Genomic Landscapes and Hallmarks of Mutant RAS in Human Cancers.

Autor:	Scharpf RB; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland., Balan A; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Ricciuti B; Department of Medicine, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Fiksel J; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland., Cherry C; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Wang C; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Lenoue-Newton ML; Division of Hematology-Oncology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee., Rizvi HA; Department of Medicine, Collaborative Research Centers, Memorial Sloan Kettering Cancer Center, New York, New York., White JR; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Baras AS; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Anaya J; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Landon BV; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Majcherska-Agrawal M; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Ghanem P; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Lee J; AACR Project GENIE, American Association for Cancer Research, Pennsylvania., Raskin L; Center for Observational Research, Amgen Inc., Thousand Oaks, California., Park AS; Center for Observational Research, Amgen Inc., Thousand Oaks, California., Tu H; Center for Observational Research, Amgen Inc., Thousand Oaks, California., Hsu H; Center for Observational Research, Amgen Inc., Thousand Oaks, California., Arbour KC; Department of Medicine, Division of Clinical Research, Memorial Sloan Kettering Cancer Center, New York, New York., Awad MM; Department of Medicine, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Riely GJ; Department of Medicine, Division of Clinical Research, Memorial Sloan Kettering Cancer Center, New York, New York., Lovly CM; Division of Hematology-Oncology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee., Anagnostou V; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2022 Nov 02; Vol. 82 (21), pp. 4058-4078.
DOI:	10.1158/0008-5472.CAN-22-1731
Abstrakt:	The RAS family of small GTPases represents the most commonly activated oncogenes in human cancers. To better understand the prevalence of somatic RAS mutations and the compendium of genes that are coaltered in RAS-mutant tumors, we analyzed targeted next-generation sequencing data of 607,863 mutations from 66,372 tumors in 51 cancer types in the AACR Project GENIE Registry. Bayesian hierarchical models were implemented to estimate the cancer-specific prevalence of RAS and non-RAS somatic mutations, to evaluate co-occurrence and mutual exclusivity, and to model the effects of tumor mutation burden and mutational signatures on comutation patterns. These analyses revealed differential RAS prevalence and comutations with non-RAS genes in a cancer lineage-dependent and context-dependent manner, with differences across age, sex, and ethnic groups. Allele-specific RAS co-mutational patterns included an enrichment in NTRK3 and chromatin-regulating gene mutations in KRAS G12C-mutant non-small cell lung cancer. Integrated multiomic analyses of 10,217 tumors from The Cancer Genome Atlas (TCGA) revealed distinct genotype-driven gene expression programs pointing to differential recruitment of cancer hallmarks as well as phenotypic differences and immune surveillance states in the tumor microenvironment of RAS-mutant tumors. The distinct genomic tracks discovered in RAS-mutant tumors reflected differential clinical outcomes in TCGA cohort and in an independent cohort of patients with KRAS G12C-mutant non-small cell lung cancer that received immunotherapy-containing regimens. The RAS genetic architecture points to cancer lineage-specific therapeutic vulnerabilities that can be leveraged for rationally combining RAS-mutant allele-directed therapies with targeted therapies and immunotherapy. Significance: The complex genomic landscape of RAS-mutant tumors is reflective of selection processes in a cancer lineage-specific and context-dependent manner, highlighting differential therapeutic vulnerabilities that can be clinically translated. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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