AUTHOR=Labriet Adrien , De Mattia Elena , Cecchin Erika , Lévesque Éric , Jonker Derek , Couture Félix , Buonadonna Angela , D’Andrea Mario , Villeneuve Lyne , Toffoli Giuseppe , Guillemette Chantal 

TITLE=Improved Progression-Free Survival in Irinotecan-Treated Metastatic Colorectal Cancer Patients Carrying the HNF1A Coding Variant p.I27L

JOURNAL=Frontiers in Pharmacology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00712

DOI=10.3389/fphar.2017.00712

ISSN=1663-9812

ABSTRACT=<p>Hepatocyte nuclear factor 1-alpha (HNF1A) is a liver-enriched transcription factor that plays a key role in many aspects of hepatic functions including detoxification processes. We examined whether <italic>HNF1A</italic> polymorphisms are associated with clinical outcomes in two independent cohorts combining 417 European ancestry patients with metastatic colorectal cancer (mCRC) treated with irinotecan-based chemotherapy. The intronic rs2244608A&gt;G marker was predictive of an improved progression-free survival with a trend in the Canadian cohort and reaching significance in the Italian cohort, with hazard ratios (HR) of 0.74 and 0.72, <italic>P</italic> = 0.076 and 0.038, respectively. A strong association between rs2244608A&gt;G and improved PFS was found in the combined analysis of both cohorts (HR = 0.72; <italic>P</italic> = 0.002). Consistent with an altered HNF1A function, mCRC carriers of the <italic>rs2244608G</italic> minor allele displayed enhanced drug exposure by 45% (<italic>P</italic> = 0.032) compared to non-carriers. In Caucasians, rs2244608A&gt;G is in strong linkage with the coding variant rs1169288c.79A&gt;C (HNF1A p.I27L). In healthy donors, we observed an altered hepatic (<italic>ABCC1</italic>, <italic>P</italic> = 0.009, <italic>ABCC2</italic>, <italic>P</italic> = 0.048 and <italic>CYP3A5</italic>, <italic>P</italic> = 0.001; <italic>n</italic> = 89) and intestinal (<italic>TOP1</italic>, <italic>P</italic> = 0.004; <italic>n</italic> = 75) gene expression associated with the <italic>rs1169288C</italic> allele. In addition, the <italic>rs1169288C</italic> polymorphism could significantly increase the <italic>ABCC1</italic> promoter activity by 27% (<italic>P</italic> = 0.008) and 15% (<italic>P</italic> = 0.041) in the human kidney HEK293 and the human liver HepG2 cell lines, respectively. Our findings suggest that the <italic>HNF1A</italic> rs2244608, or the tightly linked functional coding variant p.I27L, might be a potential prognostic marker with irinotecan-based regimens.</p>