Detecting genetic hypermutability of gastrointestinal tumor by using a forensic STR kit

Area of Science:

• Oncology
• Genetics
• Immunotherapy

Background:

• Somatic hypermutation and PD-1 overexpression are predictive biomarkers for immunotherapy response.
• Biomarker-matched trials are limited, and many genomic alterations are difficult to target.

Purpose of the Study:

• To investigate the utility of forensic short tandem repeat (STR) analysis for identifying hypermutational status in gastrointestinal (GI) cancers.
• To assess the potential of STR alternations as biomarkers for predicting immunotherapy response, particularly in microsatellite instability-low/microsatellite stability (MSI-L/MSS) cases.

Main Methods:

• Analyzed 250 GI tumors using two commercial kits for microsatellite instability (MSI) and forensic STR alternations.
• Identified three types of STR alternations: allelic loss, Aadd, and Anew.
• Determined a potential cutoff threshold for STR alternations (26.32%) to identify hypermutational status.

Main Results:

• 62.4% of GI tumors exhibited STR alternations, including 100% of MSI-high and 60% of MSI-L/MSS cases.
• 30% of patients showed STR instability with >26.32% STR alternations.
• The 26.32% STR alternation cutoff successfully identified all 15 MSI cases, suggesting its potential as a threshold.

Conclusions:

• Forensic STR kits, due to similar mutation mechanisms with MSI, show potential for identifying hypermutation in GI cancers.
• STR analysis may offer a viable method for identifying hypermutational status, aiding in patient stratification for immunotherapy.