Somatic mutations of the KEAP1 gene in common solid cancers

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Nuclear factor erythroid 2-related factor 2 (NRF2) induces cytoprotection, and its inhibitor KEAP1 is a potential tumor suppressor.
• KEAP1 mutations were previously reported mainly in lung and gallbladder cancers.
• The prevalence of KEAP1 mutations across various human cancers remained largely unexplored.

Purpose of the Study:

• To investigate the frequency and distribution of KEAP1 somatic mutations in a broad spectrum of human solid cancers.
• To determine if KEAP1 mutations are associated with NRF2 pathway activation and cytoprotective protein expression.

Main Methods:

• Analysis of 499 cancer tissue samples from lung, breast, colon, stomach, liver, larynx, prostate, and leukemias.
• Single-strand conformation polymorphism (SSCP) analysis was used to detect somatic mutations in KEAP1.
• Assessed allelic losses at the KEAP1 locus and expression of NRF2-activated proteins.

Main Results:

• KEAP1 somatic mutations were detected in gastric (11.1%), hepatocellular (8.9%), colorectal (7.8%), lung (4.6%), breast (2.0%), and prostate (1.3%) carcinomas.
• Allelic losses of KEAP1 were found in 42.9% of cancers with KEAP1 mutations; no NRF2 mutations were detected in these cases.
• All cancers with KEAP1 mutations showed expression of NRF2-activated cytoprotective proteins.

Conclusions:

• KEAP1 mutations are prevalent across diverse histological types of solid cancers.
• Biallelic inactivation of KEAP1 and elevated cytoprotective proteins suggest KEAP1 mutations contribute to solid cancer development.
• KEAP1 mutations may confer resistance to oxidative stress, aiding cancer cell survival and progression.