Pan-cancer analysis of whole genomes

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 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 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 diverse 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).Peer reviewe

Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases

Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events42Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: 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 samples, 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 divergences between two reproducible somatic variant detection efforts

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

The association between red blood cell distribution width and acute pancreatitis associated lung injury in patients with acute pancreatitis

B ackground: Red blood cell distribution width (RDW) that describes red blood cell volume heterogeneity is a common laboratory test. Our aim was to focus on th e association between RDW and a c ute pancreatitis associated lung injury (APALI). Methodology: A total of 152 acute pancreatitis (AP) patients who conformed to the criteria w ere included in this study. The demographic data, medical histories and laboratory measures was obtained from each patient on admission, further, the medical histories and biological data were analyzed, retrospectively. Results: Increased RDW at admission was observed in patients with APALI compared with the non-APALI groups. Our results exhibited that RDW was an independent risk factor for APALI after adjusting leukocyte, neutrophil percentage, random blood glucose (RBG), total bilirubin (TB) and total bile acid（TBA）(Crude model) (OR=2.671;CI 95% 1.145-6.230; P=0.023), further adjustment based on Crude model for sex and age did not attenuate the significantly high risk of APALI in patients with AP, RWD still remained a ro les as an independent risk factor for APALI (OR=2.653;CI95 % 1.123-6.138; P=0.026). Conclusions: Our study demonstrate that RDW at admission is associated with APALI and should be considered as an underlying risk factor of APALI

Increased Resting-State Cerebellar-Cerebral Functional Connectivity Underlying Chronic Tinnitus

Purpose: Chronic subjective tinnitus may arise from aberrant functional coupling between the cerebellum and the cerebral cortex. To explore this hypothesis, we used resting-state functional magnetic resonance imaging (fMRI) to illuminate the functional connectivity network of the cerebellar regions in chronic tinnitus patients and controls.Methods: Resting-state fMRI scans were obtained from 28 chronic tinnitus patients and 29 healthy controls (well matched for age, sex and education) in this study. Cerebellar-cerebral functional connectivity was characterized using a seed-based whole-brain correlation method. The resulting cerebellar functional connectivity measures were correlated with each clinical tinnitus characteristic.Results: Chronic tinnitus patients demonstrated increased functional connectivity between the cerebellum and several cerebral regions, including the superior temporal gyrus (STG), parahippocampal gyrus (PHG), inferior occipital gyrus (IOG), and precentral gyrus. The enhanced functional connectivity between the left cerebellar Lobule VIIb and the right STG was positively correlated with the Tinnitus Handicap Questionnaires (THQ) score (r = 0.577, p = 0.004). Furthermore, the increased functional connectivity between the cerebellar vermis and the right STG was also associated with the THQ score (r = 0.432, p = 0.039).Conclusions: Chronic tinnitus patients have greater cerebellar functional connectivity to certain cerebral brain regions which is associated with specific tinnitus characteristics. Resting-state cerebellar-cerebral functional connectivity disturbances may play a pivotal role in neuropathological features of tinnitus