Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.

Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels.

Exome sequencing study of Russian breast cancer patients suggests a predisposing role for USP39.

PURPOSE: Germline variants in known breast cancer (BC) predisposing genes explain less than half of hereditary BC cases. This study aimed to identify missing genetic determinants of BC. METHODS: Whole exome sequencing (WES) of lymphocyte DNA was performed for 49 Russian patients with clinical signs of genetic BC predisposition, who lacked Slavic founder mutations in BRCA1, BRCA2, CHEK2, and NBS1 genes. RESULTS: Bioinformatic analysis of WES data was allowed to compile a list of 229 candidate mutations. 79 of these mutations were subjected to a three-stage case-control analysis. The initial two stages, which involved up to 797 high-risk BC patients, 1504 consecutive BC cases, and 1081 healthy women, indicated a potentially BC-predisposing role for 6 candidates, i.e., USP39 c.*208G > C, PZP p.Arg680Ter, LEPREL1 p.Pro636Ser, SLIT3 p.Arg154Cys, CREB3 p.Lys157Glu, and ING1 p.Pro319Leu. USP39 c.*208G > C was strongly associated with triple-negative breast tumors (p = 0.0001). In the third replication stage, we genotyped the truncating variant of PZP (rs145240281) and the potential splice variant of USP39 (rs112653307) in three independent cohorts of Russian, Byelorussian, and German ancestry, comprising a total of 3216 cases and 2525 controls. The data obtained for USP39 rs112653307 supported the association identified in the initial stages (the combined OR 1.72, p = 0.035). CONCLUSIONS: This study suggests the role of a rare splicing variant in BC susceptibility. USP39 encodes an ubiquitin-specific peptidase that regulates cancer-relevant tumor suppressors including CHEK2. Further epidemiological and functional studies involving these gene variants are warranted.

MicroRNA-200 family expression analysis in metastatic clear cell renal cell carcinoma patients.

The aim of this study is to analyse the of expression levels of microRNA-200 family members in patients with metastatic clear cell renal cell carcinoma (ccRCC). Analysis of microRNA expression was performed on 23 paired DNA samples extracted from kidney tumour tissue and the surrounding normal renal parenchyma. MicroRna-200c was found to have significantly lower expression (in kidney tumour tissue compared to normal renal parenchyma. No other microRna-200 family members showed statistically significant differences in expression levels between tumour and normal kidney tissue. Recent data suggest that the role of microRNA-200c in tumour pathogenesis is rather contradictory, and the underlying mechanisms by which microRNA-200c affects the carcinogenic potential of malignant cells remains unclear and requires further investigation at the molecular level.

A counter-clockwise northern route of the Y-chromosome haplogroup N from Southeast Asia towards Europe.

A large part of Y chromosome lineages in East European and East Asian human populations belong to haplogroup (hg) NO, which is composed of two sister clades N-M231 and O-M175. The O-clade is relatively old (around 30 thousand years (ky)) and encompasses the vast majority of east and Southeast Asian male lineages, as well as significant proportion of those in Oceanian males. On the other hand, our detailed analysis of hg N suggests that its high frequency in east Europe is due to its more recent expansion westward on a counter-clock northern route from inner Asia/southern Siberia, approximately 12-14 ky ago. The widespread presence of hg N in Siberia, together with its absence in Native Americans, implies its spread happened after the founder event for the Americas. The most frequent subclade N3, arose probably in the region of present day China, and subsequently experienced serial bottlenecks in Siberia and secondary expansions in eastern Europe. Another branch, N2, forms two distinctive subclusters of STR haplotypes, Asian (N2-A) and European (N2-E), the latter now mostly distributed in Finno-Ugric and related populations. These phylogeographic patterns provide evidence consistent with male-mediated counter-clockwise late Pleistocene-Holocene migratory trajectories toward Northwestern Europe from an ancestral East Asian source of Paleolithic heritage.