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

Fiche publication

Date publication

février 2023

Journal

Oncotarget

Auteurs

Membres identifiés du Cancéropôle Est :
Dr BOIDOT Romain , Pr CALLIER Patrick , Pr GHIRINGHELLI François , Pr FAIVRE Laurence , Dr COLLONGE-RAME Marie-Agnès , Dr NAMBOT Sophie , Mr DUFFOURD Yannis , Dr SELMANI Zohair , Pr THAUVIN-ROBINET Christel , Pr KUENTZ Paul , Dr ALBUISSON Juliette

Tous les auteurs :
Chevarin M, Alcantara D, Albuisson J, Collonge-Rame MA, Populaire C, Selmani Z, Baurand A, Sawka C, Bertolone G, Callier P, Duffourd Y, Jonveaux P, Bignon YJ, Coupier I, Cornelis F, Cordier C, Mozelle-Nivoix M, Rivière JB, Kuentz P, Thauvin C, Boidot R, Ghiringhelli F, O'Driscoll M, Faivre L, Nambot S

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/36749285

Résumé

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 EXTRICAN 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.