Molecular epidemiology and diagnostics of KRAS mutations in human cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• RAS mutations, especially KRAS and NRAS, are the most frequent oncogenic alterations in human cancers.
• KRAS mutations are prevalent in pancreatic, colorectal, lung adenocarcinomas, and urogenital cancers, with generally stable worldwide frequencies except in lung adenocarcinoma.
• Allelic imbalances leading to mutant allele predominance are common, alongside cancer-type-specific co-occurring mutations and distinct gene expression signatures in KRAS-mutant cancers.

Purpose of the Study:

• To review the landscape of RAS (specifically KRAS) mutations in human cancers.
• To highlight the significance of KRAS variant allele frequencies and tumor heterogeneity in cancer development and progression.
• To underscore the clinical relevance of determining KRAS mutant allele frequency in primary and metastatic tissues.

Main Methods:

• Review of existing literature on RAS mutations in human cancers.
• Analysis of KRAS mutation frequencies and variant allele frequencies across different cancer types.
• Discussion of the implications of tumor heterogeneity and clonal selection in KRAS-mutant cancers.

Main Results:

• KRAS mutations are the most frequent oncogenic alterations, followed by NRAS.
• KRAS mutation frequencies are largely stable globally, with notable exceptions like lung adenocarcinoma.
• Tumor heterogeneity, variant allele frequencies, and clonal selection significantly impact cancer progression and therapeutic resistance.

Conclusions:

• KRAS mutations are a central feature of many human cancers, with distinct molecular characteristics.
• Understanding the heterogeneity and variant allele frequencies of KRAS mutations is critical for predicting treatment outcomes and resistance.
• Advanced diagnostic techniques for determining mutant allele frequency hold significant clinical potential for managing KRAS-mutant cancers.