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Principal Investigator
Name
FangFang Zhang
Degrees
-
Institution
UNT Health Science Center
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2007-0251
Initial CDAS Request Approval
May 28, 2008
Title
Gene-Specific Hypermethylation in the Colorectal Adenoma-Carcinoma Sequence
Summary
Hypermethylation of tumor-suppressor genes has been recognized as one of the most important molecular signatures of human tumors. A loss of gene function resulted from aberrant methylation promotes cell proliferation leading to tumorigenesis. Accumulating evidence suggests that tumor-suppressor genes are frequently methylated in colorectal cancer tissues, supporting aberrant methylation as a cancer-inducing mechanism of colorectal cancer. However, most existing studies analyzed methylation patterns in biospecimens collected after cancer diagnosis so cannot determine whether methylation abnormalities increase cancer risk or may only result secondarily from cancer. The majority of colorectal cancer arises from adenomatous polyps following the adenoma-carcinoma sequence. However, the role of gene-specific hypermethylation in determining the multistep colorectal cancer pathogenesis has not been well characterized. Using a nested case-control design within the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening trial, we will examine whether hypermethylation of tumor-suppressor genes in various cellular pathways including cell cycle control, cell-to-cell adhesion, DNA repair, apoptosis and angiogenesis increases the risk of colorectal adenoma and cancer. We will analyze methylation patterns of 12 tumor-suppressor genes using prediagnostic peripheral blood collected from 500 colorectal cancer cases and 400 adenoma cases that occurred during the follow-up and 900 frequency-matched controls. The causes of methylation abnormalities are largely unknown. Using a wide breadth of epidemiologic data collected in the PLCO trial, we will determine whether modifiable risk factors such as diet, alcohol and tobacco use, physical activity and the use of nonsteroidal anti-inflammatory drugs affect methylation patterns of the 900 healthy controls. These investigations will advance our knowledge on the role of gene-specific hypermethylation in the multistep colorectal cancer pathogenesis and provide valuable information to develop prevention strategies against methylation abnormalities.
Aims

The overall objective of this study is to identify patterns of gene-specific hypermethylation that are associated with the adenoma-carcinoma sequence in colorectal cancer development. The majority of colorectal cancer arises from adenomatous polyps following the adenoma-carcinoma sequence. However, factors that contribute to the multi-step pathogenesis of colorectal cancer have not been well characterized. In recent years, hypermethylation of tumor-suppressor genes has been found as a common event in cancer cells. A loss of gene function resulted from aberrant methylation can promote cell proliferation and lead to tumorigenesis. Several tumor-suppressor genes are found to be hypermethylated in tissues of patients with colorectal cancer. However, studies that simultaneously examined the methylation patterns in adenomas are limited. No prior studies used a prospective design to examine the association between gene-specific hypermethylation and colorectal cancer risk.
Taking advantage of the availability of prediagnostic blood samples collected from colorectal cancer and adenoma patients and their frequency-matched controls, the first two aims of this study is to determine whether hypermethylation of multiple tumor-suppressor genes at baseline contributes to the subsequent development of colorectal cancer and adenoma among study participants randomized to receive the flexible sigmoidscopy screening in the prostate, lung, colorectal and ovarian (PLCO) screening trial. We will use a nested case-control design to investigate the first aim among 500 colorectal cancer cases and 500 controls and the second aim among 400 adenoma cases and 400 controls. Although exploratory, we will further examine whether gene-specific hypermethylation is associated with a heterogeneous risk of colorectal adenoma/cancer according to the clinicopathological features of the lesion such as the size and villous histology of the adenoma and the location, stage and histology of the cancer.
The causes of methylation abnormalities are poorly understood. Although the impact of age, dietary folate intake and alcohol consumption on methylation has been investigated in colorectal cancer patients, little is known with regard to the determinants of methylation abnormalities in healthy individuals whose methylation status will not be affected by cancer occurrence or treatment allocation. Using a wide breadth of epidemiologic data collected in the PLCO trial, the third aim of this study is to evaluate the association between gene-specific hypermethylation and dietary and behavioral risk factors in 900 controls. Because dietary and behavioral risk factors are modifiable, these investigations may provide valuable information to develop prevention strategies against methylation abnormalities.
To summarize, we plan to investigate the following specific aims:
Specific Aim 1: To investigate whether peripheral blood cell promoter hypermethylation in key tumor-suppressor genes involved in colorectal carcinogenesis is associated with an increased risk of colorectal cancer using a prospective design. Specifically, we will:
Aim 1a: Examine whether baseline promoter hypermethylation of 12 tumor-suppressor genes in various cellular pathways of colorectal cancer development (including APC, CDH1, CDH13, p16INK4a, p14ARF, MLH1, MGMT, DPAK, RASSF1A, THBS1, HLTF and TPEF/HPP1) is associated with a subsequent increased risk of colorectal cancer, among 500 incident colorectal cancer cases and 500 frequency-matched controls.
Aim 1b: Examine whether gene-specific hypermethylation is associated with a heterogeneous risk of colorectal cancer according to the clinicopathologic features of the tumor such as location, stage and histological grade.
Specific Aim 2: To investigate whether peripheral blood cell promoter hypermethylation in key tumor-suppressor genes involved in colorectal carcinogenesis is associated with an increased risk of adenomatous polyps using a prospective design. Specifically, we will:
Aim 2a: Examine whether baseline promoter hypermethylation of 12 tumor-suppressor genes in various cellular pathways of colorectal cancer development (including APC, CDH1, CDH13, p16INK4a, p14ARF, MLH1, MGMT, DPAK, RASSF1A, THBS1, HLTF and TPEF/HPP1) is associated with a subsequent increased risk of colorectal adenomas, among 400 incident colorectal adenoma cases and 400 frequency matched controls;
Aim 2b: Examine whether gene-specific hypermethylation is associated with a heterogeneous risk of colorectal adenoma according to the clinicopathologic features of the adenomas such as size, villous histology and multiplicity.
Specific Aim 3: To assess in healthy controls whether modifiable risk factors such as diet, alcohol and tobacco use, physical activity, the use of non-steroidal anti-inflammatory drugs and the use of hormone replacement therapy among women are associated with hypermethylation in the genes under study.
Overall, the proposed study differs from previous studies in its prospective design and capability of assessing gene-specific hypermethylation of colorectal adenoma, cancer and controls who underwent the same screening procedure from the same source population. Investigations on the specific aims of this study are expected to provide important data regarding the role of gene-specific hypermethylation in multi-step colorectal cancer development, as well as to advance our knowledge on the determinants of methylation abnormalities.

Collaborators

Fang Fang (UNT Health Science Center)
Richard Hayes (NCI, DCEG)
Wen-Yi Huang (NCI, DCEG)
Regina Santella (Columbia University)
Ruth Pfeiffer (NCI, DCEG)
Ying Wei (Columbia University)
Yujin Zhang (Columbia University)