A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

To date, most BC GWASs have been performed Background Polygenic risk score (PRS), calculated in individuals of European (EUR) ancestry, and based on genome-wide association studies (GWASs), the generalisation of EUR-based PRS to other can improve breast cancer (BC) risk assessment. populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.</p

Breast cancer risks associated with missense variants in breast cancer susceptibility genes

BACKGROUND: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q  Conclusions Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10−5), demonstrating the importance of diversifying study cohorts

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Peer reviewedPublisher PD

Genes reveal traces of common recent demographic history for most of the Uralic-speaking populations

Background: The genetic origins of Uralic speakers from across a vast territory in the temperate zone of North Eurasia have remained elusive. Previous studies have shown contrasting proportions of Eastern and Western Eurasian ancestry in their mitochondrial and Y chromosomal gene pools. While the maternal lineages reflect by and large the geographic background of a given Uralic-speaking population, the frequency of Y chromosomes of Eastern Eurasian origin is distinctively high among European Uralic speakers. The autosomal variation of Uralic speakers, however, has not yet been studied comprehensively.Results: Here, we present a genome-wide analysis of 15 Uralic-speaking populations which cover all main groups of the linguistic family. We show that contemporary Uralic speakers are genetically very similar to their local geographical neighbours. However, when studying relationships among geographically distant populations, we find that most of the Uralic speakers and some of their neighbours share a genetic component of possibly Siberian origin. Additionally, we show that most Uralic speakers share significantly more genomic segments identity-by-descent with each other than with geographically equidistant speakers of other languages. We find that correlated genome-wide genetic and lexical distances among Uralic speakers suggest co-dispersion of genes and languages. Yet, we do not find long-range genetic ties between Estonians and Hungarians with their linguistic sisters that would distinguish them from their non-Uralic-speaking neighbours.Conclusions: We show that most Uralic speakers share a distinct ancestry component of likely Siberian origin, which suggests that the spread of Uralic languages involved at least some demic component

Genes reveal traces of common recent demographic history for most of the Uralic-speaking populations.

BACKGROUND: The genetic origins of Uralic speakers from across a vast territory in the temperate zone of North Eurasia have remained elusive. Previous studies have shown contrasting proportions of Eastern and Western Eurasian ancestry in their mitochondrial and Y chromosomal gene pools. While the maternal lineages reflect by and large the geographic background of a given Uralic-speaking population, the frequency of Y chromosomes of Eastern Eurasian origin is distinctively high among European Uralic speakers. The autosomal variation of Uralic speakers, however, has not yet been studied comprehensively. RESULTS: Here, we present a genome-wide analysis of 15 Uralic-speaking populations which cover all main groups of the linguistic family. We show that contemporary Uralic speakers are genetically very similar to their local geographical neighbours. However, when studying relationships among geographically distant populations, we find that most of the Uralic speakers and some of their neighbours share a genetic component of possibly Siberian origin. Additionally, we show that most Uralic speakers share significantly more genomic segments identity-by-descent with each other than with geographically equidistant speakers of other languages. We find that correlated genome-wide genetic and lexical distances among Uralic speakers suggest co-dispersion of genes and languages. Yet, we do not find long-range genetic ties between Estonians and Hungarians with their linguistic sisters that would distinguish them from their non-Uralic-speaking neighbours. CONCLUSIONS: We show that most Uralic speakers share a distinct ancestry component of likely Siberian origin, which suggests that the spread of Uralic languages involved at least some demic component