Homologous Recombination Repair Truncations Predict Hypermutation in Microsatellite Stable Colorectal and Endometrial...

Area of Science:

• Genomics
• Cancer Biology
• Biomarker Discovery

Background:

• Somatic mutations in homologous recombination repair (HRR) genes like BRCA1/2 are linked to PARP inhibitor/platinum sensitivity.
• Hypermutant tumors from POLE or mismatch repair gene alterations respond well to immunotherapy.
• The relationship between HRR gene truncations and hypermutation in colorectal cancer (CRC) and endometrial cancer (EC) requires investigation.

Purpose of the Study:

• To investigate the association between somatic HRR gene truncations and hypermutation in CRC and EC.
• To develop and validate a classifier predicting hypermutator status in microsatellite-stable (MSS) tumors using HRR genes.
• To assess the classifier's ability to identify MSS hypermutators and clarify POLE variants of unknown significance.

Main Methods:

• Analysis of mutational spectra in genomic cohorts (N=2,335) associated with somatic BRCA1/2 truncations.
• Development of an HRR gene-based classifier to predict hypermutator status in MSS tumors.
• Validation of the classifier in additional cohorts (N=1,439) using signature analyses and in vivo assays.

Main Results:

• Somatic BRCA1/2 truncations were prevalent in hypermutator CRCs (80.6%) and ECs (93.6%).
• The classifier achieved high accuracy in predicting MSS hypermutators: 100% true-positive rate in CRC and 98.0% in EC.
• The classifier successfully identified MSS hypermutators without POLE exonuclease domain mutations and reclassified POLE variants of unknown significance.

Conclusions:

• Somatic HRR truncations serve as an accurate biomarker for identifying MSS hypermutators in CRC and EC.
• This approach can identify hypermutators irrespective of POLE exonuclease domain mutations.
• HRR gene truncations may offer a cost-effective biomarker for guiding immunotherapy decisions in MSS CRC and EC.