious mutations, gene disruption and chromosome rearrangements that may lead to several pathologies including cancer. This mini-review aims to give a brief overview of the relationship that transposons and retrotransposons may have in the genetic cause of human cancer onset, or conversely creating protection against cancer. Finally, the cause of TE mobility may also be the cancer cell environment itself.
    Biochimica et Biophysica Acta 09/2012; 1835(1):28-35. DOI:10.1016/j.bbcan.2012.09.001 · 4.66 Impact Factor
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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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    ABSTRACT: Background Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors. Due to the high frequency of breast cancer in LFS/LFL families, these syndromes clinically overlap with hereditary breast cancer (HBC). Germline point mutations in BRCA1, BRCA2, and TP53 genes are associated with high risk of breast cancer. Large rearrangements involving these genes are also implicated in the HBC phenotype. Methods We have screened DNA copy number changes by MLPA on BRCA1, BRCA2, and TP53 genes in 23 breast cancer patients with a clinical diagnosis consistent with LFS/LFL; most of these families also met the clinical criteria for other HBC syndromes. Results We found no DNA copy number alterations in the BRCA2 and TP53 genes, but we detected in one patient a 36.4 Kb BRCA1 microdeletion, confirmed and further mapped by array-CGH, encompassing exons 9–19. Breakpoints sequencing analysis suggests that this rearrangement was mediated by flanking Alu sequences. Conclusion This is the first description of a germline intragenic BRCA1 deletion in a breast cancer patient with a family history consistent with both LFL and HBC syndromes. Our results show that large rearrangements in these known cancer predisposition genes occur, but are not a frequent cause of cancer susceptibility.
    BMC Cancer 06/2012; 12(1):237. DOI:10.1186/1471-2407-12-237 · 3.36 Impact Factor
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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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    ABSTRACT: Breast cancer is the most common cancer among women, accounting for about 30% of all cancers. In contrast, breast cancer is a rare disease in men, accounting for less than 1% of all cancers. Up to 10% of all breast cancers are hereditary forms, caused by inherited germ-line mutations in "high-penetrance," "moderate-penetrance," and "low-penetrance" breast cancer susceptibility genes. The remaining 90% of breast cancers are due to acquired somatic genetic and epigenetic alterations. A heterogeneous set of somatic alterations, including mutations and gene amplification, are reported to be involved in the etiology of breast cancer. Promoter hypermethylation of genes involved in DNA repair and hormone-mediated cell signaling, as well as altered expression of micro RNAs predicted to regulate key breast cancer genes, play an equally important role as genetic factors in development of breast cancer. Elucidation of the inherited and acquired genetic and epigenetic alterations involved in breast cancer may not only clarify molecular pathways involved in the development and progression of breast cancer itself, but may also have an important clinical and therapeutic impact on improving the management of patients with the disease.
    The Application of Clinical Genetics 11/2011; 4:145-58. DOI:10.2147/TACG.S13226
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