Association between a single nucleotide polymorphism in the R3HCC1 gene and irinotecan toxicity

Area of Science:

• Pharmacogenomics
• Oncology
• Molecular Biology

Background:

• Irinotecan is a key chemotherapy for colorectal cancer, but its use is limited by severe toxicity.
• Known genetic factors like UGT1A1 polymorphisms do not explain all irinotecan-associated adverse events.
• There is a need for novel biomarkers to predict irinotecan toxicity.

Purpose of the Study:

• To identify novel genetic biomarkers for irinotecan-induced toxicity beyond UGT1A1.
• To investigate whole-exome gene polymorphisms associated with irinotecan toxicity in cancer patients.

Main Methods:

• Whole-exome sequencing (WES) was performed on 178 metastatic colorectal cancer and 87 pancreatic cancer patients treated with irinotecan-containing regimens.
• Validation of candidate single nucleotide polymorphisms (SNPs) was conducted using qPCR.
• Analysis compared SNP associations with neutropenia across different chemotherapy regimens.

Main Results:

• Seven candidate SNPs were identified for irinotecan-associated neutropenia.
• A significant association was found between an SNP in the R3HCC1 gene (rs2272761) and severe neutropenia (>grade 3) in patients receiving irinotecan.
• This association was consistent across doublet and triplet irinotecan-based chemotherapy regimens for colorectal and pancreatic cancers.

Conclusions:

• A single nucleotide polymorphism in the R3HCC1 gene may serve as a valuable predictive biomarker for irinotecan-related neutropenia.
• This discovery could aid in personalizing irinotecan chemotherapy, improving patient outcomes and safety.
• R3HCC1 polymorphism offers a potential alternative to UGT1A1 for predicting irinotecan toxicity.