徳島大学 教育・研究者情報データベース(EDB)

1. (英) Inoue Atsushi

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2. 岡本 耕一([徳島大学.病院.診療科.内科.消化器内科])

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3. 藤野 泰輝

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4. (英) Nakagawa Tadahiko

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5. 六車 直樹

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6. (英) Sannomiya Katsutaka

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7. (英) Mitsui Yasuhiro

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8. (英) Takaoka Toshi

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9. 北村 晋志

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10. 宮本 弘志([徳島大学.大学院医歯薬学研究部.医学域.医科学部門.内科系.消化器内科学]/[徳島大学.病院.診療科.内科.消化器内科])

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11. 岡久 稔也([徳島大学.大学院医歯薬学研究部.医学域.連携研究部門(医学域).寄附講座系(医学域).地域総合医療学]/[徳島大学.病院.診療科.内科.消化器内科])

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12. (英) Fujimori Takahiro

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13. 井本 逸勢

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14. 高山 哲治([徳島大学.大学院医歯薬学研究部.医学域.医科学部門.内科系.消化器内科学])

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(英) B-RAF mutation and accumulated gene methylation in aberrant crypt foci (ACF),sessile serrated adenoma/polyp (SSA/P) and cancer in SSA/P.

(英) Sessile serrated adenomas/polyps (SSA/Ps) are a putative precursor of colon cancer with microsatellite instability (MSI). However, the developmental mechanism of SSA/P remains unknown. We performed genetic analysis and genome-wide DNA methylation analysis in aberrant crypt foci (ACF), SSA/P, and cancer in SSA/P specimens to show a close association between ACF and the SSA/P-cancer sequence. We also evaluated the prevalence and number of ACF in SSA/P patients. ACF in the right-side colon were observed in 36 patients with SSA/Ps alone, 2 with cancers in SSA/P, and 20 normal subjects and biopsied under magnifying endoscopy. B-RAF mutation and MSI were analysed by PCR-restriction fragment length polymorphism (RFLP) and PCR-SSCP, respectively, in 15 ACF, 20 SSA/P, and 2 cancer specimens. DNA methylation array analysis of seven ACF, seven SSA/P, and two cancer in SSA/P specimens was performed using the microarray-based integrated analysis of methylation by isochizomers (MIAMI) method. B-RAF mutations were frequently detected in ACF, SSA/P, and cancer in SSA/P tissues. The number of methylated genes increased significantly in the order of ACF<SSA/P<cancer. The most commonly methylated genes in SSA/P were PQLC1, HDHD3, RASL10B, FLI1, GJA3, and SLC26A2. Some of these genes were methylated in ACF, whereas all genes were methylated in cancers. Immunohistochemistry revealed their silenced expression. Microsatellite instability and MLH1 methylation were observed only in cancer. The prevalence and number of ACF were significantly higher in SSA/P patients than in normal subjects. A significant correlation was seen between the numbers of SSA/P and ACF in SSA/P patients. Our results suggest that ACF are precursor lesions of the SSA/P-cancer sequence in patients with SSA/P, where ACF arise by B-RAF mutation and methylation of some of the six identified genes and develop into SSA/Ps through accumulated methylation of these genes.

1. (英) Aberrant Crypt Foci
2. (英) Adenoma
3. (英) Aged
4. (英) Case-Control Studies
5. (英) Colonic Neoplasms
6. (英) DNA Methylation
7. (英) Female
8. (英) Genetic Association Studies
9. (英) Genetic Predisposition to Disease
10. (英) Humans
11. (英) Male
12. (英) Middle Aged
13. (英) Mutation, Missense
14. (英) Proto-Oncogene Proteins B-raf

1. (英) Article.ELocationID: 10.1038/bjc.2014.545

2. (英) Article.PublicationTypeList.PublicationType: Journal Article

3. (英) OtherID: PMC4453443 [Available on 01/20/16]