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

• Published in: Oncotarget Vol. 14; no. 1; pp. 111 - 125
• Main Authors: Chevarin, Martin, Alcantara, Diana, Albuisson, Juliette, Collonge-Rame, Marie-Agnès, Populaire, Céline, Selmani, Zohair, Baurand, Amandine, Sawka, Caroline, Bertolone, Geoffrey, Callier, Patrick, Duffourd, Yannis, Jonveaux, Philippe, Bignon, Yves-Jean, Coupier, Isabelle, Cornelis, François, Cordier, Christophe, Mozelle-Nivoix, Monique, Rivière, Jean-Baptiste, Kuentz, Paul, Thauvin, Christel, Boidot, Romain, Ghiringhelli, François, O'Driscoll, Marc, Faivre, Laurence, Nambot, Sophie
• Format: Journal Article
• Language: English
• Published: United States Impact journals 07.02.2023; Impact Journals LLC
• Subjects: Alleles; Ataxia Telangiectasia Mutated Proteins - genetics; Breast Neoplasms - genetics; Breast Neoplasms, Male - genetics; Cancer; Female; Genetic Predisposition to Disease; Humans; Life Sciences; Male; Phenotype; Phosphorylation; Research Paper; male breast cancer; exome sequencing; genetic predisposition to cancer; extreme phenotype; ATR
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.28358

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 EX TRICAN project, exploring unresolved extreme cancer phenotypes, we applied exome sequencing on rare familial cases with male breast cancer, identifying a novel pathogenic variant of (p.Leu1808*). has already been suspected as being a predisposing gene to breast cancer in women. We next identified 3 additional 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.