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Grant Details

Grant Number: 5R01CA118699-05 Interpret this number
Primary Investigator: Laird, Peter
Organization: University Of Southern California
Project Title: Cpg Island Methylator Phenotype in Human Colorectal Cancer
Fiscal Year: 2011


Abstract

DESCRIPTION (provided by applicant): Human colorectal cancer arises as a consequence of both genetic and epigenetic alterations, including promoter CpG island hypermethylation. A subset of colorectal tumors has been described to have an unusually high number of hypermethylated CpG islands, leading to the definition of a distinct phenotype, referred to as "CpG Island Methylator Phenotype", or "CIMP". The long-term objective of this proposal is to study the association between CIMP status and molecular, demographic, and histopathologic features, and environmental risk factors, using colorectal cancer samples collected through the Cooperative Family Registry for Colorectal Cancer Studies (Colon CFR), an NCI-supported consortium intended as a resource to promote collaborative and interdisciplinary studies in the genetic epidemiology of colorectal cancer. We have recently published an improved DMA methylation marker set and analysis technology with which CIMP can be efficiently defined with high accuracy in archival colorectal cancer specimens. We propose to 1) estimate the association between CIMP status and age, sex, family history, race and country of origin, using 4,943 population-based colorectal cancer samples collected through the Colon CFR, 2) estimate the association between CIMP status and tumor location, grade, invasive margin, lymphocytic infiltration, direct spread, lymph node spread, venous spread and type of residual adjacent polyp, if present, and 3) estimate the association between CIMP status and selected risk factors, both genetic and environmental/lifestyle factors, including somatic mutations in BRAF, germline mutations in the MMR genes, smoking history, red meat and alcohol intakes, dietary folate intake, folate metabolic enzyme polymorphisms and history of hormone use. This study will contribute to our understanding of the etiology of CIMP, and its relationship to other molecular and histopathologic features of colorectal cancer. Colorectal cancer involves changes to genes that control cell growth and division. These changes can be structural, as in the case of genetic mutations, or they can reflect an alteration in how actively the gene is being used, referred to as an epigenetic change. This study will investigate how some colorectal tumors acquire an unusually high number of epigenetic changes, with the long-term goal of using this knowledge to block or reverse these types of deleterious changes.



Publications

Timing of Aspirin and Other Nonsteroidal Anti-Inflammatory Drug Use Among Patients With Colorectal Cancer in Relation to Tumor Markers and Survival.
Authors: Hua X. , Phipps A.I. , Burnett-Hartman A.N. , Adams S.V. , Hardikar S. , Cohen S.A. , Kocarnik J.M. , Ahnen D.J. , Lindor N.M. , Baron J.A. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017-08-20; 35(24), p. 2806-2813.
EPub date: 2017-06-15.
PMID: 28617623
Related Citations

Clinicopathologic Risk Factor Distributions for MLH1 Promoter Region Methylation in CIMP-Positive Tumors.
Authors: Levine A.J. , Phipps A.I. , Baron J.A. , Buchanan D.D. , Ahnen D.J. , Cohen S.A. , Lindor N.M. , Newcomb P.A. , Rosty C. , Haile R.W. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2016 Jan; 25(1), p. 68-75.
EPub date: 2015-10-28.
PMID: 26512054
Related Citations

Association of the colorectal CpG island methylator phenotype with molecular features, risk factors, and family history.
Authors: Weisenberger D.J. , Levine A.J. , Long T.I. , Buchanan D.D. , Walters R. , Clendenning M. , Rosty C. , Joshi A.D. , Stern M.C. , LeMarchand L. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2015 Mar; 24(3), p. 512-519.
EPub date: 2015-01-13.
PMID: 25587051
Related Citations

Association between molecular subtypes of colorectal cancer and patient survival.
Authors: Phipps A.I. , Limburg P.J. , Baron J.A. , Burnett-Hartman A.N. , Weisenberger D.J. , Laird P.W. , Sinicrope F.A. , Rosty C. , Buchanan D.D. , Potter J.D. , et al. .
Source: Gastroenterology, 2015 Jan; 148(1), p. 77-87.e2.
EPub date: 2014-09-30.
PMID: 25280443
Related Citations

Bis-SNP: combined DNA methylation and SNP calling for Bisulfite-seq data.
Authors: Liu Y. , Siegmund K.D. , Laird P.W. , Berman B.P. .
Source: Genome biology, 2012-07-11; 13(7), p. R61.
EPub date: 2012-07-11.
PMID: 22784381
Related Citations

Cancer risks for the relatives of colorectal cancer cases with a methylated MLH1 promoter region: data from the Colorectal Cancer Family Registry.
Authors: Levine A.J. , Win A.K. , Buchanan D.D. , Jenkins M.A. , Baron J.A. , Young J.P. , Long T.I. , Weisenberger D.J. , Laird P.W. , McCall R.L. , et al. .
Source: Cancer prevention research (Philadelphia, Pa.), 2012 Feb; 5(2), p. 328-35.
EPub date: 2011-12-05.
PMID: 22144422
Related Citations

Genome-scale analysis of aberrant DNA methylation in colorectal cancer.
Authors: Hinoue T. , Weisenberger D.J. , Lange C.P. , Shen H. , Byun H.M. , Van Den Berg D. , Malik S. , Pan F. , Noushmehr H. , van Dijk C.M. , et al. .
Source: Genome research, 2012 Feb; 22(2), p. 271-82.
EPub date: 2011-06-09.
PMID: 21659424
Related Citations

Genome-scale discovery of DNA-methylation biomarkers for blood-based detection of colorectal cancer.
Authors: Lange C.P. , Campan M. , Hinoue T. , Schmitz R.F. , van der Meulen-de Jong A.E. , Slingerland H. , Kok P.J. , van Dijk C.M. , Weisenberger D.J. , Shen H. , et al. .
Source: PloS one, 2012; 7(11), p. e50266.
EPub date: 2012-11-28.
PMID: 23209692
Related Citations

Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains.
Authors: Berman B.P. , Weisenberger D.J. , Aman J.F. , Hinoue T. , Ramjan Z. , Liu Y. , Noushmehr H. , Lange C.P. , van Dijk C.M. , Tollenaar R.A. , et al. .
Source: Nature genetics, 2011-11-27; 44(1), p. 40-6.
EPub date: 2011-11-27.
PMID: 22120008
Related Citations

Modeling measurement error in tumor characterization studies.
Authors: Rakovski C. , Weisenberger D.J. , Marjoram P. , Laird P.W. , Siegmund K.D. .
Source: BMC bioinformatics, 2011-07-13; 12, p. 284.
EPub date: 2011-07-13.
PMID: 21752297
Related Citations

Altered folate availability modifies the molecular environment of the human colorectum: implications for colorectal carcinogenesis.
Authors: Protiva P. , Mason J.B. , Liu Z. , Hopkins M.E. , Nelson C. , Marshall J.R. , Lambrecht R.W. , Pendyala S. , Kopelovich L. , Kim M. , et al. .
Source: Cancer prevention research (Philadelphia, Pa.), 2011 Apr; 4(4), p. 530-43.
EPub date: 2011-02-14.
PMID: 21321062
Related Citations

Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases.
Authors: Rumilla K. , Schowalter K.V. , Lindor N.M. , Thomas B.C. , Mensink K.A. , Gallinger S. , Holter S. , Newcomb P.A. , Potter J.D. , Jenkins M.A. , et al. .
Source: The Journal of molecular diagnostics : JMD, 2011 Jan; 13(1), p. 93-9.
EPub date: 2010-12-23.
PMID: 21227399
Related Citations

Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer.
Authors: Mrkonjic M. , Roslin N.M. , Greenwood C.M. , Raptis S. , Pollett A. , Laird P.W. , Pethe V.V. , Chiang T. , Daftary D. , Dicks E. , et al. .
Source: PloS one, 2010-10-13; 5(10), p. e13314.
EPub date: 2010-10-13.
PMID: 20967208
Related Citations

Epigenomics-based diagnostics.
Authors: Diamandis E.P. , Sidransky D. , Laird P.W. , Cairns P. , Bapat B. .
Source: Clinical chemistry, 2010 Aug; 56(8), p. 1216-9.
EPub date: 2010-05-14.
PMID: 20472819
Related Citations

Principles and challenges of genomewide DNA methylation analysis.
Authors: Laird P.W. .
Source: Nature reviews. Genetics, 2010 Mar; 11(3), p. 191-203.
PMID: 20125086
Related Citations

Analysis of the association between CIMP and BRAF in colorectal cancer by DNA methylation profiling.
Authors: Hinoue T. , Weisenberger D.J. , Pan F. , Campan M. , Kim M. , Young J. , Whitehall V.L. , Leggett B.A. , Laird P.W. .
Source: PloS one, 2009-12-21; 4(12), p. e8357.
EPub date: 2009-12-21.
PMID: 20027224
Related Citations

Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual-specific DNA methylation patterns.
Authors: Byun H.M. , Siegmund K.D. , Pan F. , Weisenberger D.J. , Kanel G. , Laird P.W. , Yang A.S. .
Source: Human molecular genetics, 2009-12-15; 18(24), p. 4808-17.
EPub date: 2009-09-23.
PMID: 19776032
Related Citations

The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: a possible molecular basis for the site-specific cancer risk modification.
Authors: Sohn K.J. , Jang H. , Campan M. , Weisenberger D.J. , Dickhout J. , Wang Y.C. , Cho R.C. , Yates Z. , Lucock M. , Chiang E.P. , et al. .
Source: International journal of cancer, 2009-05-01; 124(9), p. 1999-2005.
PMID: 19123462
Related Citations

Locking in on the human methylome.
Authors: Berman B.P. , Weisenberger D.J. , Laird P.W. .
Source: Nature biotechnology, 2009 Apr; 27(4), p. 341-2.
PMID: 19352369
Related Citations

Molecular characterization of MSI-H colorectal cancer by MLHI promoter methylation, immunohistochemistry, and mismatch repair germline mutation screening.
Authors: Poynter J.N. , Siegmund K.D. , Weisenberger D.J. , Long T.I. , Thibodeau S.N. , Lindor N. , Young J. , Jenkins M.A. , Hopper J.L. , Baron J.A. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2008 Nov; 17(11), p. 3208-15.
PMID: 18990764
Related Citations

Kaiso contributes to DNA methylation-dependent silencing of tumor suppressor genes in colon cancer cell lines.
Authors: Lopes E.C. , Valls E. , Figueroa M.E. , Mazur A. , Meng F.G. , Chiosis G. , Laird P.W. , Schreiber-Agus N. , Greally J.M. , Prokhortchouk E. , et al. .
Source: Cancer research, 2008-09-15; 68(18), p. 7258-63.
PMID: 18794111
Related Citations

DNA methylation analysis by digital bisulfite genomic sequencing and digital MethyLight.
Authors: Weisenberger D.J. , Trinh B.N. , Campan M. , Sharma S. , Long T.I. , Ananthnarayan S. , Liang G. , Esteva F.J. , Hortobagyi G.N. , McCormick F. , et al. .
Source: Nucleic acids research, 2008 Aug; 36(14), p. 4689-98.
EPub date: 2008-07-15.
PMID: 18628296
Related Citations

Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer.
Authors: Kohonen-Corish M.R. , Sigglekow N.D. , Susanto J. , Chapuis P.H. , Bokey E.L. , Dent O.F. , Chan C. , Lin B.P. , Seng T.J. , Laird P.W. , et al. .
Source: Oncogene, 2007-06-28; 26(30), p. 4435-41.
EPub date: 2007-01-29.
PMID: 17260021
Related Citations




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