MLH1 and MSH2 Proteins as Potential Biomarkers of Risk forColorectal Cancer Público

Sidelnikov, Eduard (2009)

Permanent URL: https://etd.library.emory.edu/concern/etds/1r66j178v?locale=es
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Abstract

MLH1 and MSH2 Proteins as Potential Biomarkers of Risk for Colorectal Cancer By Eduard Sidelnikov

Colorectal cancer is the third most common incident cancer in the United States and the second cause of cancer deaths in men and women combined. Impairment of DNA mismatch repair (MMR) mechanisms in colonocytes is responsible for about 15% of colorectal cancers. MLH1 and MSH2 proteins play a crucial role in DNA MMR and loss of expression of either (or both) of these proteins is the main cause of DNA MMR insufficiency.

Two investigations from a colonoscopy based case-control study of incident, sporadic colorectal adenoma, and one investigation from a randomized, placebo-controlled, 2 × 2 factorial clinical trial of calcium and vitamin D3 were conducted to characterize the expression of the mismatch repair genes MLH1 and MSH2 in normal colorectal crypt in humans and to assess parameters of their expression as potential modifiable biomarkers of risk for colorectal neoplasms.

The results from the case-control study showed that MLH1 and MSH2 expression in the ascending colon was statistically significantly lower in sporadic adenoma cases than in controls, but there was little evidence of case-control differences in the rectum and sigmoid colon. The clinical trial results showed that MLH1 and MSH2 expression along the full length of crypts increased in the vitamin D and calcium groups relative to the placebo group; vitamin D appeared to have the strongest effect on the expression of both proteins.

These pilot data suggest that lower MLH1 and MSH2 expression in the normal colonic mucosa, at least in the ascending colon, may be associated with increased risk of incident, sporadic colorectal adenoma as well as with modifiable risk factors for colorectal neoplasms, specifically, regular use of NSAIDs. Higher calcium and vitamin D intakes result in increased DNA MMR system activity in the normal colorectal mucosa of sporadic adenoma patients, and the strongest effects may be vitamin D related. These data support further investigation of MLH1 and MSH2 expression as potential modifiable biomarkers of risk for colorectal neoplasms.

Table of Contents

Table of Contents CHAPTER 1. BACKGROUND AND SIGNIFICANCE...1

INTRODUCTION...1 PATHOGENESIS AND PROGRESSION OF COLORECTAL CANCER...2 RISK FACTORS FOR COLORECTAL CANCER...7 DIETARY FACTORS...7 CALCIUM AND VITAMIN D...12 BODY MASS AND PHYSICAL ACTIVITY...15 OTHER RISK FACTORS...17 BIOMARKERS OF RISK FOR COLORECTAL CANCER...19 CONCLUSION...19

CHAPTER 2. MATERIALS AND METHODS...21

SPECIFIC AIMS...21 HYPOTHESES...23 STUDY DESIGNS AND DATA COLLECTION...24 LABORATORY METHODS AND IMAGE ANALYSIS...27 STATISTICAL METHODS...29 POWER CONSIDERATIONS...36

CHAPTER 3. MUTL-HOMOLOG 1 (MLH1) EXPRESSION AND RISK OF INCIDENT, SPORADIC COLORECTAL ADENOMA: SEARCH FOR PROSPECTIVE BIOMARKERS OF RISK FOR COLORECTAL CANCER...39

ABSTRACT...39 INTRODUCTION...40 PARTICIPANTS AND METHODS...41 RESULTS...49 DISCUSSION...57

CHAPTER 4. COLORECTAL MUCOSAL EXPRESSION OF MSH2 AS A POTENTIAL MODIFIABLE BIOMARKER OF RISK FOR COLORECTAL NEOPLASMS...64

ABSTRACT...64 INTRODUCTION...65 PARTICIPANTS AND METHODS...66 RESULTS...74 DISCUSSION...80

CHAPTER 5. EFFECTS OF CALCIUM AND VITAMIN D ON MLH1 AND MSH2 EXPRESSION IN RECTAL MUCOSA OF SPORADIC COLORECTAL ADENOMA PATIENTS...85

ABSTRACT...85 INTRODUCTION...86 PARTICIPANTS AND METHODS...87 RESULTS...97 DISCUSSION...105

CHAPTER 6. STRENGTHS AND LIMITATIONS OF THE PROJECT...110

STRENGTHS...110 LIMITATIONS...111

CHAPTER 7. CONCLUSIONS...112 CHAPTER 8. IMPLICATIONS AND FUTURE RESEARCH DIRECTIONS...116

IMPLICATIONS FOR CANCER RESEARCH AND PUBLIC HEALTH...116 FUTURE RESEARCH DIRECTIONS...116

REFERENCES...119 APPENDIX A. SUPPLEMENTARY TABLES FOR MAPII CASE-CONTROL STUDY...134 APPENDIX B. SUPPLEMENTARY TABLE FOR CADVMAP CLINICAL TRIAL...138

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