“Extreme Phenotype Approach” Applied to Male Breast Cancer Allows ID of Rare Variants…

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Oncotarget published this research paper in Volume 14, entitled, “The 'extreme phenotype approach' applied to male breast cancer allows the identification of rare variants of ATR as potential breast cancer susceptibility alleles" by researchers from the Inserm UMR 1231 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France; Unité Fonctionnelle Innovation diagnostique dans les maladies rares, laboratoire de génétique chromosomique et moléculaire, Plateau Technique de Biologie, CHU Dijon Bourgogne, Dijon, France; Human DNA Damage Response Disorders Group, University of Sussex, Genome Damage and Stability Centre, Brighton, United Kingdom; Service d’Oncogénétique, Centre Georges François Leclerc, Dijon, France; Département de biologie et pathologie des tumeurs, Centre Georges François Leclerc, Dijon, France; Oncobiologie Génétique Bioinformatique, PCBio, CHU Besançon, Besançon, France; Centre de Génétique et Centre de Référence Maladies Rares Anomalies du Développement de l’Interrégion Est, Hôpital d’Enfants, CHU Dijon Bourgogne, Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), CHU Dijon Bourgogne et Université de Bourgogne-Franche Comté, Dijon, France; Laboratoire de Génétique Médicale, INSERM U954, Hôpitaux de Brabois, Vandoeuvre les Nancy, France; Laboratoire d’Oncologie Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; Unité d’Oncogénétique, ICM Val d’Aurel, Montpellier, France; Université Bordeaux, IMB, UMR 5251, Talence, France; Service d’imagerie diagnostique et interventionnelle de l’adulte, Hôpital Pellegrin, CHU de Bordeaux, France; UF6948 oncogénétique, CHRU de Strasbourg, France; Service de génétique, CHU-Reims, France; Département d’oncologie médicale, INSERM LNC U1231, Centre Georges François Leclerc, Dijon, France. DOI - https://doi.org/10.18632/oncotarget.28358 Correspondence to - Sophie Nambot - sophie.nambot@chu-dijon.fr Abstract 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 remain 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. Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28358 Keywords - male breast cancer, genetic predisposition to cancer, exome sequencing, ATR, extreme phenotype About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957