Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Renal cell carcinoma(RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival

Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas

We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1. Liu et al. analyze 921 gastrointestinal (GI) tract adenocarcinomas and find that hypermutated tumors are enriched for insertions/deletions, upper GI tumors with chromosomal instability harbor fragmented genomes, and a group of genome-stable colorectal tumors are enriched in mutations in SOX9 and PCBP1

Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development. Comprehensive, integrated molecular analysis identifies molecular relationships across a large diverse set of human cancers, suggesting future directions for exploring clinical actionability in cancer treatment

The Immune Landscape of Cancer

We performed an extensive immunogenomic anal-ysis of more than 10,000 tumors comprising 33diverse cancer types by utilizing data compiled byTCGA. Across cancer types, we identified six im-mune subtypes\u2014wound healing, IFN-gdominant,inflammatory, lymphocyte depleted, immunologi-cally quiet, and TGF-bdominant\u2014characterized bydifferences in macrophage or lymphocyte signa-tures, Th1:Th2 cell ratio, extent of intratumoral het-erogeneity, aneuploidy, extent of neoantigen load,overall cell proliferation, expression of immunomod-ulatory genes, and prognosis. Specific drivermutations correlated with lower (CTNNB1,NRAS,orIDH1) or higher (BRAF,TP53,orCASP8) leukocytelevels across all cancers. Multiple control modalitiesof the intracellular and extracellular networks (tran-scription, microRNAs, copy number, and epigeneticprocesses) were involved in tumor-immune cell inter-actions, both across and within immune subtypes.Our immunogenomics pipeline to characterize theseheterogeneous tumors and the resulting data areintended to serve as a resource for future targetedstudies to further advance the field

Enhanced numbers of two temperate reef fishes in a small, partial-take marine protected area related to spearfisher exclusion

Reviews of global studies suggest that even small no-take marine protected areas (MPAs) can have localized benefits on harvested organisms of varying mobility. The generality of this conclusion, however, has been questioned due to poor experimental designs of some studies included in reviews, and the relatively small proportion of studies which focused on very small MPAs (≤1 km²). Here we use a correlative approach to test for possible effects of a 0.1 km² partial-take MPA (closed to spearfishing for 12.5 years) on the abundance and size of key harvested fishes using an asymmetrical spatial comparison of the MPA vs. three unprotected control areas. Positive impacts were detected, despite our prediction that a small MPA would not provide protection to highly mobile taxa. Densities of legal-sized (≥200 mm SL) Cheilodactylus fuscus (red morwong; relatively sedentary) were 2.8 times greater within the MPA than at the controls and densities of legal-sized Acanthopagrus australis (yellow-fin bream; relatively mobile) were 2.3 times greater on shallow (≤3.5 m) but not deeper (4–12 m) areas of reef within the MPA. While benefits of protection were evident, the cost-benefit of implementing similar MPAs should be carefully considered as the partial protection status and small size of the MPA limit both the adequacy of the MPA for protecting a larger range of species, and the magnitude and thus detectability of effects

Relação entre genótipos e temperamento de novilhos Charolês x Nelore em confinamento Relations among genotypes and temperament of Charolais x Nellore steers in confinement

Avaliou-se a influência da interação entre genótipos e do temperamento de bovinos sobre os ganhos diretos e indiretos para a produção de carne. Utilizaram-se 79 machos castrados com 19 a 20 meses de idade, divididos em oito grupos genéticos resultantes de cruzamentos Charolês x Nelore: 0, 25, 31, 38, 63, 69, 75 ou 100% Charolês. Os animais foram mantidos em confinamento e alimentados com uma dieta contendo 50% de volumoso e 50% de concentrado. O temperamento foi avaliado utilizando-se quatro metodologias adotadas durante as pesagens: escore composto (EC); tempo de saída (TS); distância de fuga (DF); e escore de localização do redemoinho de pêlos faciais (RED). Maiores porcentagens de sangue Charolês estiveram relacionadas positivamente ao ganho de peso diário. Independentemente do grupo genético, os animais mais reativos ganharam menos peso. O temperamento é influenciado pelo grupo genético, uma vez que animais com maiores proporções de sangue Nelore são mais agitados e excitáveis.<br>The influence of the relation among genotype and temperament of cattle on the direct and indirect gains for meat production. Seventy-nine steers with 19-20 mo old from eight genotype groups of Charolais x Nellore crossbred were evaluated: CH (100CH), ¾ CH1/4N (0.75CH), 11/16CH5/16N (0.69CH), 5/8CH3/8N (0.63CH), 3/8CH5/8N (0.38CH), 5/16CH11/16N (0.31CH), 1/4CH3/4N (0.25CH) e N (0CH) animals were kept in feedlot and were fed with diet containing 50:50 forage to concentrate ratio (%DM). The temperament was evaluated using are four methods adopted during the cattle weights: composite behavior score (BC), flight time (FT); flight distance (FD), and facial whorl (W) position score. Higher percentages of blood Charolais were positively related to daily weight gain. Regardless of the genetic group, the animals more reactive gained less daily weight gain. The temperament is influenced by genetic group, since animals with higher proportions of blood Nellore are more agitated and excited

Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing. A synthesized view on oncogenic processes based on PanCancer Atlas analyses highlights the complex impact of genome alterations on the signaling and multi-omic profiles of human cancers as well as their influence on tumor microenvironment