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Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

Emilie Degrolard-Courcet 1 Joanna Sokolowska 2, 3 Marie-Martine Martin 4 Séverine Guiu 5 Myriam Bronner 2, 3 Carole Chery 2, 3 Fanny Coron 6 Côme Lepage 7 Caroline Chapusot 1 Catherine Loustalot 4 Jean-Louis Jouve 7 Cyril Hatem 8 Emmanuelle Ferrant 9 Laurent Martin 1 Charles Coutant 4 Amandine Baurand 6 Gerard Couillault 10 Alexandra Delignette 11 Salima El Chehadeh 6 Sarab Lizard 12 Laurent Arnould 13 Pierre Fumoleau 5 Patrick Callier 14 Francine Mugneret 14 C. Philippe 2, 3 Thierry Frebourg 15, 16 Philippe Jonveaux 2, 3 Laurence Faivre 6
Abstract : Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A>G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A>G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.
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Emilie Degrolard-Courcet, Joanna Sokolowska, Marie-Martine Martin, Séverine Guiu, Myriam Bronner, et al.. Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene. European Journal of Human Genetics, Nature Publishing Group, 2013, 22 (8), pp.979 - 987. ⟨10.1038/ejhg.2013.278⟩. ⟨hal-01688120⟩



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