Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D.

BACKGROUND: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. CONCLUSIONS: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models

Multiple, single trait GWAS and supervised machine learning reveal the genetic architecture of Fraxinus excelsior tolerance to ash dieback in Europe

Abstract Common ash ( Fraxinus excelsior ) is under intensive attack from the invasive alien pathogenic fungus Hymenoscyphus fraxineus , causing ash dieback at epidemic levels throughout Europe. Previous studies have found significant genetic variation among clones in ash dieback susceptibility and that host phenology, such as autumn yellowing, is correlated with susceptibility of ash trees to H. fraxineus ; however, the genomic basis of ash dieback tolerance in F. excelsior remains poorly understood. Here, we integrate quantitative genetics and genome-wide association analyses with machine learning to reveal the genetic architecture of ash dieback tolerance and its relationship to phenological traits in F. excelsior populations in six European countries (Austria, Denmark, Germany, Ireland, Lithuania, Sweden). We use whole-genome sequencing of 486 F. excelsior genotypes to confirm the genotypic correlation between crown damage caused by ash dieback and intensity of autumn leaf yellowing within multiple sampling sites. Although, our results suggest that the examined traits are polygenic, a relatively small number of single nucleotide polymorphisms (SNPs) explained a large proportion of the variation in both disease tolerance and autumn leaf yellowing. We could explain up to 63% (based on 9155 unlinked SNPs) of variation in individual response to ash dieback crown damage and up to 72% (based on 3740 unlinked SNPs) of variation in autumn yellowing. We identified eight SNPs encoding non-synonymous substitutions, of which those with the highest predictive power were located within genes related to plant defence (pattern triggered immunity, pathogen detection) and phenology (regulation of flowering and seed maturation, auxin transport). Overall, our results provide insights of a multifaceted defence response, according to which a combination of direct defence mechanisms and phenological avoidance of pathogen spread constitute tolerance to ash dieback