Biology subjects

Spisak, S.

Publications and source records attributed to Spisak, S..

3 recordsLinked to original sources

bioRxiv2019

Allelic imbalance reveals widespread germline-somatic regulatory differences and prioritizes risk loci in Renal Cell Carcinoma

Determining the function of non-coding regulatory variants in cancer is a key challenge transcriptional biology. We investigated genetic (germline and somatic) determinants of regulatory mechanisms in renal cell carcinoma (RCC) using H3K27ac ChIP-seq data in 10 matched tumor/normal samples and RNA-seq data from 496/66 tumor/normal samples from The Cancer Genome Atlas (TCGA). Unsupervised clustering of H3K27ac activity cleanly separated tumor from normal individuals, highlighting extensive epigenetic reprogramming during transformation. We developed a novel method to test each chromatin feature for evidence of an allele-specific quantitative trait locus (asQTL) and evaluate tumor/normal differences in allele-specificity (d-asQTLs) while modelling local structural variation and read overdispersion. At an FDR of 5%, we identified 1,356 unique asQTL chromatin peaks in normal tissues; 2,868 in tumors; and 1,054 d-asQTLs (primarily imbalanced in tumor). The d-asQTL peaks were significantly enriched for RCC genome-wide association study (GWAS) heritability (32x, P=1.8x10-3), more so than any other functional feature including all H3K27ac peaks (12x), super-enhancers (5x), and asQTL genes (4x). Intersection of asQTLs with RCC GWAS loci identified putative functional features for 6/17 known loci including tumor-specific activity at SCARB1, a cholesterol metabolism mediator, which has recently been implicated in RCC progression. We validated the asQTL variant through CRISPR interference (CRISPRi) and demonstrated a concomitant allelic effect on the overlapping enhancer and on downstream SCARB1 expression. Knockdowns of master transcription factors (TFs) involved in the hypoxia pathway altered the expression of SCARB1 in a kidney cancer cell line, consistent with a variant-TF interaction. Genome-wide, d-asQTLs were significantly enriched for tumor-specific binding of hypoxic transcription factors, implicating a more general mechanism for polygenic germline-somatic interaction.

genetics↗

bioRxiv2019

Family aggregation analysis reveals a heritable background of equine grass sickness (dysautonomia)

Equine grass sickness (also known as dysautonomia) is a life-threatening polyneuropathic disease affecting horses with approx. 80% mortality. Since its first description over a hundred years ago, several factors including phenotypic, environmental, management, climate, and intestinal microbiome) have been associated with increased risk of dysautonomia. But despite the extensive research on dysautonomia, its causative factors have yet been identified. A retrospective pedigree and phenotype based genetic epidemiological study was performed to analyze the associations of disease occurrence and the kinship in a Hungarian large scale stud. The pedigree data set containing 1233 horses with 49 affected animals was used in the analysis. The first finding was that among the descendants of some stallions the proportion of affected animals are unexpectedly high, with a maximum of 25% of a stallions descendants affected. Animals with affected siblings have higher odds to be a case (OR: 1.27, 95% CI: 1.01-1.57, p=0.033). Among males in the affected population the odds of dysautonomia is higher than in females (OR: 1.76, 95% CI: 0.95-3.29, p=0.057). Significant familial clustering was observed among the affected animals (GIF p=0.001). Further subgroups were identified with significant (p<0.001) aggregation among close relatives using kinship-based methods. Our analysis of the data and the observed higher disease frequency in males suggests that dysautonomia may have X-linked recessive inheritance as a causal factor. This is the first study providing ancestry data and suggesting a genetic contribution to the likely multifactorial causes of the disease.

genetics↗

bioRxiv2019

A subset of lung cancer cases shows robust signs of homologous recombination deficiency associated genomic aberration based molecular signatures

BackgroundConsistent with their assumed mechanism of action, PARP inhibitors show significant therapeutic efficacy in breast, ovarian and prostate cancer, which are the solid tumor types most often associated with the loss of function of key homologous recombination genes. It remains unknown, however, how frequent homologous recombination deficiency (HRD) is in other solid tumor types. Since it is well established, that HRD induces specific DNA aberration profiles and genomic scars that can be captured by various next-generation sequencing (NGS) based biomarkers, it is possible to assess the presence or absence of this DNA repair pathway aberration in any given tumor biopsy. MethodsWe derived the various HRD associated mutational signatures from whole genome and whole exome sequencing data in the lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) cases from TCGA, in a patient of ours with stage IVA lung cancer with exceptionally good response to platinum-based therapy and in lung cancer cell lines. ResultsWe have found evidence that a subset of the investigated cases shows robust signs of HR deficiency, some of which exhibiting similar patterns to those with a complete loss of function of either BRCA1 or BRCA2 genes, however, without any signs of genetic alterations being present in either of those genes. The extreme platinum responder case also showed a robust HRD associated genomic mutational profile. HRD associated mutational signatures were also associated with PARP inhibitor sensitivity in lung cancer cell lines. ConclusionsLung cancer cases with high levels of HRD associated mutational signatures could be candidates for PARP inhibitor treatment, and in general, the prioritization of patients for clinical trials might be achieved using the combined analysis of the HRD-related next-generation sequencing-based mutational signatures.

cancer biology↗