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Colorectal Cancer With Mutation in BRAF, KRAS, and Wild-Type With Respect to Both Oncogenes Showing Different Patterns of DNA Methylation

From the Departments of Gastroenterological Surgery and Surgical Oncology and Pathological Research, Okayama University Graduate School of Medicine and Dentistry, Okayama; Department of Statistics, Radiation Effects Research Foundation, Hiroshima, Japan; Conjoint Gastroenterology Laboratory, Royal Brisbane and Women's Hospital Research Foundation and Queensland Institute of Medical Research, Brisbane, Australia; and Department of Pathology, McGill University, Montreal, Quebec, Canada

Address reprint requests to Nagahide Matsubara, MD, Department of Gastroenterological Surgery and Surgical Oncology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan; e-mail: nagamb{at}cc.okayama-u.ac.jp

PURPOSE: BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1, whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT. The aim of this study was to further investigate the link between genetic alterations in the RAS/RAF/ERK pathway and an underlying epigenetic disorder.

PATIENTS AND METHODS: Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNA1G, p16^INK4a, p14^ARF, COX2, DAPK, MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa.

RESULTS: BRAF V599E mutations were identified in 21 (9%) of 234 CRCs, and KRAS mutations were identified in 72 (31%) of 234 CRCs. Mutations in BRAF and KRAS were never found in the same tumor. CRCs with BRAF mutations showed high-level promoter methylation in multiple loci, with a mean number of methylated loci of 7.2 (95% CI, 6.6 to 7.9) among 11 loci examined (P < .0001). Tumors with KRAS mutations showed low-level promoter methylation, and CRCs with neither mutation showed a weak association with promoter methylation, with an average number of methylated loci of 1.8 (95% CI, 1.5 to 2.1) and 1.0 (95% CI, 0.79 to 1.3), respectively.

CONCLUSION: In CRC, the methylation status of multiple promoters can be predicted through knowledge of BRAF and, to a lesser extent, KRAS activating mutations, indicating that these mutations are closely associated with different patterns of DNA hypermethylation. These changes may be important events in colorectal tumorigenesis.

Supported in part by a grant-in aid from the Japanese Ministry of Education, Science, Sports and Culture of Japan (grant Nos. 12671227, 11671237, 11671240, 14031227).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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