Biology subjects

Gumus, Z.

Publications and source records attributed to Gumus, Z..

3 recordsLinked to original sources

bioRxiv2018

Rare germline variants in Fanconi Anemia genes increase risk for squamous lung cancer

PurposeLung cancer is the leading cause of cancer deaths worldwide, with substantially better prognosis in early stage as opposed to late stage disease. Identifying genetic factors for lung squamous carcinoma (SqCC) risk will enable their use in risk stratification, and personalized intensive surveillance, early detection, and prevention strategies for high-risk individuals.\n\nStudy Design and ParticipantsWe analyzed whole-exome sequencing datasets of 318 cases and 814 controls (discovery cohort) and then validated our findings in an independent cohort of 444 patients and 3,479 controls (validation cohort), all of European descent, totaling a combined cohort of 765 cases and 4,344 controls. We focused on rare pathogenic variants found in the ClinVar database and used penalized logistic regression to identify genes in which such variants are enriched in cases. All statistical tests were two-sided.\n\nResultsWe observed an overall enrichment of rare, deleterious germline variants in Fanconi Anemia genes in cases with SqCC (joint analysis OR=3.08, p=1.4e-09, 95% confidence interval [CI]=2.2-4.3). Consistent with previous studies, BRCA2 in particular exhibited an increased overall burden of rare, deleterious variants (joint OR=3.2, p=8.7e-08, 95% CI=2.1-4.7). More importantly, rare deleterious germline variants were enriched in Fanconi Anemia genes even without the BRCA2 rs11571833 variant that is strongly enriched in lung SqCC cases (joint OR=2.76, p=7.0e-04, 95% CI=1.6-4.7).\n\nConclusionsThese findings can be used towards the development of a genetic diagnostic test in the clinic to identify SqCC high-risk individuals, who can benefit from personalized programs, improving prognosis.

genomics↗

bioRxiv2017

The Effects Of Oncogenic G12D Mutation On K-Ras Structure, Conformation And Dynamics

K-Ras is the most frequently mutated oncoprotein in human cancers, and G12D is its most prevalent mutation. To understand how G12D mutation impacts K-Ras function, we need to understand how it alters the regulation of its dynamics. Here, we present local changes in K-Ras structure, conformation and dynamics upon G12D mutation, from long-timescale Molecular Dynamics simulations of active (GTP-bound) and inactive (GDP-bound) forms of wild-type and mutant K-Ras, with an integrated investigation of atomistic-level changes, local conformational shifts and correlated residue motions. Our results reveal that the local changes in K-Ras are specific to bound nucleotide (GTP or GDP), and we provide a structural basis for this. Specifically, we show that G12D mutation causes a shift in the population of local conformational states of K-Ras, especially in Switch-II (SII) and 3-helix regions, in favor of a conformation that is associated with a catalytically impaired state through structural changes; it also causes SII motions to anti-correlate with other regions. This detailed picture of G12D mutation effects on the local dynamic characteristics of both active and inactive protein helps enhance our understanding of local K-Ras dynamics, and can inform studies on the development of direct inhibitors towards the treatment of K-RasG12D-driven cancers.

biophysics↗

bioRxiv2017

High-depth whole genome sequencing of a large population-specific reference panel: Enhancing sensitivity, accuracy, and imputation

BackgroundWhile increasingly large reference panels for genome-wide imputation have been recently made available, the degree to which imputation accuracy can be enhanced by population-specific reference panels remains an open question. In the present study, we sequenced at full-depth ([≥]30x) a moderately large (n=738) cohort of samples drawn from the Ashkenazi Jewish population across two platforms (Illumina X Ten and Complete Genomics, Inc.). We developed and refined a series of quality control steps to optimize sensitivity, specificity, and comprehensiveness of variant calls in the reference panel, and then tested the accuracy of imputation against target cohorts drawn from the same population.\n\nResultsFor samples sequenced on the Illumina X Ten platform, quality thresholds were identified that permitted highly accurate calling of single nucleotide variants across 94% of the genome. The Complete Genomics, Inc. platform was more conservative (fewer variants called) compared to the Illumina platform, but also demonstrated relatively greater numbers of false positives that needed to be filtered. Quality control procedures also permitted detection of novel genome reads that are not mapped to current reference or alternate assemblies. After stringent quality control, the population-specific reference panel produced more accurate and comprehensive imputation results relative to publicly available, large cosmopolitan reference panels. The population-specific reference panel also permitted enhanced filtering of clinically irrelevant variants from personal genomes.\n\nConclusionsOur primary results demonstrate enhanced accuracy of a population-specific imputation panel relative to cosmopolitan panels, especially in the range of infrequent (<5% non-reference allele frequency) and rare (<1% non-reference allele frequency) variants that may be most critical to further progress in mapping of complex phenotypes.

genomics↗