Research Papers:

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

Martin Chevarin, Diana Alcantara, Juliette Albuisson, Marie-Agnès Collonge-Rame, Céline Populaire, Zohair Selmani, Amandine Baurand, Caroline Sawka, Geoffrey Bertolone, Patrick Callier, Yannis Duffourd, Philippe Jonveaux, Yves-Jean Bignon, Isabelle Coupier, François Cornelis, Christophe Cordier, Monique Mozelle-Nivoix, Jean-Baptiste Rivière, Paul Kuentz, Christel Thauvin, Romain Boidot, François Ghiringhelli, Marc O'Driscoll, Laurence Faivre and Sophie Nambot _

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Oncotarget. 2023; 14:111-125. https://doi.org/10.18632/oncotarget.28358

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Martin Chevarin1,2, Diana Alcantara3, Juliette Albuisson4,5, Marie-Agnès Collonge-Rame6, Céline Populaire6, Zohair Selmani6, Amandine Baurand4,7, Caroline Sawka7, Geoffrey Bertolone7, Patrick Callier1,2,8, Yannis Duffourd1,8, Philippe Jonveaux9, Yves-Jean Bignon10, Isabelle Coupier11, François Cornelis12,13, Christophe Cordier14, Monique Mozelle-Nivoix15, Jean-Baptiste Rivière1,7,8, Paul Kuentz1,6,8, Christel Thauvin1,7, Romain Boidot5, François Ghiringhelli16, Marc O'Driscoll3, Laurence Faivre1,4,7,8 and Sophie Nambot1,4,7,8

1 Inserm UMR 1231 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France

2 Unité Fonctionnelle Innovation diagnostique dans les maladies rares, laboratoire de génétique chromosomique et moléculaire, Plateau Technique de Biologie, CHU Dijon Bourgogne, Dijon, France

3 Human DNA Damage Response Disorders Group, University of Sussex, Genome Damage and Stability Centre, Brighton, United Kingdom

4 Service d’Oncogénétique, Centre Georges François Leclerc, Dijon, France

5 Département de biologie et pathologie des tumeurs, Centre Georges François Leclerc, Dijon, France

6 Oncobiologie Génétique Bioinformatique, PCBio, CHU Besançon, Besançon, France

7 Centre de Génétique et Centre de Référence Maladies Rares Anomalies du Développement de l’Interrégion Est, Hôpital d’Enfants, CHU Dijon Bourgogne, Dijon, France

8 Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), CHU Dijon Bourgogne et Université de Bourgogne-Franche Comté, Dijon, France

9 Laboratoire de Génétique Médicale, INSERM U954, Hôpitaux de Brabois, Vandoeuvre les Nancy, France

10 Laboratoire d’Oncologie Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France

11 Unité d’Oncogénétique, ICM Val d’Aurel, Montpellier, France

12 Université Bordeaux, IMB, UMR 5251, Talence, France

13 Service d’imagerie diagnostique et interventionnelle de l’adulte, Hôpital Pellegrin, CHU de Bordeaux, France

14 UF6948 oncogénétique, CHRU de Strasbourg, France

15 Service de génétique, CHU-Reims, France

16 Département d’oncologie médicale, INSERM LNC U1231, Centre Georges François Leclerc, Dijon, France

Correspondence to:

Sophie Nambot, email: [email protected]

Keywords: male breast cancer; genetic predisposition to cancer; exome sequencing; ATR; extreme phenotype

Received: June 23, 2022     Accepted: January 23, 2023     Published: February 07, 2023

Copyright: © 2023 Chevarin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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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PII: 28358