COMPREHENSIVE ANALYSIS OF GENETIC POLYMORPHISMS AND IRINOTECAN-INDUCED ADVERSE EVENTS IN JAPANESE GASTROINTESTINAL CANCER PATIENTS: A DMET MICROARRAY PROFILING STUDY

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Abstract

Background

Irinotecan is a key drug in the treatment of colorectal and gastric cancer, which may occasionally cause severe adverse events (AEs), especially neutropenia and diarrhea. Although UDP-glucuronosyltransferase (UGT)1A1 polymorphisms are used as biomarkers for predicting AEs, the effect of UGT1a1 in clinical use is limited, suggesting that there is a possibility of the existence of other, unknown biomarkers.

Methods

Fourteen gastrointestinal cancer (five gastric, nine colorectal) patients who had undergone irinotecan-based chemotherapy were enrolled. DNA extracted from peripheral blood cells was genotyped by the DMET Plus microarray system, and 1931 gene polymorphisms were investigated. The relationship between AEs and polymorphisms was analyzed statistically.

Results

Eleven polymorphisms showed the P-value of <0.05 with grade 3, 4 neutropenia, but no statistically significant polymorphisms were found after the correction of multiple comparisons. With respect to the association with diarrhea, 12 polymorphisms showed P < 0.05, and even after the correction of multiple comparisons, CYP2F1_96G > A(P32P) showed a significant relationship (P < 0.00001). With respect to the relationship between UGT1A1*6, *28 polymorphisms and AEs, *6 polymorphisms showed significant (P = 0.044) association with grade 4 neutropenia.

Conclusions

CYP2F1_96G > A polymorphism showed significant association with diarrhea. The association of UGT1A1*6 polymorphism and neutropenia was confirmed, as in previous reports.

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