University of Sussex
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The "extreme phenotype approach" applied to male breast cancer allows the identification of rare variants of ATR as potential breast cancer susceptibility alleles

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posted on 2023-06-10, 07:04 authored by Martin Chevarin, Diana AlcantaraDiana Alcantara, Julliette Albuisson, Marie-Agnes Collonge-Rame, Celine Populaire, Zohair Selmani, Amandine Baurand, Caroline Sawka, Geoffrey Bertolone, Patrick Callier, Yannis Duffourd, Phillipe Jonveaux, Yves-Jean Bignon, Isabelle Coupier, Francios Cornelis, Christophe Cordier, Monique Mozelle-Nivoix, Jean-Baptiste Rivière, Paul Kuentz, Christal Thauvin, Romain Boidot, Francios Ghiringhelli, Mark O'DriscollMark O'Driscoll, Lawrence Faivre, Sophie Nambot
In oncogenetics, some patients could be considered as "extreme phenotypes", such as those with very early onset presentation or multiple primary malignancies, unusually high numbers of cancers of the same spectrum or rare cancer types in the same parental branch. For these cases, a genetic predisposition is very likely, but classical candidate gene panel analyses often and frustratingly remains negative. In the framework of the EX2TRICAN project, exploring unresolved extreme cancer phenotypes, we applied exome sequencing on rare familial cases with male breast cancer, identifying a novel pathogenic variant of ATR (p.Leu1808*). ATR has already been suspected as being a predisposing gene to breast cancer in women. We next identified 3 additional ATR variants in a cohort of both male and female with early onset and familial breast cancers (c.7762-2A>C; c.2078+1G>A; c.1A>G). Further molecular and cellular investigations showed impacts on transcripts for variants affecting splicing sites and reduction of ATR expression and phosphorylation of the ATR substrate CHEK1. This work further demonstrates the interest of an extended genetic analysis such as exome sequencing to identify very rare variants that can play a role in cancer predisposition in extreme phenotype cancer cases unexplained by classical cancer gene panels testing.


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United States

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  • Global Health and Infection Publications

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