Hypothesis-based Biomarkers for Managing Gastric and Colorectal Cancer Precursors Open Access

Abstract

Gastric cancer (GC) and colorectal cancer (CRC) are leading causes of cancer deaths; effectively managing their precursors could reduce the burden from these diseases, but biomarkers are currently not used in their management. The primary objective of this dissertation was to evaluate potential roles for plausible GC- and CRC-related biomarkers for 1) identifying precursor lesions, 2) risk stratification, and 3) surrogate endpoints in chemoprevention trials.

In the first study,I used cross-sectional data from a population-based, serologic/endoscopic screening program for gastric diseases, particularly GC, and found that serum PGII combined with anti-H. pylori IgG may be useful for identifying persons with gastric histopathology. In the second study, from the same screening program, I used prospective serological and histological data from repeated blood sample collections and gastric mucosal biopsies from repeated esophagogastroduodenoscopies and found that temporal changes in serum PGI, PGII, PGI/II ratio, and anti-H. pylori IgG levels (especially PGII and anti-H. pylori IgG combined) are associated with risk for progression of gastric precancerous lesions. In the third study, I used data from a pilot colonoscopy-based case-control study of colorectal adenoma and found that the mean ratio of rectal TGFα to TGFβ1 expression and mean rectal TGFα expression in biopsies of normal-appearing colorectal mucosa were higher in adenoma cases than in controls. In the fourth study, I used data from a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial of calcium 2,000 mg and/or vitamin D3 800 IU daily over 6 months in sporadic colorectal adenoma patients and found that those in the calcium and vitamin D groups relative to those in the placebo group had non-statistically significant decreases in the mean ratio of rectal TGFα to TGFβ1 expression in their normal-appearing rectal mucosa. Taken together, these results suggest that 1) the combination of serum PGII and anti-H. pylori IgG could be used to identify, monitor, and manage individuals at increased risk for GC; and 2) the combination of TGFα and TGFβ1 expression in the normal-appearing colorectal mucosa may be a valid indicator of risk for colorectal neoplasms that may be favorably modifiable by supplemental calcium and/or vitamin D3.

Table of Contents

Table of Contents Chapter 1. Introduction and Background.................................................................................................................................... 1 Introduction............................................................................................................................................................................... 1 Background................................................................................................................................................................................ 3 Morphology of Human Stomach...................................................................................................................................................... 3 Histopathology of Gastric Cancer................................................................................................................................................... 4 Descriptive Epidemiology of Gastric Cancer...................................................................................................................................... 5 Molecular Basis of Gastric Carcinogenesis. .................................................................................................................................... 10 Risk Factors for Gastric Cancer...................................................................................................................................................... 15 Screen and Early Detection for Gastric Cancer and Precursors............................................................................................................. 42 Current Recommendations for Management of Gastric Cancer Precursors............................................................................................. 58 A Proposed Screening and Management Strategy for Gastric Cancer and Precursors................................................................................ 58 Morphology of Human Colon and Rectum.......................................................................................................................................... 60 Descriptive Epidemiology of Colorectal Cancer................................................................................................................................... 60 Risk Factors for Colorectal Cancer.................................................................................................................................................... 62 Calcium and Vitamin D................................................................................................................................................................... 66 Molecular Basis of Colorectal Cancer................................................................................................................................................ 68 TGFα and TGFβ1.............................................................................................................................................................................70 The Colorectal Adenoma - Carcinoma Sequence.................................................................................................................................. 71 Current Recommendations for Management of Colorectal Adenoma....................................................................................................... 72 Gaps in the Literature Addressed by This Dissertation......................................................................................................................... 72 Chapter 2. Objectives, Specific Aims, and Hypotheses..................................................................................................................... 74 Overall Goal...................................................................................................................... ............................................................ 74 Specific Aims....................................................................................................................... .......................................................... 74 Hypotheses....................................................................................................................... ............................................................ 75 Chapter 3. Serological Biomarkers for Identification of Precancerous Gastric Lesions ......................................................................... 77 Abstract....................................................................................................................... ................................................................. 79 Introduction........................................................................................................................ ........................................................... 80 Material and Methods..................................................................................................... ................................................................. 81 Results........................................................................................................................ ................................................................. 83 Discussion........................................................................................................................ ............................................................. 86 Chapter 4. Temporal Changes in Serum Biomarkers and Risk for Progression of Gastric Precancerous Lesions: a Longitudinal Study...... 100 Abstract....................................................................................................................... ................................................................. 102 Introduction................................................................................................................. .................................................................. 103 Materials and Methods........................................................................................................................ ............................................. 104 Results........................................................................................................................ .................................................................. 107 Discussion........................................................................................................................ .............................................................. 112 Chapter 5. Transforming growth factors and receptor as potential modifiable pre-neoplastic biomarkers of risk for colorectal neoplasms. 142 Abstract....................................................................................................................... ................................................................... 144 Introduction........................................................................................................................ ............................................................. 145 Materials and Methods........................................................................................................................ ............................................... 146 Results........................................................................................................................ ................................................................... 151 Discussion....................................................................................................................... ................................................................ 154 Chapter 6. Effects of calcium and vitamin D3 on transforming growth factors in rectal mucosa of sporadic colorectal adenoma patients: a randomized controlled trial ....................................................................................................................... .....................................168 Abstract....................................................................................................................... .................................................................... 170 Introduction....................................................................................................................... ............................................................... 171 Materials and Methods....................................................................................................................... ................................................. 172 Results....................................................................................................................... ...................................................................... 177 Discussion....................................................................................................................... .................................................................. 181 Chapter 7. Conclusions and Implications..................................................................................................................... ....................... 193 Chapter 8. Future Directions........................................................................................................................ ..................................... 195 References....................................................................................................................... ................................................................ 198 Appendix........................................................................................................................ .................................................................. 267

About this Dissertation

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School	Laney Graduate School
Department	Epidemiology
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Oncology Biology, Microbiology Health Sciences, Epidemiology
Keyword	precancerous lesions gastric neoplasm biomarkers colorectal neoplasm managment transforming growth factors cancer epidemiology serological biomarkers
Committee Chair / Thesis Advisor	Bostick, Roberd M, Emory University
Committee Members	Long, Qi, Emory University Yuan, Yuan, China Medical University Smith, Robert, American Cancer Society Flanders, W Dana, Emory University

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