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Concordant DNA Methylation in Synchronous Colorectal Carcinomas

Authors' Affiliations: Departments of ¹ Leukemia and ² Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; ³ Department of Gastroenterology, Showa University School of Medicine and ⁴ Promotion Center of Pharmaceutical Education, Showa University School of Pharmacy, Tokyo, Japan; ⁵ Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; and ⁶ Department of Diagnostic Pathology, St. Marianna University School of Medicine, Kanagawa, Japan

Requests for reprints: Jean-Pierre J. Issa, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit428, Houston, TX 77030. Phone: 713-745-2260; Fax: 713-745-2261; E-mail: jpissa{at}mdanderson.org.

Epigenetic changes have been proposed as mediators of the field defect in colorectal carcinogenesis, which has implications for risk assessment and cancer prevention. As a test of this hypothesis, we evaluated the methylation status of eight genes (MINT1, 2, 31, MLH1, p16, p14, MGMT, and ESR1), as well as BRAF and KRAS mutations, in 57 multiple colorectal neoplasias (M-CRN) and compared these to 69 solitary colorectal cancers (S-CRC). There were no significant differences in methylation between M-CRNs and S-CRCs except for p14 and MGMT that was significantly higher in M-CRNs than S-CRCs (16.1% versus 9.3%; 26.5% versus 17.3%, respectively; P < 0.05). We found significant (P < 0.05) correlations for MINT1 (r = 0.8), p16 (r = 0.8), MLH1 (r = 0.9), and MGMT (r = 0.6) methylation between tumors pairs of the same site (proximal/proximal and distal/distal). KRAS showed no concordance in mutations. BRAF mutation showed concordance in proximal site pairs but was discordant in different site pairs. Histologically, eight of 10 paired cancers with similar locations were concordant for a cribriform glandular configuration. We conclude that synchronous colorectal tumors of the same site are highly concordant for methylation of multiple genes, BRAF mutations, and a cribriform glandular configuration, all consistent with a patient-specific predisposition to particular subtypes of colorectal cancers. Screening for and secondary prevention of colon cancer should take this fact into account.

Key Words: colorectal carcinoma • DNA methylation • synchronous colorectal cancer • CpG island methylator phenotype • field cancerization