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CDX2 Polymorphisms, RNA Expression, and Risk of Colorectal Cancer

Departments of ¹ Internal Medicine, ² Human Genetics, ³ Pathology, and ⁴ Pediatrics, University of Michigan Medical School; Departments of ⁵ Epidemiology and ⁶ Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan; ⁷ Division of Hematology-Oncology, Department of Medicine, University of California, Irvine, California; ⁸ Department of Community Medicine and Epidemiology, Carmel Medical Center and Technion Faculty of Medicine; and ⁹ CHS National Cancer Control Center, Haifa, Israel

Requests for reprints: Stephen B. Gruber, Division of Molecular Medicine and Genetics, University of Michigan, 4301 MSRB III, Box 0638, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0638. Phone: 734-615-9712; Fax: 734-763-7672; E-mail: sgruber{at}umich.edu.

In adult mammals, CDX2 acts as a transcription factor and is expressed in intestinal epithelial cells. Down-regulation of CDX2 is frequently observed in colorectal cancer, suggesting its loss may cause dedifferentiation of gastrointestinal epithelial cells. However, it is not clear whether inherited variants of CDX2 are associated with risk of colorectal cancer. Using epidemiologic data and tumors from a population-based case-control study in Israel, we identified novel single nucleotide polymorphisms (SNPs) by resequencing 35 cases, compared genotype and haplotype frequencies in 455 matched pairs, and characterized the tumor characteristics of all 455 cases by microsatellite instability analysis, in addition to a partially overlapping set of 201 frozen tumors with expression profiling data (82/201) from the same study. Nine polymorphisms were identified in the 35 cases, and none of the SNPs or haplotypes were associated with risk of colorectal cancer in the 455 matched pairs. These variants were not associated with CDX2 expression in the 83 subjects with expression data. We evaluated subject and tumor characteristics in the 201 subjects with CDX2 tumor expression data. Reduced CDX2 expression was associated with tumor location (right sided), poor differentiation, high microsatellite instability status, and a positive first-degree family history. We conclude that it is unlikely that common CDX2 variants account for a measurable fraction of susceptibility to colorectal cancer in this population. However, CDX2 expression levels were strongly associated with microsatellite instability and tumor location in the gastrointestinal tract, consistent with a possible role in the specification of gastrointestinal epithelial cell fate in humans.

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