A study of the association between UGT1A1*28 variant allele of UGT1A1 gene and colonic phenotype of sporadic colorectal cancer.

INTRODUCTION: The transcriptional activity of the UGT1A1 gene is modulated by a variable number of repetitions of the dinucleotide (TA) within its promoter region. By comparison to the most common allele (TA)6 (UGT1A1*1), decreased activity is observed with increasing TA repetitions. The aim of this study was to determine whether the presence of the variant allele UGT1A1*28, harbouring seven TA repetitions, (TA)7, in the homozygous state, is associated with precancerous colonic lesions and/or with specific colorectal cancer characteristics. MATERIAL AND METHODS: All patients treated for colorectal cancer in a tertiary care centre, between January 2009 and December 2013, who had routine UGT1A1 genotyping for irinotecan dose-adjustment were included. Data were retrospectively collected. RESULTS: 292 patients were enrolled, including 23 UGT1A1*28/*28 homozygous (7.9%), 137 wild type homozygous (46.9%) and 132 heterozygous (45.2%). There were no significant differences in phenotypic colonic characteristics between homozygous and heterozygous patients carrying the UGT1A1*28 allele as compared to *1/*1 homozygous. Patients treated with aspirin were significantly more common in the UGT1A1*28/*28 homozygous group than in the other groups (7/23 (30.4%) compared to 22/269 (8.2%), p = 0.001). CONCLUSION: Dinucleotide polymorphism in the promoter region of the UGT1A1 gene is not associated with a specific colonic phenotype in patients with sporadic colorectal cancer.

Possible association of CAG repeat polymorphism in KCNN3 encoding the potassium channel SK3 with oxaliplatin-induced neurotoxicity.

INTRODUCTION: Data suggest a role of the potassium channel SK3 (KCNN3 gene) in oxaliplatin-induced neurotoxicity (OIN). Length variations in the polymorphic CAG repeat of the KCNN3 gene may be associated with the risk of OIN. MATERIALS AND METHODS: We performed patch-clamp experiments on HEK293 cell lines, expressing SK3 channel isoforms with short (11) or long (24) CAG repetitions, to measure intracellular calcium concentrations to test the effects of oxaliplatin on current density. A retrospective study was carried out on patients with colorectal cancer who had received oxaliplatin-based chemotherapy. DNA for KCNN3 genotyping was extracted from leukocytes. The region containing the CAG repeats was amplified by PCR and the products separated by capillary electrophoresis for length analysis. The patients were divided into three groups depending on whether they carried two short alleles, one short allele and one long allele, or two long alleles. The primary endpoint was the onset of grade 2 or 3 neuropathy to oxaliplatin. RESULTS: There was no difference in current density, but oxaliplatin induced a differential effect on apamin-sensitive current density between the two isoforms expressed in the HEK cell lines. There was a significant reduction of store-operated calcium entry into cells expressing the short and more active isoform only after high concentration of oxaliplatin exposition. Eighty-six patients were included in the clinical study. There was no significant association between OIN and KCNN3 polymorphism for the three groups. CONCLUSION: We observed a slight association between OIN and CAG repeat polymorphisms of the KCNN3 gene in a preclinical model, but not a clinical study.