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Updated: Aug 29, 2025
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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
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Genomic Landscapes and Hallmarks of Mutant RAS in Human Cancers
Robert B Scharpf1,2, Archana Balan1, Biagio Ricciuti3
1Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Cancer Research
|September 8, 2022
Summary
RAS mutations are common in cancer. This study analyzed over 66,000 tumors, revealing how RAS mutations interact with other genes differently across cancer types, influencing treatment strategies.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- RAS family small GTPases are frequently activated oncogenes in human cancers.
- Understanding the prevalence and co-alterations of RAS mutations is crucial for cancer research.
Purpose of the Study:
- To analyze the prevalence of somatic RAS mutations and co-occurring genes in a large cancer cohort.
- To investigate cancer lineage-specific and context-dependent patterns of RAS mutations and their clinical implications.
Main Methods:
- Analysis of targeted next-generation sequencing data from the AACR Project GENIE Registry (66,372 tumors).
- Application of Bayesian hierarchical models to estimate mutation prevalence and co-occurrence.
- Integrated multiomic analyses of The Cancer Genome Atlas (TCGA) data.
Main Results:
- Identified differential RAS prevalence and co-mutations across 51 cancer types, varying by cancer lineage, age, sex, and ethnicity.
- Found specific co-mutational patterns, such as in KRAS G12C-mutant non-small cell lung cancer.
- Discovered distinct genotype-driven gene expression programs and tumor microenvironment differences in RAS-mutant tumors.
- Linked genomic findings to differential clinical outcomes and response to immunotherapy.
Conclusions:
- The genomic landscape of RAS-mutant tumors is complex and cancer lineage-specific.
- RAS mutations present differential therapeutic vulnerabilities exploitable for combination therapies.
- Findings support rationally combining RAS-mutant allele-directed therapies with targeted agents and immunotherapy.
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