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

Abstract

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 HNF1A 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>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, P = 0.076 and 0.038, respectively. A strong association between rs2244608A>G and improved PFS was found in the combined analysis of both cohorts (HR = 0.72; P = 0.002). Consistent with an altered HNF1A function, mCRC carriers of the rs2244608G minor allele displayed enhanced drug exposure by 45% (P = 0.032) compared to non-carriers. In Caucasians, rs2244608A>G is in strong linkage with the coding variant rs1169288c.79A>C (HNF1A p.I27L). In healthy donors, we observed an altered hepatic (ABCC1, P = 0.009, ABCC2, P = 0.048 and CYP3A5, P = 0.001; n = 89) and intestinal (TOP1, P = 0.004; n = 75) gene expression associated with the rs1169288C allele. In addition, the rs1169288C polymorphism could significantly increase the ABCC1 promoter activity by 27% (P = 0.008) and 15% (P = 0.041) in the human kidney HEK293 and the human liver HepG2 cell lines, respectively. Our findings suggest that the HNF1A rs2244608, or the tightly linked functional coding variant p.I27L, might be a potential prognostic marker with irinotecan-based regimens.

Association of STAT-3 rs1053004 and VDR rs11574077 With FOLFIRI-Related Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients

“…Altered transcriptional functionality could impact irinotecan drug pharmacokinetic and pharmacodynamic profiles via the regulation of ADME gene expression. In this context a significant effect on irinotecan exposure and clinical outcome of some genetic variants in HNF1A gene was previously reported ( Labriet et al, 2017 ).…”

Germline Polymorphisms in the Nuclear Receptors PXR and VDR as Novel Prognostic Markers in Metastatic Colorectal Cancer Patients Treated With FOLFIRI

“…These results have opened up a novel field of investigation that focuses on the contribution of inherited genetic variability in transcriptional regulators and inflammation cascade genes to the inter-individual differences in pharmacological profiles and therapeutic outcomes. In this context, significant associations between some genetic variants in signal transducer and activator of transcription 3 ( STAT-3), vitamin D receptor (VDR) , and hepatocyte nuclear factor 1 alpha (HNF1A) with the clinical outcomes of FOLFIRI were previously reported by our group (16, 17).…”

“…All patients received a 180 mg/m 2 intravenous dose of irinotecan in FOLFIRI regimen every 2 weeks. Details on eligibility, treatment modalities, and clinical data were documented elsewhere (17, 21). In both cohorts, survival data were obtained through an active follow-up.…”

DNA repair gene polymorphisms, tumor control, and treatment toxicity in prostate cancer patients treated with permanent implant prostate brachytherapy

“…For each gene, a region covering all exons, introns, and 5 kb of each 5′‐ and 3′‐flanking region were screened to maximize coverage and to explain most of the haplotype diversity in the HapMap population of European ancestry. The htSNPs were genotyped as described previously 7,17 . Among them, 215 htSNPs were successfully assayed (listed in Table S1).…”