Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels.

08:00 EDT 29th March 2019 | BioPortfolio

Summary of "Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels."

Multigene panels provide a powerful tool for analyzing several genes simultaneously. We evaluated the frequency of pathogenic variants (PV) in customized pre-defined panels according to clinical suspicion by phenotype and compared it to the yield obtained in the analysis of our clinical research gene panel. We also investigated mutational yield of opportunistic testing of BRCA1/2 and mismatch repair (MMR) genes in all patients. A total of 1205 unrelated probands with clinical suspicion of hereditary cancer were screened for germline mutations using panel testing. Overall, 1048 females and 157 males were analyzed, mean age at cancer diagnosis was 48; 883 had hereditary breast/ovarian cancer-suspicion, 205 hereditary non-polyposis colorectal cancer (HNPCC)-suspicion, 73 adenomatous-polyposis-suspicion and 44 with other/multiple clinical criteria. At least one PV was found in 150 probands (12%) analysed by our customized phenotype-driven panel. Tumoral MMR deficiency predicted for the presence of germline MMR gene mutations in patients with HNPCC-suspicion (46/136 vs 0/56 in patients with and without MMR deficiency, respectively). Opportunistic testing additionally identified 5 MSH6, 1 BRCA1 and 1 BRCA2 carriers (0.6%). The analysis of the extended 24-gene panel provided 25 additional PVs (2%), including in 4 out of 51 individuals harboring MMR-proficient colorectal tumors (2 CHEK2 and 2 ATM). Phenotype-based panels provide a notable rate of PVs with clinical actionability. Opportunistic testing of MMR and BRCA genes leads to a significant straightforward identification of MSH6, BRCA1 and BRCA2 mutation carriers, and endorses the model of opportunistic testing of genes with clinical utility within a standard genetic counseling framework. This article is protected by copyright. All rights reserved.


Journal Details

This article was published in the following journal.

Name: International journal of cancer
ISSN: 1097-0215


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Medical and Biotech [MESH] Definitions

A large, nuclear protein, encoded by the BRCA2 gene (GENE, BRCA2). Mutations in this gene predispose humans to breast and ovarian cancer. The BRCA2 protein is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (from Genes Dev. 2000;14(11):1400-6)

Eukaryotic homolog of the bacterial MutL DNA MISMATCH REPAIR protein. It heterodimerizes with MISMATCH REPAIR ENDONUCLEASE PMS2 to form MutL alpha, which is recruited to DNA mismatch sites by the MUTS DNA MISMATCH-BINDING PROTEIN. Mutations in the human MLH1 gene are associated with COLORECTAL NEOPLASMS, HEREDITARY NONPOLYPOSIS.

A MutL protein and component of the DNA MISMATCH REPAIR system. Its ENDONUCLEASE activity introduces SINGLE-STRAND DNA BREAKS which create entry points for EXO1 exonuclease to remove the strand containing the mismatch. It may also function in DNA DAMAGE signaling.

DNA repair proteins that include the bacterial MutL protein and its eukaryotic homologs. They consist of a conserved N-terminal region with weak ATPase activity, an endonuclease motif, and a C-terminal domain that forms MutL homodimers or heterodimers between MLH1 and the PMS1, MISMATCH REPAIR ENDONUCLEASE PMS2; or MLH3 proteins. These complexes function in DNA repair pathways, primarily DNA MISMATCH REPAIR, where MutL/MLH1 and the MUTS DNA MISMATCH-BINDING PROTEIN are targeted to damaged DNA.

A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human chromosome 13 at locus 13q12.3. Mutations in this gene predispose humans to breast and ovarian cancer. It encodes a large, nuclear protein that is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (from Genes Dev 2000;14(11):1400-6)

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