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

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.

Web-based return of BRCA2 research results: one-year genetic counselling experience in Iceland.

There is an increased pressure to return results from research studies. In Iceland, deCODE Genetics has emphasised the importance of returning results to research participants, particularly the founder pathogenic BRCA2 variant; NM_000059.3:c.771_775del. To do so, they opened the website www.arfgerd.is . Individuals who received positive results via the website were offered genetic counselling (GC) at Landspitali in Reykjavik. At the end of May 2019, over 46.000 (19% of adults of Icelandic origin) had registered at the website and 352 (0.77%) received text message informing them about their positive results. Of those, 195 (55%) contacted the GC unit. Additionally, 129 relatives asked for GC and confirmatory testing, a total of 324 individuals. Various information such as gender and age, prior knowledge of the variant and perceived emotional impact, was collected. Of the BRCA2 positive individuals from the website, 74 (38%) had prior knowledge of the pathogenic variant (PV) in the family. The majority initially stated worries, anxiety or other negative emotion but later in the process many communicated gratitude for the knowledge gained. Males represented 41% of counsellees as opposed to less than 30% in the regular hereditary breast and ovarian (HBOC) clinic. It appears that counselling in clinical settings was more reassuring for worried counsellees. In this article, we describe one-year experience of the GC service to those who received positive results via the website. This experience offers a unique opportunity to study the public response of a successful method of the return of genetic results from research.

[Multidisciplinary team meetings settings on the management of women at high risk of inherited breast cancer. A French study]. / Mise en place des modalités de réunions de concertation pluridisciplinaire pour la prise en charge des patientes prédisposées héréditairement au cancer du sein. Une étude française.

INTRODUCTION: In France, 126 centers for cancer genetics coordinate genetic testing and high-risk cancer surveillance for individuals and their families with hereditary cancer syndromes. Since 2012, the French National Cancer Institute (INCa) supports 17 projects to promote and manage the monitoring of individuals genetically predisposed to cancer. They were assigned 4 missions by INCa including expertise for difficult cases. METHODS: We initiated a national survey to assess how the oncogenetic clinics responded to the 4th mission for women at high risk of developing breast cancers. We sent the survey to all the French oncogeneticists. We aimed at evaluating the modalities and the extent of implementation of the Multidisciplinary team (MDT) meetings regarding the management of women who have genetically higher risks to develop breast cancer. RESULTS: Fourteen people from 12 administrative regions, who represent 10 of the 17 projects, answered the form. Eleven participants reported the submission of medical cases in Oncogenetics MDT meetings (79 %), 5 in senology MDT meetings (36 %), 5 in MDT meetings dedicated to patients at high risk for breast cancer (36 %) and 2 in network meetings (14 %). Some structures discuss medical cases through different MDT meetings. CONCLUSION: Although MDT meetings are valuable practices to optimize treatment or management options for patients, its settings might be subject to difficulties to federate the appropriate-number of participants as well as cost-effectiveness issues. This survey thus suggests the need of a standardized process of MDT meetings while taking account specificities of oncogenetics.