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.

First description of a double heterozygosity for BRCA1 and BRCA2 pathogenic variants in a French metastatic breast cancer patient: A case report.

Hereditary breast and ovarian cancer syndrome is an autosomal dominant disease caused primarily by germline mutations in the BRCA1 or BRCA2 gene. Rare cases of double heterozygosity for BRCA1 and BRCA2 mutations have been reported quite exceptionally in non-Ashkenazi individuals. We describe the case of a woman who developed a bilateral breast cancer, discovered concomitantly, at 46 years old. Biopsies confirmed the presence of two breast cancers with distinct histology. BRCA analysis was tested due to a positive family history of breast cancer, and two pathogenic monoallelic mutations were detected, one in the BRCA1 gene and one in the BRCA2 gene. There is no known Ashkenazi Jewish ancestry. We report the first description of a never described double heterozygosity for BRCA1 and BRCA2 pathogenic variants in a French metastatic breast cancer patient, with two distinct histology, and two distinct mutations.

Conversely to its sibling Drosophila melanogaster, D. simulans overcomes the immunosuppressive effects of the parasitoid Asobara citri.

The endoparasitoid Asobara citri avoids Drosophila melanogaster immune defenses, thanks to immune suppressive effects. We investigated whether this parasitoid could also circumvent the immune reaction of D. simulans, a sibling species of D. melanogaster. The rates of infestation, successful parasitism, total encapsulation and mortality were measured after complete development of both D. melanogaster and D. simulans larvae parasitized by A. citri. Results showed that the parasitoids were almost never encapsulated in D. melanogaster larvae, while 45% were encapsulated in D. simulans. A. citri induced a targeted disruption of the hematopoietic organs and a decrease of the hemocytes load in host larvae of both species. Despite such disruptive immune effects most D. simulans larvae succeeded in encapsulating A. citri eggs, probably thanks to their ability to immediately mount a capsule after infestation. This work brings some insight into the diversity of the immune potentials evolved by Drosophila species towards parasitoids.