ABSTRACT
Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases involved in cellular growth and division. Somatic mutations in one of the PI3K catalytic subunit genes, PIK3CA, are frequently found in numerous malignancies, including colorectal cancer (CRC). Several PIK3CA inhibitors are approved for the treatment of breast cancer and lymphoma. Activating mutations in PIK3CA tend to occur in exons 9 and 20, with mutations in other exons 1, 4, and 7 being less common. Most test systems for PIK3CA mutation screening are designed to detect mutations in exons 9 and 20, leaving exons 1-7 overlooked. We have developed a multiplex AS-PCR to screen for PIK3CA mutations in exons 1, 4, 7, 9, and 20. Validation was performed on 515 CRC samples of patients from Siberia and the Far East of Russia. The assay sensitivity was 0.05-0.5% of mutant DNA, and the overall PIK3CA mutation frequency was 13.01%, with 9.32% of mutations in exon 9, 1.94% in exon 20, and 1.74% in exons 1-7. The assay designed is suitable for the analysis of activating PIK3CA mutations in formalin-fixed paraffin-embedded tissue samples. The present work is the first study characterizing the PIK3CA mutation frequency in CRC patients from the eastern part of Russia.
ABSTRACT
INTRODUCTION: Multiple genetic studies have confirmed association of 8q24 variants with susceptibility to prostate cancer (CaP). However, the risk conferred in men living in Russia is unknown. MATERIALS AND METHODS: In this work we studied the association of rs6983267, rs10090154, and rs1447295 single nucleotide polymorphisms (SNPs) with a risk of CaP development in men of Caucasoid descent living in the Siberian region of Russia. Three 8q24 SNPs were genotyped by real-time polymerase chain reaction in histologically confirmed CaP "cases" (n = 392) and clinically evaluated "controls" (n = 344). To evaluate the SNP effects on CaP susceptibility, odds ratio (OR) and confidence interval (CI) 95% were calculated. Allele and genotype frequencies in the groups were compared using logistic regression; differences were considered statistically significant if P<0.05. RESULTS: We showed statistically significant association of the A allele of rs1447295 (OR [CI 95%] = 1.96 [1.37-2.81], P<0.0001) and the T allele of rs10090154 (OR [CI 95%] = 2.14 [1.41-3.26], P<0.0001) with CaP. The T-A rs10090154 to rs1447295 haplotype was also associated with CaP (OR [CI 95%] = 2.47 [1.59-3.85], P<0.0001). There was no significant association with the T allele of rs6983267: OR [CI 95%] = 0.9 [0.73-1.11], P> 0.05. CONCLUSION: Thus, our investigation confirms the role of chromosomal region 8q24 in the development of CaP in the Russian population.
