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. 2020 Mar 30;12(4):829.
doi: 10.3390/cancers12040829.

Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients

Jesús Del Valle  1   2   3 , Paula Rofes  1   2   3 , José Marcos Moreno-Cabrera  1   2   3 , Adriana López-Dóriga  4   5 , Sami Belhadj  1   2   3 , Gardenia Vargas-Parra  1   2   3 , Àlex Teulé  1   2   6 , Raquel Cuesta  1   2   3 , Xavier Muñoz  1   2   3 , Olga Campos  1   2   3 , Mónica Salinas  1   2 , Rafael de Cid  7 , Joan Brunet  1   2   3 , Sara González  1   2   3 , Gabriel Capellá  1   2   3 , Marta Pineda  1   2   3 , Lídia Feliubadaló  1   2   3 , Conxi Lázaro  1   2   3
Affiliations

Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients

Jesús Del Valle et al. Cancers (Basel). .

Abstract

Fanconi anemia (FA) is caused by biallelic mutations in FA genes. Monoallelic mutations in five of these genes (BRCA1, BRCA2, PALB2, BRIP1 and RAD51C) increase the susceptibility to breast/ovarian cancer and are used in clinical diagnostics as bona-fide hereditary cancer genes. Increasing evidence suggests that monoallelic mutations in other FA genes could predispose to tumor development, especially breast cancer. The objective of this study is to assess the mutational spectrum of 14 additional FA genes (FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FANCP, FANCQ, FANCR and FANCU) in a cohort of hereditary cancer patients, to compare with local cancer-free controls as well as GnomAD. A total of 1021 hereditary cancer patients and 194 controls were analyzed using our next generation custom sequencing panel. We identified 35 pathogenic variants in eight genes. A significant association with the risk of breast cancer/breast and ovarian cancer was found for carriers of FANCA mutations (odds ratio (OR) = 3.14 95% confidence interval (CI) 1.4-6.17, p = 0.003). Two patients with early-onset cancer showed a pathogenic FA variant in addition to another germline mutation, suggesting a modifier role for FA variants. Our results encourage a comprehensive analysis of FA genes in larger studies to better assess their role in cancer risk.

Keywords: Breast and ovarian cancer risk; Breast cancer risk; Fanconi Anemia; Hereditary Cancer; NGS panel sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The diagram represents the percentage of pathogenic variants in the 14 Fanconi anemia (FA) genes analyzed per clinical suspicion group. HBC: Hereditary Breast Cancer Patients; HOC: Hereditary Ovarian Cancer Patients; HBOC: Hereditary Breast and Ovarian Cancer Patients; HNPCC: Hereditary non-polyposis colorectal cancer.
See this image and copyright information in PMC

References

    1. Mamrak N.E., Shimamura A., Howlett N.G. Recent discoveries in the molecular pathogenesis of the inherited bone marrow failure syndrome Fanconi anemia. Blood Rev. 2017;31:93–99. doi: 10.1016/j.blre.2016.10.002. - DOI - PMC - PubMed
    1. Asur R.S., Kimble D.C., Lach F.P., Jung M., Donovan F.X., Kamat A., Noonan R.J., Thomas J.W., Park M., Chines P., et al. Somatic mosaicism of an intragenic FANCB duplication in both fibroblast and peripheral blood cells observed in a Fanconi anemia patient leads to milder phenotype. Mol. Genet. Genom. Med. 2018;6:77–91. doi: 10.1002/mgg3.350. - DOI - PMC - PubMed
    1. Kottemann M.C., Smogorzewska A. Fanconi anaemia and the repair of Watson and Crick DNA crosslinks. Nature. 2013;493:356–363. doi: 10.1038/nature11863. - DOI - PMC - PubMed
    1. Bogliolo M., Surrallés J. Fanconi anemia: A model disease for studies on human genetics and advanced therapeutics. Curr. Opin. Genet. Dev. 2015;33:32–40. doi: 10.1016/j.gde.2015.07.002. - DOI - PubMed
    1. Catucci I., Osorio A., Arver B., Neidhardt G., Bogliolo M., Zanardi F., Riboni M., Minardi S., Pujol R., Azzollini J., et al. Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility. Genet. Med. 2018;20:452–457. doi: 10.1038/gim.2017.123. - DOI - PubMed