An insulin-like growth factor-II intronic variant affects local DNA conformation and ovarian cancer survival

Abstract

Insulin-like growth factor-II (IGF-II) may be a prognostic marker in ovarian cancer, and its intronic single nucleotide polymorphism (SNP) rs4320932 has been associated with risk of the disease. We determined whether rs4320932 is associated with IGF-II expression and patient survival in ovarian cancer, and explored whether the SNP variation affects DNA conformation both in the absence of and presence of carboplatin. IGF-II genotype (rs4320932) and phenotype were analyzed in 212 primary invasive epithelial ovarian cancer tissue samples with Taqman® SNP genotyping assays, quantitative reverse transcription-polymerase chain reaction and commercial enzyme-linked immunosorbent assay. DNA conformation was evaluated by circular dichroism (CD) spectra. Kaplan-Meier survival curves and Cox proportional hazard regression models were used to analyze the SNP associations with patient survival. The C allele of rs4320932, previously associated with decreased risk of ovarian cancer development, was here associated with significantly elevated risks of relapse (Ptrend = 0.0002) and death (Ptrend = 0.0006), remaining significant in multivariate analyses. The adjusted hazard ratios were 3.05 (95% confidence interval [CI]: 1.47-6.37) for relapse and 3.28 (95% CI: 1.64-6.57) for death, respectively. The variant was also significantly associated with chemotherapy response, but not with other clinicopathologic variables or with IGF-II expression. DNA with genotypes TT and CC had distinct CD spectra in both the absence of and presence of carboplatin. These findings suggest that the intronic SNP rs4320932 affects patient survival and chemotherapy response via alteration of DNA conformation, but not through regulation of IGF-II expression. This novel finding may have implications in individualized medicine for the design of specific molecules targeting DNA of specific conformations.

Genetic polymorphism ofNFKB1andNFKBIAgenes and liver cancer risk: a nested case–control study in Shanghai, China

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Association of Genetic Variations in XRCC1 and ERCC1 Genes with Sporadic Breast Cancer

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DNA Repair GenesXRCC1andERCC1Polymorphisms and the Risk of Sporadic Breast Cancer in Han Women in the Gansu Province of China

“…Single nucleotide polymorphism (SNP) is a single nucleotide change in a DNA sequence, which may change DNA or RNA conformations (Lu et al, 2012(Lu et al, , 2013 or lead to amino acid substitution (Roberts et al, 2011), thereby resulting in corresponding phenotypes. SNPs may cause human diseases and/or contribute to the risk of diseases, and their identification may help us discover new ways to diagnose, treat, and prevent human diseases (Ulrich et al, 2003).…”