ORCID Profile
0000-0002-3725-4173
Current Organisation
National Institutes of Health
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Publisher: Elsevier BV
Date: 08-2017
Publisher: Elsevier BV
Date: 03-2018
Publisher: Elsevier BV
Date: 03-2018
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1969-6
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution in acral melanoma, for ex le, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 analyses timings and patterns of tumour evolution 7 describes the erse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 and evaluates a range of more-specialized features of cancer genomes 8,10–18 .
Publisher: Springer Science and Business Media LLC
Date: 08-1997
DOI: 10.1007/S11626-997-0112-4
Abstract: Closure of rat mesenteric perforation is considered to occur by connective tissue contraction, a process that has been shown to be stimulated by transforming growth factor-beta 1. In the present study, we assessed the expression of alpha-smooth muscle actin during closure by quantitative-reverse transcription-polymerase chain reaction and in situ hybridization. The expression of transforming growth factor-beta 1 and transforming growth factor-beta type II receptor was also estimated in mesenteric membranes and free peritoneal cells after wounding. A larger expression of alpha-smooth muscle actin was seen around the wound edges compared to unwounded tissue. Both alpha-smooth muscle actin and transforming growth factor-beta type II receptor were expressed during Days 0, 3, 5, 7, and 10. The expression of alpha-smooth muscle actin on Day 5 was > 100 times higher than on Day 0. Transforming growth factor-beta 1 was expressed in both membranes and free peritoneal cells of unoperated control animals but down-regulated after wounding, a finding that has not been reported previously. It reappeared on Days 7 and 10 in free peritoneal cells but not in perforated membranes. The enhanced expression of alpha-smooth muscle actin and down-regulation of transforming growth factor-beta 1 expression after wounding appears to be important phenomena in tissue contraction and repair.
Publisher: Elsevier BV
Date: 06-2015
Publisher: Springer Science and Business Media LLC
Date: 21-09-2020
DOI: 10.1038/S41467-020-18151-Y
Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA s les, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological ergences between two reproducible somatic variant detection efforts.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Springer Science and Business Media LLC
Date: 29-05-2020
DOI: 10.1186/S13073-020-00744-3
Abstract: Distinct prevalence of inherited genetic predisposition may partially explain the difference of cancer risks across ancestries. Ancestry-specific analyses of germline genomes are required to inform cancer genetic risk and prognosis of erse populations. We conducted analyses using germline and somatic sequencing data generated by The Cancer Genome Atlas. Collapsing pathogenic and likely pathogenic variants to cancer predisposition genes (CPG), we analyzed the association between CPGs and cancer types within ancestral groups. We also identified the predisposition-associated two-hit events and gene expression effects in tumors. Genetic ancestry analysis classified the cohort of 9899 cancer cases into in iduals of primarily European ( N = 8184, 82.7%), African ( N = 966, 9.8%), East Asian ( N = 649, 6.6%), South Asian ( N = 48, 0.5%), Native/Latin American ( N = 41, 0.4%), and admixed ( N = 11, 0.1%) ancestries. In the African ancestry, we discovered a potentially novel association of BRCA2 in lung squamous cell carcinoma (OR = 41.4 [95% CI, 6.1–275.6] FDR = 0.002) previously identified in Europeans, along with a known association of BRCA2 in ovarian serous cystadenocarcinoma (OR = 8.5 [95% CI, 1.5–47.4] FDR = 0.045). In the East Asian ancestry, we discovered one previously known association of BRIP1 in stomach adenocarcinoma (OR = 12.8 [95% CI, 1.8–90.8] FDR = 0.038). Rare variant burden analysis further identified 7 suggestive associations in African ancestry in iduals previously described in European ancestry, including SDHB in pheochromocytoma and paraganglioma, ATM in prostate adenocarcinoma, VHL in kidney renal clear cell carcinoma, FH in kidney renal papillary cell carcinoma, and PTEN in uterine corpus endometrial carcinoma. Most predisposing variants were found exclusively in one ancestry in the TCGA and gnomAD datasets. Loss of heterozygosity was identified for 7 out of the 15 African ancestry carriers of predisposing variants. Further, tumors from the SDHB or BRCA2 carriers showed simultaneous allelic-specific expression and low gene expression of their respective affected genes, and FH splice-site variant carriers showed mis-splicing of FH . While several CPGs are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects. Studies using larger cohorts of erse ancestries are required to pinpoint ancestry-specific genetic predisposition and inform genetic screening strategies.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 05-2020
Publisher: Wiley
Date: 10-1997
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.CCELL.2018.07.001
Abstract: Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects alternative splicing events and tumor variants by reanalyzing RNA and whole-exome sequencing data. Tumors have up to 30% more alternative splicing events than normal s les. Association analysis of somatic variants with alternative splicing events confirmed known trans associations with variants in SF3B1 and U2AF1 and identified additional trans-acting variants (e.g., TADA1, PPP2R1A). Many tumors have thousands of alternative splicing events not detectable in normal s les on average, we identified ≈930 exon-exon junctions ("neojunctions") in tumors not typically found in GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumor s les, we confirmed ≈1.7 neojunction- and ≈0.6 single nucleotide variant-derived peptides per tumor s le that are also predicted major histocompatibility complex-I binders ("putative neoantigens").
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 08-2019
Publisher: Elsevier BV
Date: 04-2018
Publisher: Springer Science and Business Media LLC
Date: 30-11-2020
DOI: 10.1038/S41467-020-20128-W
Abstract: Correction to this paper has been published: 0.1038/s41467-020-20128-w
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-10-2018
Abstract: The Cancer Genome Atlas (TCGA) provides a high-quality resource of molecular data on a large variety of human cancers. Corces et al. used a recently modified assay to profile chromatin accessibility to determine the accessible chromatin landscape in 410 TCGA s les from 23 cancer types (see the Perspective by Taipale). When the data were integrated with other omics data available for the same tumor s les, inherited risk loci for cancer predisposition were revealed, transcription factors and enhancers driving molecular subtypes of cancer with patient survival differences were identified, and noncoding mutations associated with clinical prognosis were discovered. Science , this issue p. eaav1898 see also p. 401
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 06-2018
Publisher: Springer Science and Business Media LLC
Date: 28-08-2020
DOI: 10.1038/S41467-020-17359-2
Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.
Publisher: Elsevier BV
Date: 08-2016
Publisher: Elsevier BV
Date: 10-2018
Publisher: Springer Science and Business Media LLC
Date: 09-07-0077
DOI: 10.1038/NATURE13385
Publisher: Elsevier BV
Date: 04-2018
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Roy Tarnuzzer.