[Clinical application of next-generation sequencing technologies to achieve cancer precision medicine]

Area of Science:

• Oncology
• Genomics
• Translational Research

Background:

• Clinical applications of genomic biomarkers and targeted therapies are expanding for various cancers.
• Ras activation is a negative predictive marker for anti-epidermal growth factor receptor (EGFR) antibody therapy in colorectal cancer.
• Current clinical practice primarily detects KRAS mutations in codons 12 and 13.

Purpose of the Study:

• To evaluate novel biomarker candidates using whole-exome sequencing (WES) data.
• To investigate the role of "minor" KRAS and NRAS mutations in anti-EGFR antibody resistance.
• To assess the potential for multiplex mutation testing in clinical settings.

Main Methods:

• Whole-exome sequencing (WES) of anti-EGFR antibody-treated samples from multiple Japanese centers.
• Analysis of mutation profiles, including KRAS codons 61 and 146, and NRAS mutations.
• Translational research approach to identify and validate biomarker candidates.

Main Results:

• Identified "minor" activating mutations in KRAS (codons 61, 146) and NRAS as contributors to resistance.
• Demonstrated the potential for multiplex mutation testing to include these resistance-associated mutations.
• Highlighted the importance of infrastructure for handling genetic testing data in clinical practice.

Conclusions:

• Expanded mutation profiling beyond KRAS codons 12 and 13 is crucial for predicting anti-EGFR antibody therapy response.
• Multiplex mutation testing holds promise for enhancing precision medicine in colorectal cancer.
• Establishing robust data infrastructure is essential for the successful implementation of genetic testing in clinical oncology.