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Int J Mol Epidemiol Genet 2011;2(4):300-315

Original Article
Genetic variability in EGFR, Src and HER2 and risk of colorectal adenoma and
cancer

Elizabeth M Poole, Karen Curtin, Li Hsu, Richard J Kulmacz, David J Duggan, Karen W Makar, Liren Xiao, Christopher S
Carlson, Martha L Slattery, Bette J Caan, John D Potter, Cornelia M Ulrich

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston,
Massachusetts, USA; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA; Fred
Hutchinson Cancer Research Center, Seattle, Washington, 98109; University of Utah Health Sciences Center, Salt Lake City,
UT, 84108; Departments of Internal Medicine and Biochemistry and Molecular Biology, University of Texas Health Science
Center at Houston, Houston, Texas, 77030; Translational Genomics Research Institute, Phoenix, AZ, 85004; Division of
Research, Kaiser Permanente Medical Care Program, Oakland, CA 94612; Department of Epidemiology, University of
Washington, Seattle, Washington, 98195; National Center for Tumor Diseases and German Cancer Research Center,
Heidelberg, Germany, D-69120

Received July 17, 2011; accepted October 3, 2011; Epub December 3, 2011; Published December 15, 2011

Abstract: The EGFR signaling pathway is involved in carcinogenesis at multiple sites, particularly colorectal cancer, and is a
target of colorectal cancer chemotherapy. EGFR signaling is linked to pro-carcinogenic mechanisms, including cell
proliferation, survival, angiogenesis, and more recently prostaglandin synthesis. Genetic variability in this pathway has not yet
been studied in relation to colorectal carcinogenesis. In three case-control studies of colorectal adenoma (n=485 cases/578
controls), colon cancer (n=1424 cases/1780 controls) and rectal cancer (n=583 cases/775 controls), we investigated
associations between candidate SNPs, tagSNPs and haplotypes in EGFR signaling (EGFR, Src, and HER2) and risk. We also
examined associations with tumor subtypes: TP53 and KRAS2 mutations, CpG island methylator phenotype, and microsatellite
instability. All three studies were genotyped using an identical Illumina GoldenGate assay, allowing thorough investigation of
genetic variability across stages and locations of colorectal neoplasia. The EGFR tagSNP 142572T>C (rs3752651) CC
genotype was associated with a suggested increased risk for both colon (OR: 1.40; 95% CI: 1.00-1.96; p-trend=0.04) and rectal
cancer (OR: 1.39; 95% CI: 0.81-2.41; p-trend=0.65). In tumor subtype analyses, the association was limited to TP53-mutated
colon tumors. Using the Chatterjee 1 df Tukey test to assess gene-gene interactions, we observed a statistically significant
(p<0.01) interaction between SNPs in EGFR and Src for colorectal adenoma risk. The association with EGFR 142572 should
be investigated in additional studies and the significant gene-gene interaction between EGFR and Src in relation to adenoma
risk suggests that these two genes are jointly affecting early stages in colorectal carcinogenesis and requires further follow-up.
(IJMEG1107003).

Key words: EGFR, colorectal cancer, colorectal polyps, genetics

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Address all correspondence to:
Cornelia Ulrich, PhD
Division of Preventive Oncology
German Cancer Research Center
Im Neuenheimer Feld 280, G110
D-69120, Heidelberg, Germany
Phone: +49 6221 42-2263 Fax: +49 6221 42-1619
Email: n.ulrich@dkfz.de