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Association Analyses between Mitochondrial DNA Content and Colorectal Cancer Risk and Clinical Prognosis

Author: ZuoFaLin
Tutor: HeXianLi;XingJinLiang
School: Fourth Military Medical University
Course: Surgery
Keywords: Mitochondrial DNA copy number Colorectal cancer Risk of Prognosis
CLC: R735.34
Type: Master's thesis
Year: 2011
Downloads: 118
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Abstract


Background colorectal cancer (Colorectal Cancer, CRC) including colon and rectal cancer, is one of the common malignant tumors of the digestive system and the database of the World Health Organization shows that global annual increase of about 1 million patients with colorectal cancer, 510,000 cases of death, for the third cause of cancer death. Over the past 10 years, in areas with a lower risk of colorectal cancer, and its incidence is increasing rapidly. National survey data show that of colorectal cancer mortality in a significant rise. The incidence of colorectal cancer is a multi-factor, multi-step process, is the result of the role of environmental carcinogenic factors and genetic susceptibility factors. The study found that the prognosis of colorectal cancer is closely related to early diagnosis. Up to now, has proven to early screening and diagnosis can effectively reduce the morbidity and mortality of colorectal cancer with colonoscopy and sigmoidoscopy. However, although these methods have a relatively high sensitivity and specificity, but they are an invasive examination method and the price is very expensive, is not suitable for mass CENSUS. With the development of molecular biology, genetics and biotechnology, the last few years of research in basic, clinical and prevention of colorectal made great progress, but so far its understanding of the mechanisms of disease, recurrence and metastasis still very lacking. Census of the high-risk groups (aged 40 or above, there is a family history of colorectal cancer or intestinal polyps) early discovery of colorectal cancer, but when small colorectal lesions, clinical performance, carcinoembryonic antigen (Carcinoma embryonic antigen, CEA) etc. without high specificity of tumor markers, colonoscopy is not yet completely universal, so the lack of a simple and effective means of early diagnosis of colorectal. Therefore, the search for a new simple can be applied to colorectal cancer screening, diagnosis, prognosis, and treatment monitoring of tumor markers is very important. In view of the special status of the mitochondrial energy metabolism, oxygen free radicals and apoptosis, especially mitochondrial DNA (Mitochondrial DNA, the completion of the sequencing of mtDNA), people come to realize the biological characteristics of the tumor depends not only on the genetic material in the nucleus, and has a very important relationship with nuclear outer mitochondrial DNA variation. Each human cell contains 102 to 104 mitochondria, about 2 to 10 gene copies of each of the mitochondrial DNA, mitochondrial DNA containing the 16569 base pairs (Base pair, bp), is a circular double-stranded DNA molecule. Intron of the mitochondrial DNA, unlike nuclear genes, mitochondrial DNA lacks histone protection and effective repair mechanisms, it is more susceptible to the damage of reactive oxygen species (Reactive Oxygen Species, ROS) and other genotoxic, carcinogenic effects targets. This makes mitochondrial DNA characteristics significantly different from nuclear DNA, including the high copy number, high mutation rate, highly polymorphic strict maternal inheritance. Mitochondrial DNA mutations and copy number abnormalities and tumor development is closely related to, and mitochondrial DNA abnormalities with significant tumor-specific. MtDNA mutations and copy number changes, has been found in a variety of solid tumor cells detected this mutation in the patient's white blood cells in the tumor, but the specific biological significance in tumor development and the process is not clear. This research project aims to discover the characteristics and laws of mtDNA copy number variation, and mtDNA copy number in peripheral blood of patients with colorectal cancer (peripheral blood lymphocytes, PBLs) in the peripheral blood of patients with colorectal cancer and normal colorectal tissue, in order to explore the possibility of peripheral blood substitute organizations to study the relationship between mtDNA copy number variation in the incidence of colorectal cancer risk and prognosis, and is expected to provide a new simple and effective markers for early diagnosis and prognosis of colorectal cancer in the future, to the early detection of colorectal cancer to improve the survival of patients with colorectal cancer. Method 1. Cases - controlled experimental design methods, included 320 cases from the Affiliated Hospital of the Fourth Military Medical University, Xi'an Tangdu Hospital age of 22-87 years of age in patients with primary colorectal cancer and 320 cases of 22-88 year-old healthy people as controls. The group of patients in all eligible cases are first diagnosed with colorectal cancer, all enrolled subjects were not chemoradiotherapy. The case group into no restrictions of age, sex and stage of disease. 320 healthy controls from Tang Du Hospital in the same period of healthy people to undergo a medical examination, and there is no history of cancer (other than benign melanoma). The control group and the patient group in terms of gender, age (± 3 years), living on the ground strict pairing. All of the subjects were Han. Collected from the peripheral blood of 320 patients with colorectal cancer and 320 healthy controls, and normal colon tissue of 10 patients with colorectal cancer were randomly collected from the case group, Omega Blood \u0026 Tissue DNA extraction kit to extract blood DNA and tissue DNA -40 ℃ refrigerator. Real-time quantitative polymerase chain reaction (real-time Quantatitative Polymerase Chain Reaction, real-timeQPCR) determination of mitochondrial DNA copy number in the peripheral blood of selected patient group and control subjects, and detected on peripheral blood and colon tissue (per the number of copies of mitochondrial DNA in the peripheral blood and colon tissue from the same individual). 4. Obtain informed consent form, collect all study participants of age, gender, smoking, alcohol consumption, level of education, physical quality index (body mass index, BMI), diet, family history of cancer, environmental exposure situations, physical activity, the use of non-steroidal anti-inflammatory drugs (Non-steroidal anti-inflammatory drugs, NSAIDs) and hormone replacement therapy (Hormone replacement therapy, HRT) as well as the patient's operative time, tumor location, histological type, histological grade, clinical stage , chemotherapy and other clinical data, and postoperative treatment, follow-up of recurrence, metastasis, and death situation. 5. Use of the SPSS16.0 package for analysis of mitochondrial DNA copy number in the peripheral blood of patients with colorectal cancer and colorectal tissue and peripheral blood mitochondrial DNA copy number and colorectal cancer risk and prognosis. Odds ratio (odds radio, OR), hazard ratio (hazard radio, HR) and 95% confidence interval (confidence interval, CI) to estimate the relative risk between mtDNA copy number and CRC risk and prognosis. All P values ??are two-tailed P lt; 0.05 or 95% confidence interval (CI) does not include 1.0 was considered statistically significant. Results 1. Cases of general information distribution characteristics of the study group with the healthy control group in gender (P = 1.00) and age (58.42 ± 13.12 vs. 58.16 ± 13.53 years old, P = 0.807) on a good match in drinking no significant difference in the number of smokers in the case group and the amount of smoking (P = 0.395), education level (P = 0.169), BM (IP = 0.632), and the use of non-steroidal anti-inflammatory drugs (P = 0.477) To more than those in the healthy control group (39.37% vs. 32.81%, P = 0.084; 26.2 ± 14.94 vs. 20.29 ± 13.05 pack / year, P = 0.002). Board and board within the average coefficient of variation of 6.9% (3.9% -9.1%) and 4.2% (2.4% -6.9%). 2 mitochondrial DNA copy number (median: 1.03; range = 0.46-3.37). Distribution characteristics of mitochondrial DNA copy number in peripheral blood of patients with colorectal cancer than in healthy controls mitochondrial DNA copy number in peripheral blood (median: 0.86; range = 0.48-3.06 ) to be high, both the presence of a significant difference (P LT; 0.001). Further stratified analysis we found that in the case and control groups, gender, age, BMI, smoking, alcohol consumption has no effect on mitochondrial DNA copy number (P value range :0.151-0.909). 3 in the peripheral blood and normal tissue mitochondrial DNA copy number analysis using Pearson correlation analysis the correlation assessment mitochondrial DNA copy number in peripheral blood of patients with 10 pairs of colorectal cancer and colorectal organization found in peripheral blood of patients with colorectal cancer Mitochondrial DNA copy number in mitochondrial DNA copy number in colorectal tissue has a good correlation (r = 0.659, p = 0.038). 4. Mitochondrial DNA copy number and incidence of colorectal cancer risk associated analysis using the relationship between the non-conditional logistic regression analysis of mitochondrial DNA copy number and colorectal cancer risk found that low mitochondrial DNA copy number compared mitochondrial DNA copy number the risk of colorectal cancer was significantly higher (adjusted OR = 2.04, 95% CI = 1.48-2.82). The quartile method further analysis found that the incidence of colorectal cancer risk in peripheral blood mitochondrial DNA copy number in a dose dependent manner (P lt; 0.001). Stratified analysis found high mitochondrial DNA copy number and incidence of colorectal cancer risk is not other factors. Mitochondrial DNA copy number and colorectal cancer prognosis associated analysis of follow-up of 320 patients with colorectal cancer, of which 37 cases were lost to follow another six patients did not meet the inclusion criteria, 277 cases of adenocarcinoma of surgery patients into prognostic analysis. Cox regression model for multivariate analysis found that age, gender, smoking, alcohol consumption, tumor location, level of education had no significant effect on the prognosis (adjusted HR 0.74 - 1 .34); clinical stage, tumor grade and prognosis significantly correlated, The higher the worse the prognosis of clinical stage (0 / I reference from stage II to stage Ⅳ, adjusted HR is for 6.81,11.98,25.48) the histological differentiation worse the worse the prognosis of patients with (highly differentiated for reference Mitochondrial DNA copy number and colon adjusted HR, moderately differentiated and low degree of differentiation were 1.55,2.53); compared to non-chemotherapy patients after the implementation of adjuvant chemotherapy can significantly reduce the risk of death (adjusted HR = 0.57); cancer recurrence (P = 0.008) and death (P = 0.007) was significantly associated with low copy number of mitochondrial DNA copy number in peripheral blood of patients than patients with poor prognosis (adjusted HR of recurrence and death, respectively 1.87,2.01). Kaplan Meier analysis found that mitochondrial DNA copy number of patients compared with patients with low copy number of mitochondrial DNA, the survival rate was significantly worse (Log rank P = 0.002). Conclusion 1. Patients with colorectal carcinoma in mitochondrial DNA copy number and its colorectal tissue mitochondrial DNA copy number significant correlation. This proves that the mitochondrial DNA copy number in peripheral blood mitochondrial DNA copy number variation detection instead of intestinal tissue. Mitochondrial DNA copy number in the peripheral blood of patients with colorectal cancer increased significantly correlated with the incidence of colorectal cancer risk, high copy number of mitochondrial DNA has a high incidence of colorectal cancer risk, both dose-dependent manner. Peripheral blood of patients with colorectal cancer in mitochondrial DNA copy number and its prognosis was significantly related to mitochondrial DNA copy number of patients with poor prognosis. From the above conclusions, we speculated that the peripheral blood mitochondrial DNA copy number may be a marker of the incidence of colorectal cancer risk assessment and prognosis of monitoring.

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CLC: > Medicine, health > Oncology > Gastrointestinal Cancer > Intestinal neoplasms > Colorectal tumors
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