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The mucosal epithelium is a common target of damage by chronic bacterial infections and the accompanying toxins, and most cancers originate from this tissue. We investigated whether colibactin, a potent genotoxin 1 associated with certain strains of Escherichia coli 2 , creates a specific DNA-damage signature in infected human colorectal cells. Notably, the genomic contexts of colibactin-induced DNA double-strand breaks were enriched for an AT-rich hexameric sequence motif, associated with distinct DNA-shape characteristics. A survey of somatic mutations at colibactin target sites of several thousand cancer genomes revealed notable enrichment of this motif in colorectal cancers. Moreover, the exact double-strand-break loci corresponded with mutational hot spots in cancer genomes, reminiscent of a trinucleotide signature previously identified in healthy colorectal epithelial cells 3 . The present study provides evidence for the etiological role of colibactin in human cancer. Identification of a DNA-damage signature induced by colibactin, a toxin expressed by some strains of Escherichia coli , is enriched in human colorectal cancers.

Transposable elements (TE) are repetitive genomic elements that harbor binding sites for human transcription factors (TF). A regulatory role for TEs has been suggested in embryonal development and diseases such as cancer but systematic investigation of their functions has been limited by their widespread silencing in the genome. Here, we utilize unbiased massively parallel reporter assay data using a whole human genome library to identify TEs with functional enhancer activity in two human cancer types of endodermal lineage, colorectal and liver cancers. We show that the identified TE enhancers are characterized by genomic features associated with active enhancers, such as epigenetic marks and TF binding. Importantly, we identify distinct TE subfamilies that function as tissue-specific enhancers, namely MER11- and LTR12-elements in colon and liver cancers, respectively. These elements are bound by distinct TFs in each cell type, and they have predicted associations to differentially expressed genes. In conclusion, these data demonstrate how different cancer types can utilize distinct TEs as tissue-specific enhancers, paving the way for comprehensive understanding of the role of TEs as bona fide enhancers in the cancer genomes. A comprehensive characterisation of transposable elements (TEs) in cancer is lacking. Here, the authors identify distinct TEs with different genomic features as tissue-specific enhancers in colorectal and liver cancer.

Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (AI) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.

According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, has been shown to suppress intestinal stemness. Here, we used Paneth cells as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation in mice. Upon inflammation, Paneth cell-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in patients with inflammatory bowel disease, but also of a larger fraction of human sporadic colon cancers. The latter is possibly because of the inflammatory consequences of western-style dietary habits, a major colon cancer risk factor. Machine learning methods designed to predict the cell-of-origin of cancer from patient-derived tumor samples confirmed that, in a substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineages and not in stem cells. Upon inflammation and targeted gene mutation, some fully differentiated secretory and postmitotic intestinal epithelial lineages dedifferentiate to acquire stem-like features and promote tumor formation.

Some leiomyomas have chromosomal rearrangements implicating chromothripsis, a process involving the formation of complex chromosomal rearrangements. In three instances, tumors obtained from the same woman were documented to be clonally related. Uterine leiomyomas are benign smooth-muscle tumors with an estimated prevalence of 77% among women of reproductive age in the United States 1 and can cause a range of health problems. 2 According to a nationwide analysis of 518,828 hysterectomies performed in 2005 in the United States, 282,291 of the patients who underwent the procedure (54%) had leiomyomas. 3 Hormonal factors, family history, African ancestry, and obesity increase the risk of leiomyomas. 4 Presentation with multiple tumors is typical (an estimated average is six to seven 1 ). Whether leiomyosarcomas develop from leiomyomas or arise independently is not known. Uterine leiomyosarcoma is very rare, 5 and it . . .

Cancer genomes with mutations in the exonuclease domain of Polymerase Epsilon (POLE) present with an extraordinarily high somatic mutation burden. In vitro studies have shown that distinct POLE mutants exhibit different polymerase activity. Yet, genome-wide mutation patterns and driver mutation formation arising from different POLE mutants remains unclear. Here, we curated somatic mutation calls from 7,345 colorectal cancer samples from published studies and publicly available databases. These include 44 POLE mutant samples including 9 with whole genome sequencing data available. The POLE mutant samples were categorized based on the specific POLE mutation present. Mutation spectrum, associations of somatic mutations with epigenomics features and co-occurrence with specific driver mutations were examined across different POLE mutants. We found that different POLE mutants exhibit distinct mutation spectrum with significantly higher relative frequency of C>T mutations in POLE V411L mutants. Our analysis showed that this increase frequency in C>T mutations is not dependent on DNA methylation and not associated with other genomic features and is thus specifically due to DNA sequence context alone. Notably, we found strong association of the TP53 R213* mutation specifically with POLE P286R mutants. This truncation mutation occurs within the TT[C>T]GA context. For C>T mutations, this sequence context is significantly more likely to be mutated in POLE P286R mutants compared with other POLE exonuclease domain mutants. This study refines our understanding of DNA polymerase fidelity and underscores genome-wide mutation spectrum and specific cancer driver mutation formation observed in POLE mutant cancers.

Aberrations in the regulatory genome play a pivotal role in population-level disease predisposition. Annotation of the regulatory regions using appropriate primary tissues - instead of cell lines affected by selection and other confounding factors - could shed new light into mechanisms underlying common conditions. We test this approach in uterine leiomyomas, highly prevalent benign neoplasms of the myometrium, by creating 15-state chromatin annotations for myometrium and uterine leiomyomas. Integration with RNA-seq, ATAC-seq, HiChIP and methylation data enables us to compare the epigenomes of myometrium and ULs with distinct driver mutations, highlighting the role of bivalent regions in the neoplastic process. Subsequently, a genome wide association study meta-analysis is performed, using three different cohorts. Disease association loci are enriched at active chromatin, especially at enhancers, and harbor tumor- and driver mutation-specific chromatin states. At SATB2 locus we show the effect of the risk genotype already in the normal tissue. Integration of genome-wide association studies and deep regulatory genomics data from the correct tissue type represents a powerful approach in understanding population-level disease predisposition. The chromatin state origins of uterine leiomyoma (UL) remain to be explored. Here, the authors integrate data from genome-wide association studies and deep regulatory genomics data from myometrium and the three UL subclasses to understand population-level disease predisposition at chromatin state level.

One in four women suffers from uterine leiomyomas (ULs)—benign tumours of the uterine wall, also known as uterine fibroids—at some point in premenopausal life. ULs can cause excessive bleeding, pain and infertility 1 , and are a common cause of hysterectomy 2 . They emerge through at least three distinct genetic drivers: mutations in MED12 or FH , or genomic rearrangement of HMGA2 3 . Here we created genome-wide datasets, using DNA, RNA, assay for transposase-accessible chromatin (ATAC), chromatin immunoprecipitation (ChIP) and HiC chromatin immunoprecipitation (HiChIP) sequencing of primary tissues to profoundly understand the genesis of UL. We identified somatic mutations in genes encoding six members of the SRCAP histone-loading complex 4 , and found that germline mutations in the SRCAP members YEATS4 and ZNHIT1 predispose women to UL. Tumours bearing these mutations showed defective deposition of the histone variant H2A.Z. In ULs, H2A.Z occupancy correlated positively with chromatin accessibility and gene expression, and negatively with DNA methylation, but these correlations were weak in tumours bearing SRCAP complex mutations. In these tumours, open chromatin emerged at transcription start sites where H2A.Z was lost, which was associated with upregulation of genes. Furthermore, YEATS4 defects were associated with abnormal upregulation of bivalent embryonic stem cell genes, as previously shown in mice 5 . Our work describes a potential 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 driver mutations. Analyses of samples from 728 women with uterine leiomyomas (uterine fibroids), and public data, show that somatic and germline mutations in the SRCAP histone-loading complex genes are associated with the condition.

Using a combination of whole-genome sequencing, haplotype sharing and the genealogies of the Icelandic population, Thorunn Rafnar, Kari Stefansson and colleagues identified a rare coding mutation in the gene of a BRCA1-interacting factor, BRIP1 , that confers a high relative risk of ovarian cancer. Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries. Sixteen million sequence variants, identified through whole-genome sequencing of 457 Icelanders, were imputed to 41,675 Icelanders genotyped using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer ( N of affected individuals = 656). We discovered a rare (0.41% allelic frequency) frameshift mutation, c.2040_2041insTT, in the BRIP1 ( FANCJ ) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, P = 2.8 × 10 −14 ). The mutation was also associated with increased risk of cancer in general and reduced lifespan by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1 , c.1702_1703del, was seen in 2 out of 144 subjects with ovarian cancer and 1 out of 1,780 control subjects ( P = 0.016). This allele was also associated with breast cancer (seen in 6/927 cases; P = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation show loss of the wild-type allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer.

Uterine leiomyomas are common benign smooth muscle tumors that impose a major burden on women’s health. Recent sequencing studies have revealed recurrent and mutually exclusive mutations in leiomyomas, suggesting the involvement of molecularly distinct pathways. In this study, we explored transcriptional differences among leiomyomas harboring different genetic drivers, including high mobility group AT-hook 2 (HMGA2) rearrangements, mediator complex subunit 12 (MED12) mutations, biallelic inactivation of fumarate hydratase (FH), and collagen, type IV, alpha 5 and collagen, type IV, alpha 6 (COL4A5-COL4A6) deletions. We also explored the transcriptional consequences of 7q22, 22q, and 1p deletions, aiming to identify possible target genes. We investigated 94 leiomyomas and 60 corresponding myometrial tissues using exon arrays, whole genome sequencing, and SNP arrays. This integrative approach revealed subtype-specific expression changes in key driver pathways, including Wnt/β-catenin, Prolactin, and insulin-like growth factor (IGF)1 signaling. Leiomyomas with HMGA2 aberrations displayed highly significant up-regulation of the proto-oncogene pleomorphic adenoma gene 1 (PLAG1), suggesting that HMGA2 promotes tumorigenesis through PLAG1 activation. This was supported by the identification of genetic PLAG1 alterations resulting in expression signatures as seen in leiomyomas with HMGA2 aberrations. RAD51 paralog B (RAD51B), the preferential translocation partner of HMGA2, was up-regulated in MED12 mutant lesions, suggesting a role for this gene in the genesis of leiomyomas. FH-deficient leiomyomas were uniquely characterized by activation of nuclear factor erythroid 2-related factor 2 (NRF2) target genes, supporting the hypothesis that accumulation of fumarate leads to activation of the oncogenic transcription factor NRF2. This study emphasizes the need for molecular stratification in leiomyoma research and possibly in clinical practice as well. Further research is needed to determine whether the candidate biomarkers presented herein can provide guidance for managing the millions of patients affected by these lesions.