The pan-cancer analysis of whole genomes The expansion of whole-genome sequencing studies from individual ICGC and TCGA working groups presented the opportunity to undertake a meta-analysis of genomic features across tumour types. To achieve this, the PCAWG Consortium was established. A Technical Working Group implemented the informatics analyses by aggregating the raw sequencing data from different working groups that studied individual tumour types, aligning the sequences to the human genome and delivering a set of high-quality somatic mutation calls for downstream analysis (Extended Data Fig. 1). Given the recent meta-analysis

The incidence of biliary tract cancer (BTC), including intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and gallbladder cancer, has increased globally; however, no effective targeted molecular therapies have been approved at the present time. Here we molecularly characterized 260 BTCs and uncovered spectra of genomic alterations that included new potential therapeutic targets. Gradient spectra of mutational signatures with a higher burden of the APOBEC-associated mutation signature were observed in gallbladder cancer and ECC. Thirty-two significantly altered genes, including ELF3, were identified, and nearly 40% of cases harbored targetable genetic alterations. Gene fusions involving FGFR2 and PRKACA or PRKACB preferentially occurred in ICC and ECC, respectively, and the subtype-associated prevalence of actionable growth factor-mediated signals was noteworthy. The subgroup with the poorest prognosis had significant enrichment of hypermutated tumors and a characteristic elevation in the expression of immune checkpoint molecules. Accordingly, immune-modulating therapies might also be potentially promising options for these patients.

Background:The host immune reaction is represented by immune/inflammatory cell infiltrates. Here we systematically analysed tumour-infiltrating immune/inflammatory cells in pancreatic ductal carcinoma (PDC) and evaluated their clinicopathological impact.Methods:Using immunohistochemistry, we examined tumour-infiltrating CD68+ pan-macrophages, HLA-DR+CD68+ M1 macrophages (M1), CD163+ or CD204+ M2 macrophages (M2), CD66b+ neutrophils (Neu), CD4+ T cells (CD4+T), CD8+ T cells (CD8+T), and FOXP3+CD4+ regulatory T cells (Treg) in 212 cases of PDC, and conducted correlation and survival analyses using the Kaplan–Meier method and Cox proportional hazards model.Results:Higher levels of tumour-infiltrating pan-macrophages, M2, Neu, or the ratio of Tregs to CD4+T (%Treg) were significantly associated with shorter survival, whereas higher levels of tumour-infiltrating CD4+T, CD8+T, or the ratio of M1 to pan-macrophages (%M1) were significantly associated with longer survival. Survival analysis of pairs of these variables revealed that some of the resulting patient groups had exclusively longer survival. We then connected the apparently related factors, and two significant variables emerged: tumour-infiltrating CD4+Thigh/CD8+Thigh/%Treglow and tumour-infiltrating %M1high/M2low. Multivariate survival analysis revealed that these variables were significantly correlated with longer survival and had a higher hazard ratio.Conclusion:Tumour-infiltrating CD4+Thigh/CD8+Thigh/%Treglow and %M1high/M2low are independent prognosticators useful for evaluating the immune microenvironment of PDC.

Purpose: Antitumor immune response changes drastically during the progression of cancers.Established cancers often escape from the host immune system, although specific immune surveillance operates in the early stages of tumorigenesis in murine models. CD4 + CD25+ regulatory T cells (T R ) play a central role in self-tolerance and suppress effective antitumor immune responses. The aim of this study was to investigate the clinical significance and roles of T R in the progression and multistep carcinogenesis of pancreatic ductal adenocarcinoma. Experimental Design: We raised anti-FOXP3 antibodies and used them in immunohistochemical studies of the prevalence of FOXP3+ T R in the CD4 + T cells, which infiltrated in tissue and draining lymph nodes of 198 pancreatic ductal adenocarcinomas, their premalignant lesions (84 lesions of pancreatic intraepithelial neoplasias and 51 intraductal papillary-mucinous neoplasms), and 15 nonneoplastic pancreatic lesions.Results: The prevalence of T R was significantly increased in the ductal adenocarcinomas compared with that in the stroma of nonneoplastic inflammation (P < 0.0001). The increased prevalence of T R was significantly correlated with certain clinicopathologic factors. A better prognosis was observed in patients with a low prevalence of T R , and this was independent of other survival factors (P < 0.0001). Infiltration of intraepithelial CD8 + TIA-1 + cytotoxic T cells in pancreatic ducts was marked in low-grade premalignant lesions but diminished during the progression of both pancreatic intraepithelial neoplasias and intraductal papillary-mucinous neoplasms. Conversely, the prevalence of T R increased significantly during the progression of premalignant lesions. Conclusions: T R play a role in controlling the immune response against pancreatic ductal carcinoma from the premalignant stage to established cancer. In pancreatic ductal carcinoma, a high prevalence of T R seems to be a marker of poor prognosis.Tumors express many neoantigens originated from the vast number of genetic and epigenetic changes associated with carcinogenesis. Patients with cancer can develop tumor-specific immune responses, although established cancer usually progresses despite the antitumor immune response. It has been suggested that progressive tumors may develop immune escape strategies that include mechanisms to resist immune surveillance and induce immunotolerance. Such mechanisms might include direct deletion of immune effector cells by expression of deathinducing ligands, suppression of tumor-reactive T cells by regulatory T cells (T R ), and tolerization of host T cells by crosspresentation of tumor-derived antigens (1, 2). In contrast to established cancers, there is strong evidence from murine models that specific immune surveillance systems operate at early stages of tumorigenesis, that is, host immune system inhibits the development of tumors (3). It remains to be elucidated how and when effective immune surveillance is overcome during tumor progression. We need effective ...

Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.