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Clare Turnbull and colleagues report discovery of 19 new susceptibility loci for testicular germ cell tumor (TGCT) and provide evidence for a network of physical interactions between TGCT risk variants and candidate causal genes. Their findings implicate widespread disruption of developmental transcriptional regulators in TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis 1 . Defective microtubule assembly and dysregulation of KIT–MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.

Efforts are being directed to systematically analyze the non-coding regions of the genome for cancer-driving mutations 1 – 6 . cis-regulatory elements (CREs) represent a highly enriched subset of the non-coding regions of the genome in which to search for such mutations. Here we use high-throughput chromosome conformation capture techniques (Hi-C) for 19,023 promoter fragments to catalog the regulatory landscape of colorectal cancer in cell lines, mapping CREs and integrating these with whole-genome sequence and expression data from The Cancer Genome Atlas 7 , 8 . We identify a recurrently mutated CRE interacting with the ETV1 promoter affecting gene expression. ETV1 expression influences cell viability and is associated with patient survival. We further refine our understanding of the regulatory effects of copy-number variations, showing that RASL11A is targeted by a previously identified enhancer amplification 1 . This study reveals new insights into the complex genetic alterations driving tumor development, providing a paradigm for employing chromosome conformation capture to decipher non-coding CREs relevant to cancer biology. Promoter capture Hi-C in colorectal cancer cells integrated with cancer genome and expression data identifies a noncoding, cis-regulatory element that is recurrently mutated in cancer, affecting ETV1 expression, cell viability and patient survival.

There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P  = 2.11 × 10 −8 ), for high-hyperdiploid ALL at 5q31.1 (rs886285, P  = 1.56 × 10 −8 ) and 6p21.31 (rs210143 in BAK1 , P   =  2.21 × 10 −8 ), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1 , P  = 1.82 × 10 −8 ). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL. B-cell acute lymphoblastic leukaemia (B-ALL) is a common childhood cancer. Here, the authors conducted a meta-analysis with four genome-wide association studies, totalling 5,321 cases and 16,666 controls of European descent, identifying B-ALL risk loci, whose integration with epigenomic profiling indicates cell-cycle and B-cell development deregulation as central mechanisms in B-ALL susceptibility, often in a subtype-specific fashion.

Despite recent advances in therapy, multiple myeloma essentially remains an incurable malignancy. Targeting tumour-specific essential genes, which constitute a druggable dependency, potentially offers a strategy for developing new therapeutic agents to treat MM and overcome drug resistance. To explore this possibility, we analysed DepMap project data identifying 23 MM essential genes and examined the relationship between their expression and patient outcome in three independent series totalling 1503 cases. The expression of TCF3 and FLVCR1 were both significantly associated with progression-free survival. IKBKB is already a drug target in other diseases, offering the prospect of repurposing to treat MM, while PIM2 is currently being investigated as a treatment for the disease. Our analysis supports the rationale of using large-scale genetic perturbation screens to guide the development of new therapeutic agents for MM.

Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL. The definition of regulatory landscape at chronic lymphocytic leukaemia (CLL) risk loci is limited. Here, the authors perform an epigenomic characterisation of 42 known risk loci in CLL and normal B cells at different developmental stages and show active chromatin and target genes in the risk loci.

Genome-wide association studies (GWAS) have identified over 60 autosomal risk loci associated with clear cell renal cell carcinoma (ccRCC), yet the functional mechanisms underlying these associations remain largely unclear. To establish connections between risk variants and their target genes, we applied the activity-by-contact (ABC) model, which integrates epigenomic data and Micro-C interactions, complemented with renal-specific quantitative trait loci, to predict enhancer-gene relationships. Our analyses implicate variation in hypoxia sensing, cell cycle regulation, and telomerase maintenance pathways as central mediators of ccRCC risk. These findings provide new insights into the molecular basis of ccRCC susceptibility and highlight potential therapeutic avenues for prevention and treatment. Integration of genome-wide association data with epigenomic and chromatin interaction data identifies target genes mediating clear cell renal cell carcinoma risk, implicating disrupted hypoxia signalling, cell cycle, and telomerase regulation.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism 1 – 5 , yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study ( n  = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases. A genome-wide association study of mosaic loss of chromosome Y (LOY) in UK Biobank participants identifies 156 genetic determinants of LOY, showing that LOY is associated with cancer and non-haematological health outcomes.

Multiple myeloma (MM) is a biologically heterogeneous malignancy, however, the mechanisms underlying this complexity are incompletely understood. We report an analysis of the whole-genome sequencing of 765 MM patients from CoMMpass. By employing promoter capture Hi-C in naïve B-cells, we identify cis-regulatory elements (CREs) that represent a highly enriched subset of the non-coding genome in which to search for driver mutations. We identify regulatory regions whose mutation significantly alters the expression of genes as candidate non-coding drivers, including copy number variation (CNV) at CREs of MYC and single-nucleotide variants (SNVs) in a PAX5 enhancer. To better inform the interplay between non-coding driver mutations with other driver mechanisms, and their respective roles in oncogenic pathways, we extended our analysis identifying coding drivers in 40 genes, including 11 novel candidates. We demonstrate the same pathways can be targeted by coding and non-coding mutations; exemplified by IRF4 and PRDM1, along with BCL6 and PAX5, genes that are central to plasma cell differentiation. This study reveals new insights into the complex genetic alterations driving MM development and an enhanced understanding of oncogenic pathways.

Genome-wide association studies of colorectal cancer (CRC) have identified 170 autosomal risk loci. However, for most of these, the functional variants and their target genes are unknown. Here, we perform statistical fine-mapping incorporating tissue-specific epigenetic annotations and massively parallel reporter assays to systematically prioritize functional variants for each CRC risk locus. We identify plausible causal variants for the 170 risk loci, with a single variant for 40. We link these variants to 208 target genes by analyzing colon-specific quantitative trait loci and implementing the activity-by-contact model, which integrates epigenomic features and Micro-C data, to predict enhancer–gene connections. By deciphering CRC risk loci, we identify direct links between risk variants and target genes, providing further insight into the molecular basis of CRC susceptibility and highlighting potential pharmaceutical targets for prevention and treatment. This study uses a combination of in silico and experimental techniques to ascribe target genes to 170 risk loci for colorectal cancer.