To characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-genome seq... more To characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-genome sequencing analysis of 2,023 tumours. We provide the most detailed high-resolution map to date of somatic mutations in CRC, and demonstrate associations with clinicopathological features, in particular location in the large bowel. We refined the mutational processes and signatures acting in colorectal tumorigenesis. In analyses across the sample set or restricted to molecular subtypes, we identified 185 CRC driver genes, of which 117 were previously unreported. New drivers acted in various molecular pathways, including Wnt (CTNND1, AXIN1, TCF3), TGF-β/BMP (TGFBR1) and MAP kinase (RASGRF1, RASA1, RAF1, and several MAP2K and MAP3K loci). Non-coding drivers included intronic neo-splice site alterations in APC and SMAD4. Whilst there was evidence of an excess of mutations in functionally active regions of the non-coding genome, no specific drivers were called with high confidence. Novel recurre...
ABSTRACTTo characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-ge... more ABSTRACTTo characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-genome sequencing analysis of 2,023 tumours. We provide the most detailed high-resolution map to date of somatic mutations in CRC, and demonstrate associations with clinicopathological features, in particular location in the large bowel. We refined the mutational processes and signatures acting in colorectal tumorigenesis. In analyses across the sample set or restricted to molecular subtypes, we identified 185 CRC driver genes, of which 117 were previously unreported. New drivers acted in various molecular pathways, including Wnt (CTNND1, AXIN1, TCF3), TGF-β/BMP (TGFBR1) and MAP kinase (RASGRF1, RASA1, RAF1, and several MAP2K and MAP3K loci). Non-coding drivers included intronic neo-splice site alterations inAPCandSMAD4. Whilst there was evidence of an excess of mutations in functionally active regions of the non-coding genome, no specific drivers were called with high confidence. Novel re...
Mean (±se) (a) laughter rate (number of 15-sec scans on which subject was audibly laughing), (b) ... more Mean (±se) (a) laughter rate (number of 15-sec scans on which subject was audibly laughing), (b) change in positive affect score and (c) change in negative affect score, for men (unfilled symbols) and women (filled symbols) in Experiment 1.</p
Mean±se ratio of (a) donation to friend divided by donation to self and (b) donation to stranger ... more Mean±se ratio of (a) donation to friend divided by donation to self and (b) donation to stranger divided by donation to friend, for men (unfilled symbols) and women (filled symbols) in Experiment 1.</p
Mean±se (a) change IOS score (with respect to rest of experimental group) and (b) donation, for m... more Mean±se (a) change IOS score (with respect to rest of experimental group) and (b) donation, for men (unfilled symbols) and women (filled symbols) in Experiment 2.</p
For patients with inoperable esophageal adenocarcinoma (EAC), prognosis on conventional chemother... more For patients with inoperable esophageal adenocarcinoma (EAC), prognosis on conventional chemotherapy (CTX) remains poor. In 2021, the FDA approved two αPD-1 immune checkpoint inhibitors (ICI) for addition to fluoropyrimidine/platinum-containing CTX in this first-line setting. As ICI+CTX enters the clinic, understanding ICI responses and predicting which patients will benefit from ICI addition are key challenges. To address these challenges, we assessed clinical and molecular profiles from the experimental LUD2015-005 trial (NCT02735239, EudraCT 2015-005298-19). Treatment consisted of an initial four-week ICI-only window with durvalumab (αPD-L1) with or without a single dose of tremelimumab (αCTLA-4), followed by 6 cycles of ICI+CTX (CapOx). 38 inoperable patients received treatment (35 EAC; 3 ESCC); median overall survival (OS) and progression-free survival (PFS) were 13.4 and 9.3 months, respectively. All patients reported at least one treatment emergent adverse event (TEAE), with ...
Mean±se (a) frequency of laughter (number of laughs given) and (b) change in pain threshold, for ... more Mean±se (a) frequency of laughter (number of laughs given) and (b) change in pain threshold, for men (unfilled symbols) and women (filled symbols) in Experiment 2.</p
Mean±se (a) Change in pain threshold and (b) total donations, for men (unfilled symbols) and wome... more Mean±se (a) Change in pain threshold and (b) total donations, for men (unfilled symbols) and women (filled symbols) in Experiment 1.</p
The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation bu... more The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutation...
Barrett’s oesophagus (BE) is the main risk factor for the development of oesophageal adenocarcino... more Barrett’s oesophagus (BE) is the main risk factor for the development of oesophageal adenocarcinoma (OAC), yet few patients ever go on to progress to cancer. The acquisition of events during the metaplasia-dysplasia-cancer sequence is poorly characterised. We present a large, unbiased, multi-omics analysis of a cross-sectional cohort of pre-cancer samples, with the aim of providing a comprehensive insight into the diversity and molecular changes driving the disease to cancer. We generated and integrated the genomic (50x), transcriptomic and epigenomic (850K EPIC array) landscapes of snap-frozen endoscopic biopsies from 146 patients with a range of outcomes (27 long-standing non-dysplastic; 12 prior to progression to dysplasia; 14 low-grade; 25 high-grade; 21 intramucosal carcinoma; 47 cases of BE taken adjacent to OAC) and 642 person years of follow-up. All biopsies were reviewed independently by 3 pathologists and had associated annotation with detailed clinical information. The to...
hereright-hand corner of the article or click Receive free email alerts when new articles cite th... more hereright-hand corner of the article or click Receive free email alerts when new articles cite this article- sign up in the box at the top publication. Citations to Advance online articles must include the digital object identifier (DOIs) and date of initial online articles are citable and establish publication priority; they are indexed by PubMed from initial publication. the paper journal (edited, typeset versions may be posted when available prior to final publication). Advance Advance online articles have been peer reviewed and accepted for publication but have not yet appeared in
Humans deploy a number of specific behaviours for forming social bonds, one of which is laughter.... more Humans deploy a number of specific behaviours for forming social bonds, one of which is laughter. However, two questions have not yet been investigated with respect to laughter: (1) Does laughter increase the sense of bonding to those with whom we laugh? and (2) Does laughter facilitate prosocial generosity? Using changes in pain threshold as a proxy for endorphin upregulation in the brain and a standard economic game (the Dictator Game) as an assay of prosociality, we show that laughter does trigger the endorphin system and, through that, seems to enhance social bonding, but it does not reliably influence donations to others. This suggests that social bonding and prosociality may operate via different mechanisms, or on different time scales, and relate to different functional objectives.
Alex J. Cornish *, Daniel Chubb *, Anna Frangou, Phuc H. Hoang, Martin Kaiser, David C. Wedge and... more Alex J. Cornish *, Daniel Chubb *, Anna Frangou, Phuc H. Hoang, Martin Kaiser, David C. Wedge and Richard S. Houlston 1 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG 2, UK, Nuffield Department of Medicine, Big Data Institute University of Oxford, OX3 7LF 3, UK, Molecular Diagnostics Theme, Oxford NIHR Biomedical Research Centre, Oxford, OX3 7LF 3, UK, Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG 5, UK and Manchester Cancer Research Centre, University of Manchester, M20 4GJ, UK
Estimating the fraction of cancer cells with individual somatic mutations is central to many anal... more Estimating the fraction of cancer cells with individual somatic mutations is central to many analyses in cancer genomics, including characterisation of clonal architecture and timing of mutational events. Estimation of these cancer cell fractions (CCFs) is contingent on unbiased assessment of the fraction of reads supporting variant alleles (VAFs). We demonstrate that VAFs computed by the Illumina Isaac pipeline, used in many large-scale sequencing projects including The 100,000 Genomes Project, are biased by the preferential soft clipping of reads supporting non-reference alleles (semi-aligned reads). We show that these biased VAFs can have deleterious effects on downstream analyses reliant on unbiased CCF estimates. While Isaac bias can be corrected through realignment with alternative parameters, this is computationally intensive. We therefore developed FixVAF, a tool for removing bias introduced by soft clipping of semi-aligned reads, facilitating downstream analyses without the...
This thesis uses genealogical trees to identify, date, and quantify patterns of admixture between... more This thesis uses genealogical trees to identify, date, and quantify patterns of admixture between Neandertals and individual modern human populations, using a combination of high quality data and parametric methodology. Previous methods on this subject have either approximated features of trees, or inferred them indirectly. Here, genealogical trees are used directly to understand the admixture process between humans and Neandertals by extending a recently developed method named CEPHi: Coalescent Estimation of Population History. CEPHi uses recombinationally cold regions of the human genome to build genealogical trees specifying the relationships between individuals in two input populations (one Neandertal, one human), including estimated population size histories, split times, and coalescence and mutation times. Using CEPHi, a Neandertal-human population split time of T712,000 years in the past is estimated, as well as uncovering loci introduced by Neandertal-human admixture, reveal...
ABSTRACTInherited defects in base-excision repair (BER) predispose to adenomatous polyposis and c... more ABSTRACTInherited defects in base-excision repair (BER) predispose to adenomatous polyposis and colorectal cancer (CRC), yet our understanding of this important DNA repair pathway remains incomplete. By combining detailed clinical, histological and molecular profiling, we reveal biallelic germline loss-of-function (LOF) variants in the BER gene MBD4 to predispose to adenomatous polyposis and –uniquely amongst CRC predisposition syndromes– to myeloid neoplasms. Neoplasms from MBD4-deficient patients almost exclusively accumulate somatic CpG>TpG mutations, resembling mutational signature SBS1. MBD4-deficient adenomas harbour mutations in known CRC driver genes, although AMER1 mutations were more common and KRAS mutations less frequent. We did not find an increased risk for colorectal tumours in individuals with a monoallelic MBD4 LOF variant. We suggest that this condition should be termed MBD4-associated neoplasia syndrome (MANS) and that MBD4 is included in testing for the geneti...
To characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-genome seq... more To characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-genome sequencing analysis of 2,023 tumours. We provide the most detailed high-resolution map to date of somatic mutations in CRC, and demonstrate associations with clinicopathological features, in particular location in the large bowel. We refined the mutational processes and signatures acting in colorectal tumorigenesis. In analyses across the sample set or restricted to molecular subtypes, we identified 185 CRC driver genes, of which 117 were previously unreported. New drivers acted in various molecular pathways, including Wnt (CTNND1, AXIN1, TCF3), TGF-β/BMP (TGFBR1) and MAP kinase (RASGRF1, RASA1, RAF1, and several MAP2K and MAP3K loci). Non-coding drivers included intronic neo-splice site alterations in APC and SMAD4. Whilst there was evidence of an excess of mutations in functionally active regions of the non-coding genome, no specific drivers were called with high confidence. Novel recurre...
ABSTRACTTo characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-ge... more ABSTRACTTo characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-genome sequencing analysis of 2,023 tumours. We provide the most detailed high-resolution map to date of somatic mutations in CRC, and demonstrate associations with clinicopathological features, in particular location in the large bowel. We refined the mutational processes and signatures acting in colorectal tumorigenesis. In analyses across the sample set or restricted to molecular subtypes, we identified 185 CRC driver genes, of which 117 were previously unreported. New drivers acted in various molecular pathways, including Wnt (CTNND1, AXIN1, TCF3), TGF-β/BMP (TGFBR1) and MAP kinase (RASGRF1, RASA1, RAF1, and several MAP2K and MAP3K loci). Non-coding drivers included intronic neo-splice site alterations inAPCandSMAD4. Whilst there was evidence of an excess of mutations in functionally active regions of the non-coding genome, no specific drivers were called with high confidence. Novel re...
Mean (±se) (a) laughter rate (number of 15-sec scans on which subject was audibly laughing), (b) ... more Mean (±se) (a) laughter rate (number of 15-sec scans on which subject was audibly laughing), (b) change in positive affect score and (c) change in negative affect score, for men (unfilled symbols) and women (filled symbols) in Experiment 1.</p
Mean±se ratio of (a) donation to friend divided by donation to self and (b) donation to stranger ... more Mean±se ratio of (a) donation to friend divided by donation to self and (b) donation to stranger divided by donation to friend, for men (unfilled symbols) and women (filled symbols) in Experiment 1.</p
Mean±se (a) change IOS score (with respect to rest of experimental group) and (b) donation, for m... more Mean±se (a) change IOS score (with respect to rest of experimental group) and (b) donation, for men (unfilled symbols) and women (filled symbols) in Experiment 2.</p
For patients with inoperable esophageal adenocarcinoma (EAC), prognosis on conventional chemother... more For patients with inoperable esophageal adenocarcinoma (EAC), prognosis on conventional chemotherapy (CTX) remains poor. In 2021, the FDA approved two αPD-1 immune checkpoint inhibitors (ICI) for addition to fluoropyrimidine/platinum-containing CTX in this first-line setting. As ICI+CTX enters the clinic, understanding ICI responses and predicting which patients will benefit from ICI addition are key challenges. To address these challenges, we assessed clinical and molecular profiles from the experimental LUD2015-005 trial (NCT02735239, EudraCT 2015-005298-19). Treatment consisted of an initial four-week ICI-only window with durvalumab (αPD-L1) with or without a single dose of tremelimumab (αCTLA-4), followed by 6 cycles of ICI+CTX (CapOx). 38 inoperable patients received treatment (35 EAC; 3 ESCC); median overall survival (OS) and progression-free survival (PFS) were 13.4 and 9.3 months, respectively. All patients reported at least one treatment emergent adverse event (TEAE), with ...
Mean±se (a) frequency of laughter (number of laughs given) and (b) change in pain threshold, for ... more Mean±se (a) frequency of laughter (number of laughs given) and (b) change in pain threshold, for men (unfilled symbols) and women (filled symbols) in Experiment 2.</p
Mean±se (a) Change in pain threshold and (b) total donations, for men (unfilled symbols) and wome... more Mean±se (a) Change in pain threshold and (b) total donations, for men (unfilled symbols) and women (filled symbols) in Experiment 1.</p
The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation bu... more The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutation...
Barrett’s oesophagus (BE) is the main risk factor for the development of oesophageal adenocarcino... more Barrett’s oesophagus (BE) is the main risk factor for the development of oesophageal adenocarcinoma (OAC), yet few patients ever go on to progress to cancer. The acquisition of events during the metaplasia-dysplasia-cancer sequence is poorly characterised. We present a large, unbiased, multi-omics analysis of a cross-sectional cohort of pre-cancer samples, with the aim of providing a comprehensive insight into the diversity and molecular changes driving the disease to cancer. We generated and integrated the genomic (50x), transcriptomic and epigenomic (850K EPIC array) landscapes of snap-frozen endoscopic biopsies from 146 patients with a range of outcomes (27 long-standing non-dysplastic; 12 prior to progression to dysplasia; 14 low-grade; 25 high-grade; 21 intramucosal carcinoma; 47 cases of BE taken adjacent to OAC) and 642 person years of follow-up. All biopsies were reviewed independently by 3 pathologists and had associated annotation with detailed clinical information. The to...
hereright-hand corner of the article or click Receive free email alerts when new articles cite th... more hereright-hand corner of the article or click Receive free email alerts when new articles cite this article- sign up in the box at the top publication. Citations to Advance online articles must include the digital object identifier (DOIs) and date of initial online articles are citable and establish publication priority; they are indexed by PubMed from initial publication. the paper journal (edited, typeset versions may be posted when available prior to final publication). Advance Advance online articles have been peer reviewed and accepted for publication but have not yet appeared in
Humans deploy a number of specific behaviours for forming social bonds, one of which is laughter.... more Humans deploy a number of specific behaviours for forming social bonds, one of which is laughter. However, two questions have not yet been investigated with respect to laughter: (1) Does laughter increase the sense of bonding to those with whom we laugh? and (2) Does laughter facilitate prosocial generosity? Using changes in pain threshold as a proxy for endorphin upregulation in the brain and a standard economic game (the Dictator Game) as an assay of prosociality, we show that laughter does trigger the endorphin system and, through that, seems to enhance social bonding, but it does not reliably influence donations to others. This suggests that social bonding and prosociality may operate via different mechanisms, or on different time scales, and relate to different functional objectives.
Alex J. Cornish *, Daniel Chubb *, Anna Frangou, Phuc H. Hoang, Martin Kaiser, David C. Wedge and... more Alex J. Cornish *, Daniel Chubb *, Anna Frangou, Phuc H. Hoang, Martin Kaiser, David C. Wedge and Richard S. Houlston 1 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG 2, UK, Nuffield Department of Medicine, Big Data Institute University of Oxford, OX3 7LF 3, UK, Molecular Diagnostics Theme, Oxford NIHR Biomedical Research Centre, Oxford, OX3 7LF 3, UK, Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG 5, UK and Manchester Cancer Research Centre, University of Manchester, M20 4GJ, UK
Estimating the fraction of cancer cells with individual somatic mutations is central to many anal... more Estimating the fraction of cancer cells with individual somatic mutations is central to many analyses in cancer genomics, including characterisation of clonal architecture and timing of mutational events. Estimation of these cancer cell fractions (CCFs) is contingent on unbiased assessment of the fraction of reads supporting variant alleles (VAFs). We demonstrate that VAFs computed by the Illumina Isaac pipeline, used in many large-scale sequencing projects including The 100,000 Genomes Project, are biased by the preferential soft clipping of reads supporting non-reference alleles (semi-aligned reads). We show that these biased VAFs can have deleterious effects on downstream analyses reliant on unbiased CCF estimates. While Isaac bias can be corrected through realignment with alternative parameters, this is computationally intensive. We therefore developed FixVAF, a tool for removing bias introduced by soft clipping of semi-aligned reads, facilitating downstream analyses without the...
This thesis uses genealogical trees to identify, date, and quantify patterns of admixture between... more This thesis uses genealogical trees to identify, date, and quantify patterns of admixture between Neandertals and individual modern human populations, using a combination of high quality data and parametric methodology. Previous methods on this subject have either approximated features of trees, or inferred them indirectly. Here, genealogical trees are used directly to understand the admixture process between humans and Neandertals by extending a recently developed method named CEPHi: Coalescent Estimation of Population History. CEPHi uses recombinationally cold regions of the human genome to build genealogical trees specifying the relationships between individuals in two input populations (one Neandertal, one human), including estimated population size histories, split times, and coalescence and mutation times. Using CEPHi, a Neandertal-human population split time of T712,000 years in the past is estimated, as well as uncovering loci introduced by Neandertal-human admixture, reveal...
ABSTRACTInherited defects in base-excision repair (BER) predispose to adenomatous polyposis and c... more ABSTRACTInherited defects in base-excision repair (BER) predispose to adenomatous polyposis and colorectal cancer (CRC), yet our understanding of this important DNA repair pathway remains incomplete. By combining detailed clinical, histological and molecular profiling, we reveal biallelic germline loss-of-function (LOF) variants in the BER gene MBD4 to predispose to adenomatous polyposis and –uniquely amongst CRC predisposition syndromes– to myeloid neoplasms. Neoplasms from MBD4-deficient patients almost exclusively accumulate somatic CpG>TpG mutations, resembling mutational signature SBS1. MBD4-deficient adenomas harbour mutations in known CRC driver genes, although AMER1 mutations were more common and KRAS mutations less frequent. We did not find an increased risk for colorectal tumours in individuals with a monoallelic MBD4 LOF variant. We suggest that this condition should be termed MBD4-associated neoplasia syndrome (MANS) and that MBD4 is included in testing for the geneti...
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