Association Study On Polymorphisms Of Hsp90α Gene With Lung Cancer Risk

Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. It is caused by multiple genetic and environmental factors, and interactions among these factors. Smoking, along with occupational exposure, is major cause of lung cancer. However, only a fraction of cigarette smokers develop lung cancer suggesting inter-individual differences in susceptibility.Heat Shock proteins 90Kda (Hsp90) are molecular chaperones thought to be involved in a number of human pathological states, such as ischemia, autoimmune diseases. Also cancer progression is thought to be influenced by Hsp90. The Hsp90 chaperones in humans are coded by two distinct genes, hsp90αand hsp90β. Differences in their respective modes of regulation have been observed, with the Hsp90αbeing more inducible than Hsp90β. Hsp90αis required for the conformational maturation and stability of multiple oncogenic kinases that drive signal transduction and proliferation of lung cancer cells and plays an important role in modulating tumor cell apoptosis. Moreover, Hsp90αcan facilitate the migration and proliferation of tumor cells and associate with the poor prognosis of specific cancers.Understanding DNA variation within the human genome is fundamental to the identification and interpretation of genetic components underlying complex traits and diseases. Despite their role in many crucial cellular pathways and their reported involvement in lung cancer no data are available on the molecular variability of the genes coding for Hsp90αin Han Chinese. To study the association between hsp90αSNP_s and lung cancer in Han Chinese, we have used resequencing method to survey a sample of Han Chinese population for genetic polymorphisms in the exons and exon-flanking regions of the expressed genes of hsp90αand then selected representative tagging SNP_s to capture all common SNP_s in hsp90αgene.Part one: Polymorphisms of HSP90AA1 gene in Han ChineseIn this section we used sub-fragment amplified and directly sequenced method to study DNA sequence variation within hsp90αgene in a sample of 30 Han Chinese subjects. 1. A total of 10 SNP_s were identified in the region of HSP90AA1, three of which were novel. These new SNP_s were located in the promoter region, whose minor allele frequency was 0.20, 0.10 and 0.15 respectively. The remaining observed SNP_s were rs8005905 (t/a), rs10873531 (t/c), rs4947 (c/t), rs3742429 (t/c), rs2298877 (a/g), rs2298878 (c/t), rs35997255 (_/tg), about which there were information in NCBI database. 2. Compared with other races, we found that the frequency of SNP_s in Han Chinese population was approximately the same with that in Japanese population, and significantly different to that in European and African population. 3. There was little information about the frequency of rs4947 and rs35997255 in Chinese and Japanese population. The data of linkage disequilibrium (LD) analysis suggested that the 6 SNP_s (rs8005905, rs10873531, rs4947, rs3742429, rs2298877, rs35997255) are in 1 block, and the D'between each of the 6 SNP_s was 1.0 in Han Chinese origin. Thus, the SNP rs8005905 was sufficient to tag the region in our population.Part two: The association between HSP90AA1 polymorphisms and the susceptibility to lung cancerUsing Taqman allelic discrimination method, we investigated the association between HSP90AA1 polymorphisms and the susceptibility to lung cancer in a case-control study in two independent populations. (Shanghai population: 521 cases and 467 age- and sex-frequency matched controls; Wuhan population: 1152 cases and 1152 age- and sex-frequency matched controls). No difference had been found between cases and controls in the frequencies of rs8005905 genotypes in both populations. In stratified analysis, after adjusting for pathological type, gender, age (cut point 60-year-old), smoking status, cumulative smoking dose (pack years) data, there still was no significant difference between cases and controls. Additionally, we conducted Cox regression analysis for the SNP rs8005905. After adjusting for age, gender, smoking, pathological type, TNM stage, surgery, chemotherapy and radiotherapy, there was no association between rs8005905 polymorphism and the prognosis of lung cancer. In conclusion, we have demonstrated that there is no association between HSP90AA1 polymorphisms and the susceptibility to lung cancer in Han Chinese population.