Related Experiment Video
Updated: Sep 29, 2025
Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in
Mohamed E Salem1, Sherif M El-Refai2, Wei Sha1
1Levine Cancer Institute, Atrium Health, Charlotte, NC.
Purpose:
Promising single-agent activity from sotorasib and adagrasib in KRASG12C-mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of KRAS-variant prevalence, genomic alterations, and the relationship between KRAS and immuno-oncology biomarkers is lacking.
Materials And Methods:
Retrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher's exact test evaluated the association between cancer subtypes and KRAS variants. Logistic regression assessed KRASG12C comutations with other oncogenes and the association between KRAS variants and immuno-oncology biomarkers.
Results:
Of the 79,004 samples assessed, 13,758 (17.4%) harbored KRAS mutations, with 1,632 (11.9%) harboring KRASG12C and 12,126 (88.1%) harboring other KRAS variants (KRASnon-G12C). Compared with KRASnon-G12C across all tumor subtypes, KRASG12C was more prevalent in females (56% v 51%, false discovery rate-adjusted P value [FDR-P] = .0006), current or prior smokers (85% v 56%, FDR-P < .0001), and patients age > 60 years (73% v 63%, FDR-P ≤ .0001). The most frequent KRAS variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). KRASG12C was most prevalent in patients with non-small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with KRASnon-G12C-mutated, KRASG12C-mutated tumors were significantly associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio [OR] = 2.38; FDR-P < .0001). KRASG12C-mutated tumors exhibited a distinct comutation profile from KRASnon-G12C-mutated tumors, including higher comutations of STK11 (20.59% v 5.95%, OR = 4.10; FDR-P < .01) and KEAP1 (15.38% v 4.61%, OR = 3.76; FDR-P < .01).
Conclusion:
This study presents the first large-scale, pan-cancer genomic characterization of KRASG12C. The KRASG12C mutation was more prevalent in females and older patients and appeared to be associated with smoking status. KRASG12C tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status.
Insights
The KRAS G12C mutation, prevalent in females and smokers, shows distinct genomic alterations and is linked to higher tumor mutational burden. This large-scale study provides key insights into KRAS G12C
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- KRAS signaling pathway is crucial in cancer development.
- Targeted therapies like sotorasib and adagrasib show promise against KRAS G12C-mutant tumors.
- Limited understanding of KRAS variant prevalence and genomic landscape exists.
Purpose of the Study:
- To conduct a comprehensive pan-cancer analysis of KRAS variant prevalence.
- To investigate genomic alterations and comutations associated with KRAS G12C.
- To explore the relationship between KRAS variants and immuno-oncology biomarkers.
Main Methods:
- Retrospective analysis of 79,004 deidentified patient records with next-generation sequencing data.
- Fisher's exact test for cancer subtype and KRAS variant association.
- Logistic regression for comutation analysis and biomarker associations.
Main Results:
- KRAS mutations found in 17.4% of samples; KRAS G12C in 11.9% of those.
- KRAS G12C more common in females, smokers, and patients over 60.
- KRAS G12C tumors associated with higher tumor mutational burden, STK11, and KEAP1 comutations.
Conclusions:
- This study offers the first large-scale genomic characterization of KRAS G12C.
- KRAS G12C prevalence varies by demographics and smoking status.
- Distinct comutation profiles and association with tumor mutational burden-high status identified for KRAS G12C.
Related Concept Videos
02:38The Ras Gene
Ras is a...
02:07Tumor Progression
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...