Genomic landscapes and hallmarks of mutant RAS in human cancers Journal Article
| Authors: | Scharpf, R. B.; Balan, A.; Ricciuti, B.; Fiksel, J.; Cherry, C.; Wang, C.; Lenoue-Newton, M. L.; Rizvi, H. A.; White, J. R.; Baras, A. S.; Anaya, J.; Landon, B. V.; Majcherska-Agrawal, M.; Ghanem, P.; Lee, J.; Raskin, L.; Park, A. S.; Tu, H.; Hsu, H.; Arbour, K. C.; Awad, M. M.; Riely, G. J.; Lovly, C. M.; Anagnostou, V. |
| Article Title: | Genomic landscapes and hallmarks of mutant RAS in human cancers |
| Abstract: | 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 comutational 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. © 2022 The Authors. |
| Keywords: | genetics; mutation; bayes theorem; carcinoma, non-small-cell lung; lung neoplasms; pathology; lung tumor; genomics; protein p21; proto-oncogene proteins p21(ras); non small cell lung cancer; tumor microenvironment; humans; human |
| Journal Title: | Cancer Research |
| Volume: | 82 |
| Issue: | 21 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-11-01 |
| Start Page: | 4058 |
| End Page: | 4078 |
| Language: | English |
| DOI: | 10.1158/0008-5472.Can-22-1731 |
| PUBMED: | 36074020 |
| PROVIDER: | scopus |
| PMCID: | PMC9627127 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
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