Showing papers by "John Douglas Mcpherson published in 2020"
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TL;DR: The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.
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 scale1,2,3. 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 example, 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 promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10,11,12,13,14,15,16,17,18.
1,600 citations
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Ontario Institute for Cancer Research1, Fred Hutchinson Cancer Research Center2, University of Melbourne3, Cedars-Sinai Medical Center4, Broad Institute5, Harvard University6, German Cancer Research Center7, University of Washington8, National Institutes of Health9, Medical University of Vienna10, Royal Melbourne Hospital11, Washington University in St. Louis12, University of Hamburg13, Emory University14, University of Southern California15, Mayo Clinic16, Yale University17, Yale Cancer Center18, American Cancer Society19, City of Hope National Medical Center20, Umeå University21, Ohio State University22, University of California, Davis23, University of Barcelona24, Johns Hopkins University25, Baylor College of Medicine26, University Health Network27, University of Toronto28
TL;DR: It is determined that mutational burden and specific mutations in TP53 are associated with survival odds, and differences in mutational frequency of several genes and pathways by tumor location, stage, and sex are observed.
Abstract: Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.
49 citations
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TL;DR: The authors sought to characterize alterations in DNA repair pathway genes in both primary and metastatic prostate tumors with attention to tissue distribution as well as specific genomic alterations.
Abstract: Background Emerging evidence has suggested that DNA repair gene alterations may be important in prostate cancer pathogenesis. In the current study, the authors sought to characterize alterations in DNA repair pathway genes in both primary and metastatic prostate tumors with attention to tissue distribution as well as specific genomic alterations. Methods The authors studied the distribution and type of alterations in 24 genes that are considered important for DNA repair in 944 prostate cancers harvested from localized and metastatic tumors. Tumor DNA underwent hybrid capture for all coding exons of 287 or 395 cancer-related genes plus select introns from 19 or 31 genes frequently rearranged in cancer. Captured libraries were sequenced to a median exon coverage depth of >×500. Specific genomic alterations were characterized and the frequencies of mutations by tissue site (prostate vs metastases) were compared using logistic regression. Results A total of 152 patients from the cohort of 944 men (16%) harbored a germline or somatic mutation in ≥1 DNA repair genes. The most frequently mutated genes were BRCA2 (11.4%) and ATM (5.8%), followed by MSH6 (2.5%) and MSH2 (2.1%). Mutations were identified in approximately 20.1% of primary prostate tumors compared with 18.8% of bone metastases. When stratified by tissue site, the highest rates of DNA repair mutations were found in solid organ metastases, including brain and visceral metastases, compared with prostate. Conclusions DNA repair gene mutations are more common in metastatic than localized prostate tumors. Visceral and other solid organ metastases appear enriched for these mutations compared with localized tumors or bone and lymph node metastases.
20 citations
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TL;DR: This study investigated whether whole-genome sequencing (WGS) and whole-transcriptome sequences (RNA-seq) can resolve complex aberrations in a series of patients where conventional cytogenetics could not resolve the driver event.
Abstract: Author(s): Kim, Jaeseung C; Zuzarte, Philip C; Murphy, Tracy; Chan-Seng-Yue, Michelle; Brown, Andrew MK; Krzyzanowski, Paul M; Smith, Adam C; Notta, Faiyaz; Minden, Mark D; McPherson, John D
12 citations
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5 citations
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TL;DR: A case of DDD presenting in adolescence with prominent acral hyperpigmentation caused by a novel heterozygous truncating mutation and potential modifying single nucleotide polymorphism (SNP) in POFUT1 is reported.
Abstract: DDD: Dowling-Degos disease SNP: single nucleotide polymorphism INTRODUCTION Dowling-Degos disease (DDD) is an autosomal dominant pigmentary disorder characterized by reticular hyperpigmentation, hypopigmentation, and hyperkeratotic papules of the flexures, including the neck, axillae, antecubital fossae, inframammary area and groin, and acral sites typically presenting between ages 20 and 50. The clinical presentation is variable and is partly attributable to mutations causing DDD, including loss-of-function mutations in KRT5, POGLUT1, or POFUT1, involved in melanin synthesis and transport. Here we report a case of DDD presenting in adolescence with prominent acral hyperpigmentation caused by a novel heterozygous truncating mutation and potential modifying single nucleotide polymorphism (SNP) in POFUT1.
2 citations