Effects of KRAS Genetic Interactions on Outcomes in Cancers of the Lung, Pancreas, and Colorectum

Authors

Isabella N Grabski
John V Heymach
Kenneth L Kehl
Scott Kopetz
Ken S Lau
Gregory J Riely
Deborah Schrag
Rona Yaeger
Rafael A Irizarry
Kevin M Haigis

Publication Date

1-9-2024

Journal

Cancer Epidemiology, Biomarkers & Prevention

Abstract

Background: KRAS is among the most commonly mutated oncogenes in cancer, and previous studies have shown associations with survival in many cancer contexts. Evidence from both clinical observations and mouse experiments further suggests that these associations are allele- and tissue-specific. These findings motivate using clinical data to understand gene interactions and clinical covariates within different alleles and tissues.

Methods: We analyze genomic and clinical data from the AACR Project GENIE Biopharma Collaborative for samples from lung, colorectal, and pancreatic cancers. For each of these cancer types, we report epidemiological associations for different KRAS alleles, apply principal component analysis (PCA) to discover groups of genes co-mutated with KRAS, and identify distinct clusters of patient profiles with implications for survival.

Results: KRAS mutations were associated with inferior survival in lung, colon, and pancreas, although the specific mutations implicated varied by disease. Tissue- and allele-specific associations with smoking, sex, age, and race were found. Tissue-specific genetic interactions with KRAS were identified by PCA, which were clustered to produce five, four, and two patient profiles in lung, colon, and pancreas. Membership in these profiles was associated with survival in all three cancer types.

Conclusions: KRAS mutations have tissue- and allele-specific associations with inferior survival, clinical covariates, and genetic interactions.

Impact: Our results provide greater insight into the tissue- and allele-specific associations with KRAS mutations and identify clusters of patients that are associated with survival and clinical attributes from combinations of genetic interactions with KRAS mutations.

Keywords

Animals, Humans, Lung, Lung Neoplasms, Mutation, Pancreas, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras)

DOI

10.1158/1055-9965.EPI-23-0262

PMID

37943166

PMCID

PMC10841605

PubMedCentral® Posted Date

7-9-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

no