Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes with CTCF (CCCTC-binding factor), affecting genomic stability, expression and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/cohesin-binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in A•T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase ɛ (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.

A101555A_nrreporting-summary_2020_ 04_22 updated.pdf A. Additional Supplementary Files Type Number If there are multiple files of the same type this should be the numerical indicator. i.e. "1" for Video 1, "2" for Video 2, etc. Filename This should be the name the file is saved as when it is uploaded to our system, and should include the file extension. i.e.: Smith_ Supplementary_Video_1. mov Legend or Descriptive Caption Describe the contents of the file Supplementary Table 1 Tables.xlsx Supplementary Tables 1-2 Colibactin DNA damage signature indicates mutational impact in colorectal cancer

Every fourth woman suffers from uterine leiomyomas (ULs) -benign uterine wall tumors -at some point in premenopausal life. ULs can cause excessive bleeding, pain and infertility 1 , and are the most common cause of hysterectomy 2 . They emerge through at least three distinct genetic drivers: MED12 or FH mutation, or HMGA2 genomic rearrangement 3 . Here we created large genome-wide data sets by DNA, RNA, ATAC, ChIP and HiChIP sequencing of primary tissues to profoundly understand UL genesis. We discovered somatic mutations in genes encoding six members of the SRCAP histone loading complex 4 , and found that germline mutations in SRCAP complex members YEATS4 and ZNHIT1 predispose to UL. The mutant tumors displayed defective histone variant H2A.Z deposition. In ULs, H2A.Z occupancy correlated positively with chromatin accessibility and gene expression, and negatively with DNA methylation, but these correlations were weak in SRCAP complex mutant tumors. In such tumors, open chromatin emerged at transcription start sites where H2A.Z was lost, associated with upregulation of genes. Furthermore, YEATS4 defects associated with abnormal upregulation of bivalent embryonic stem cell genes, as previously shown in mice 5 . Our work describes a potential novel mechanism of tumorigenesis -epigenetic instability caused by deficient H2A.Z deposition -and suggests that ULs arise through an aberrant differentiation program driven by deranged chromatin, emanating from a small number of mutually exclusive genetic driver mutations.

BackgroundWhile dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk.MethodsWe analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels.ResultsRisk reduction was observed for oleic and palmitoleic MUFAs (OROA = 0.77, 95% CI: 0.65–0.92, P = 3.9 × 10−3; ORPOA = 0.36, 95% CI: 0.15–0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (ORLA = 0.95, 95% CI: 0.93–0.98, P = 3.7 × 10−4; ORAA = 1.05, 95% CI: 1.02–1.07, P = 1.7 × 10−4). The SFA stearic acid was associated with increased CRC risk (ORSA = 1.17, 95% CI: 1.01–1.35, P = 0.041).ConclusionResults from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk.