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Abstract Renal cell carcinoma (RCC) comprises several histological types characterised by different genomic and epigenomic aberrations; however, the molecular pathogenesis of each type still requires further exploration. We perform whole-genome sequencing of 128 Japanese RCC cases of different histology to elucidate the significant somatic alterations and mutagenesis processes. We also perform transcriptomic and epigenomic sequencing to identify distinguishing features, including assay for transposase-accessible chromatin sequencing (ATAC-seq) and methyl sequencing. Genomic analysis reveals that the mutational signature differs among the histological types, suggesting that different carcinogenic factors drive each histology. From the ATAC-seq results, master transcription factors are identified for each histology. Furthermore, clear cell RCC is classified into three epi-subtypes, one of which expresses highly immune checkpoint molecules with frequent loss of chromosome 14q. These genomic and epigenomic features may lead to the development of effective therapeutic strategies for RCC.

Abstract Chronic inflammation promotes development and progression of colorectal cancer (CRC). To comprehensively understand the molecular mechanisms underlying the development and progression of inflamed CRC, we perform in vivo screening and identify 142 genes that are frequently mutated in inflammation-associated colon tumors. These genes include senescence and TGFβ-activin signaling genes. We find that TNFα can induce stemness and activate senescence signaling by enhancing cell plasticity in colonic epithelial cells, which could act as a selective pressure to mutate senescence-related genes in inflammation-associated colonic tumors. Furthermore, we show the efficacy of the Cdk4/6 inhibitor in vivo for inflammation-associated colonic tumors. Finally, we functionally validate that Arhgap5 and Mecom are tumor suppressor genes, providing possible therapeutic targets for CRC. Thus, we demonstrate the importance of the inactivation of senescence pathways in CRC development and progression in an inflammatory microenvironment, which can help progress toward precision medicine.

Abstract Structural variants (SVs) are responsible for driver events in gastric cancer (GC); however, their patterns and processes remain poorly understood. Here, we examine 170 GC whole genomes to unravel the oncogenic structural aberration landscape in GC genomes and identify six rearrangement signatures (RSs). Non-random combinations of RSs elucidate distinctive GC subtypes comprising one or a few dominant RS that are associated with specific driver events (BRCA1/2 defects, mismatch repair deficiency, and TP53 mutation) and epidemiological backgrounds. Twenty-seven SV hotspots are identified as GC driver candidates. SV hotspots frequently constitute complexly clustered SVs involved in driver gene amplification, such as ERBB2, CCNE1, and FGFR2. Further deconstruction of the locally clustered SVs uncovers amplicon-generating profiles characterized by super-large SVs and intensive segmental amplifications, contributing to the extensive amplification of GC oncogenes. Comprehensive analyses using adjusted SV allele frequencies indicate the significant involvement of extra-chromosomal DNA in processes linked to specific RSs.

Myxofibrosarcoma occurs in adults and is associated with high local relapse. Here, based on exome/transcriptome sequencing and DNA methylation analysis, the authors identify driver genes and methylation clusters associated with unique combinations of mutations, outcomes, and immune cell compositions.

Genomic aberrations contribute to the development of cancer; however, their interdependence remains poorly understood. Here the authors analyze liver cancer samples to find correlation between epigenetic features and genetic aberrations including somatic substitutions, mutation signatures, and HBV integration sites.

Abstract Yaku sika deer (Cervus nippon yakushimae) are endemic to Yakushima Island, whose landscape covered with primary evergreen forest is recognized as a World Heritage Site. In this study, the rumen bacterial microbiota (RBM) of wild Yaku sika was characterized using high throughput sequencing of bacterial 16S rRNA genes combined with targeted cultivation and functional analyses. Comparative analyses of RBM datasets from other ruminant animals revealed distinct community structure among domesticated and wild ruminants. Wild Yaku sika RBM exhibited higher species richness than other sika deer (i.e. wild Ezo sika and domesticated sika deer), likely reflecting their dietary variations associated with unique ecosystem in the island. The Yaku sika RBM of high deer population density samples exhibited higher diversity and contained higher proportion of Firmicutes than those of lower density samples. Moreover, the highest abundance of tannase gene were observed in individuals from the highest population density area, consistent with the previous observation that Yaku sika in the high density areas expanded their feed to include tannin-rich unpalatable plants. This study indicated that RBM of unique wild Yaku sika contribute to the flexibility of dietary shift and thus maintaining nutritional status of Yaku sika under high density conditions.