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Molecular Epidemiology Study on the MBD4 Polymorphisms and the Susceptibility and Survival of Lung Cancer

Author: MiaoRuiFen
Tutor: ShenHongBing
School: Nanjing Medical University
Course: Epidemiology and Biostatistics,
Keywords: Lung cancer MBD4 Single nucleotide polymorphisms Case - control study Genetic predisposition Cohort study Prognosis
CLC: R734.2
Type: Master's thesis
Year: 2008
Downloads: 127
Quote: 2
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Abstract

Lung cancer is the most common worldwide and the highest mortality rate of malignant tumors. Nearly half a century, the morbidity and mortality of lung cancer in China is the rapid growth has been higher than the world average, and is still on an upward trend, to become a major public health threat to the health of our residents. At the same environmental exposure of different individuals have different risk of lung cancer, after lung cancer progression rate and survival time is often different, more and more studies show that genetic factors play an important role in lung cancer susceptibility and prognosis. The MBD4 gene encoding the MBD4 protein (Methyl-CpG Binding DomainProtein 4, methyl-CpG binding domain protein 4) is a DNA base excision repair pathway (BaseExcision Repair, BER), one of the important members. MBD4 protein can be specifically resection of the DNA sequence of methylated or hemimethylated, cytosine (C) and mismatched thymine (T) or uracil (U), and maintenance of genomic stability, inhibition of gene mutation, The MBD4 gene was considered to be a tumor suppressor gene. In addition, MBD4 protein can be combined with a variety of different types of protein and play a wide range of biological functions, and can affect platinum chemotherapy drugs mediated DNA damage repair, influence the occurrence and prognosis of the tumor through a variety of channels. Single nucleotide polymorphisms (single Nucleotide Polymorphism, SNP) is the most common genetic changes in a large number of studies have shown that the SNP can affect the the tumor genetic susceptibility and prognosis. With the human genome (Human Genome Proiect, HGP) and the completion of the international Human Genome Haplotype Map Project (International HapMap Project, HapMap plan) progress using the tag SNP (tagging-SNP, tSNP) the common sNP entire gene Changing the comprehensive study practicable. In the present study, we combined potential function learn SNP to tSNP selected point strategy to explore the relationship between the MBD4 gene polymorphisms individual genetic susceptibility of lung cancer case - control study design, prospective cohort study designed to explore MBD4 gene polymorphism to change the association between lung cancer prognosis, and tertiary prevention to provide a scientific basis for the period for lung cancer, and to provide clues for rational clinical decision-making and individual treatment. The first part of the the MBD4 gene polymorphisms and susceptibility to lung cancer case - control study subjects, including 500 cases of new hair histopathologic diagnosis of lung cancer cases and 517 cases frequency matched with cases by sex and age community controls. Combined with potential function learn SNP tSNP point selection strategies, were selected for the of MBD4 three polymorphisms points (rs2311394T> C, rs140693G> A and rs2005618T> C) in order to cover the entire MBD4 gene and its upstream and downstream 2000bp range common polymorphisms. Were genotyped using Illumina high-throughput test and direct sequencing Illumina reliability of the test results. The unit point Logistic regression analysis, after adjustment for sex, age, the cumulative amount of smoking, and family history of cancer, and carrying the GG genotype compared to carrying MBD4rs140693 GA genotype individuals suffering from a 30% reduction in the risk of lung cancer (adjusted OR = 0.70,95% CI = 0.52-0.93,), while carrying the rs140693 AA genotype and the risk of lung cancer, there is no statistically significant association (adjusted OR = 0.96, 95% CI = 0.67-1.38). The dominant model analysis showed that carry rs140693 GA / AA genotype compared with GG genotype, the risk of lung cancer was significantly reduced by 24% (adjusted OR = 0.76, 95% CI = 0.58-1.00, P = 0.047). Further stratified GA / AA genotypes can make a non-smoker's lung cancer risk was significantly reduced by 44% (adjusted OR = 0.56, 95% CI = 0.35-0.87). Interaction analysis failed to find a significant multiplication interaction between the rs140693G> A site with smoking. In addition, the results of this study are not found rs2311394 T> C and rs2005618 T> C two points between the risk of lung cancer in the presence of a significant statistical association. The results of this study showed that the MBD4 genes rs140693 G> A polymorphism changing the genetic susceptibility of lung cancer, these results early lung cancer screening and prevention has a certain significance. Successful follow-up of 240 cases of lung cancer cases, the second part of MBD4 gene polymorphism and lung cancer prognosis prospective cohort study of this study to explore the MBD4 gene polymorphism to change the association between lung cancer prognosis. The study results found the MBD4rs2005618 T> C locus survival of the three genotype significantly different (Log-rank P = 0.033). Single factor Cox regression analysis showed that, compared with the rs2005618 TT genotype CC genotype the risk of death was significantly reduced by 45% (HR = 0.55, 95% CI = 0.30-0.99). Further multi-factor adjustment, the CC genotype still has better prognostic effect, but did not reach statistical significance level (adjusted HR = 0.61, 95% CI = 0.33-1.12). Recessive model analysis showed that carrying rs2005618 TT / TC genotype compared to the CC genotype had a better prognosis, risk of death decreased (adjusted HR = 0.62, 95% CI = 0.35-1.07). Stratified analysis showed that, MBD4 rs2005618 T> C polymorphism change more apparent in elderly patients (> 60 years) receiving chemotherapy patients, the effects of lung cancer (adjusted HR = 0.37, 95% CI = 0.15- 0.89; adjust the HR = 0.44, 95% CI = 0.21-0.92). In addition, patients take chemotherapy MBD4 rs2311394T of> C locus polymorphisms with lung cancer prognosis there a statistically significant association, carrying rs2311394 TC / CC genotype compared with TT genotype The risk of death in patients with significantly decreased by 62% (adjusted HR = 0.38, 95% CI = 0.16-0.88). However, the study did not find a statistical association between MBD4 rs140693 G> A site with lung cancer prognosis significantly. The three loci joint analysis showed that the risk of death increased carrying the poor prognosis genotype increase in the number of trend, P = 0.036. The results of this study show that the the MBD4 gene polymorphisms with the prognosis of lung cancer, especially for patients taking chemotherapy are more instructions significance, which may affect the gene after platinum-based chemotherapy drug-mediated DNA damage repair related.

Molecular Epidemiology Study on the MBD4 Polymorphisms and the Susceptibility and Survival of Lung Cancer

Abstract

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