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Aberrant Methylation of p16^INK4a in Anatomic and Gender-specific Subtypes of Sporadic Colorectal Cancer¹

Laboratory for Molecular Epidemiology, Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94143-0560 [J. K. W., S. Z., C. G., M. R. W., R. M.]; Institut Salut Publica de Catalunya, Pavello Central, Campus de Bellvitge, Universitat de Barcelona, Ciutat Sanitaria de Bellvitge, Feixa Llarga s/n, 08907 Hospitalet de Llobregat, Barcelona, Spain [A. L.]; Department of Surgery, Hospital St. Pablo, Barcelona, Spain [M. J. L., M. T.]; and Department of Clinical Biochemistry, Hospital Clinic i Provincial, University of Barcelona, Spain [A. B.]

Colorectal cancer (CRC) occurring in the proximal colon and among women may represent a distinct subtype of the disease. In the present study of 120 sporadic CRCs, we used methylation-specific PCR to test whether methylation of the CpG island in the 5' region of the p16^INK4a tumor suppressor gene was associated with anatomical location, gender, or other clinicopathological characteristics. Overall, 18.3% of the tumors had detectable p16^INK4a methylation. A marked preponderance of methylated tumors occurred within the proximal colon; cancers occurring proximal to the sigmoid colon were 13.1 times more likely to contain methylated p16^INK4a compared with distal tumors. In addition, female patients were 8.8 times more likely than males to have methylation-positive cancers, and p16^INK4a methylation was also associated with poorly differentiated tumors. The localization of tumors with p16^INK4a methylation within the proximal colon and among female patients specifically adds to a growing database of molecular alterations that define important subtypes of sporadic CRC. The potentially reversible nature of CpG methylation may provide novel therapeutic opportunities for this increasing subtype of the disease, which, due to anatomical location, presents a great challenge for early detection.

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