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Frequent hypermethylation of RASSF1A in early flat-type colorectal tumors

Oncogene volume 23, pages 8900–8907 (2004)Cite this article

Abstract

Flat colorectal tumors, characterized by high-grade dysplasia from early small flat mucosal lesions, exhibit a relatively aggressive clinical behavior and are known for their infrequent K-ras mutations. In this study, we investigated the methylation status of the RASSF1A promoter in association with 3p LOH and K-ras mutations in 48 flat colorectal tumors (39 early carcinomas and nine intramucosal high-grade dysplasias). RASSF1A hypermethylation was detected in 39 of 48 (81.3%) tumors and RASSF1A methylation was also detected in 19 of 39 (49%) normal colonic mucosal tissues. 3p21.3 LOH was detected in 20 of 42 (47.6%) cases, but RASSF1 methylation was detected in cases with LOH (14 cases) and retention of 3p21.3 (20 cases). K-ras mutations were detected in seven of 48 (14.6%) tumors and the concordant occurrence of K-ras mutation and RASSF1A methylation was detected in three of 48 cases (6.3%). Overall, there was a statistically significant mutually exclusive relationship between K-ras mutations and RASSF1A methylation. In conclusion, promoter hypermethylation of RASSF1A is a frequent event and may start early in the background normal mucosa in this tumor type. An alternative cascade of abnormalities in RAS transduction pathways may be responsible for the flat morphology and aggressive nature of flat colorectal neoplasms.

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Abbreviations

RASSF1A :

Ras association domain family 1 gene A

LOH:

loss of heterozygosity

MSP:

methylation-specific PCR

SSCP:

single-strand conformation polymorphism

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Acknowledgements

We thank D Mrozek for English proofs.

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Authors and Affiliations

  1. Department of Pathology(II), Juntendo University, Juntendo University School of Medicine, 2-1-1 Hongo, Tokyo, 113-8421, Japan

    Naoto Sakamoto, Okio Hino & Hiroaki Fujii

  2. Department of Gastroenterology, Juntendo University, Juntendo University School of Medicine, 2-1-1 Hongo, Tokyo, 113-8421, Japan

    Naoto Sakamoto, Takeshi Terai, Satoshi Abe, Osamu Kobayasi & Nobuhiro Sato

  3. Division of Molecular & Cellular Medicine, Department of Molecular Genetics, Course for Molecular & Cellular Medicine, Niigata University, Graduate School of Medical & Dental Science, Niigata, 951-8514, Japan

    Yoichi Ajioka & Hidenobu Watanabe

  4. Pathology Division, Tokyo Rinkai Hospital, Tokyo, Japan

    Shu Hirai

  5. Department of Experimental Pathology, Cancer Institute, Tokyo, Japan

    Okio Hino

  6. Pathology and Clinical Laboratory Divisions, National Cancer Center Research Institute and Hospital, Tokyo, Japan

    Tadakazu Shimoda

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  1. Naoto Sakamoto
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  2. Takeshi Terai
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Correspondence to Hiroaki Fujii.

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Sakamoto, N., Terai, T., Ajioka, Y. et al. Frequent hypermethylation of RASSF1A in early flat-type colorectal tumors. Oncogene 23, 8900–8907 (2004). https://doi.org/10.1038/sj.onc.1207993

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