A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer

Norihisa Saeki; Akira Saito; Il Ju Choi; Keitaro Matsuo; Sumiko Ohnami; Hirohiko Totsuka; Suenori Chiku; Aya Kuchiba; Yeonsu Lee; Kyongah Yoon; Myeongcherl Kook; Sook Ryun Park; Youngwoo Kim; Hideo Tanaka; Kazuo Tajima; Hiroshi Hirose; Fumihiko Tanioka; Yoshihiro Matsuno; Haruhiko Sugimura; Shunji Kato; Tsuneya Nakamura; Tomohiro Nishina; Wataru Yasui; Kazuhiko Aoyagi; Hiroki Sasaki; Kazuyoshi Yanagihara; Hitoshi Katai; Tadakazu Shimoda; Teruhiko Yoshida; Yusuke Nakamura; Setsuo Hirohashi; Hiromi Sakamoto

doi:10.1053/j.gastro.2010.10.058

A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer

Norihisa Saeki, Akira Saito, Il Ju Choi, Keitaro Matsuo, Sumiko Ohnami, Hirohiko Totsuka, Suenori Chiku, Aya Kuchiba, Yeonsu Lee, Kyongah Yoon, Myeongcherl Kook, Sook Ryun Park, Youngwoo Kim, Hideo Tanaka, Kazuo Tajima, Hiroshi Hirose, Fumihiko Tanioka, Yoshihiro Matsuno, Haruhiko Sugimura, Shunji KatoTsuneya Nakamura, Tomohiro Nishina, Wataru Yasui, Kazuhiko Aoyagi, Hiroki Sasaki, Kazuyoshi Yanagihara, Hitoshi Katai, Tadakazu Shimoda, Teruhiko Yoshida, Yusuke Nakamura, Setsuo Hirohashi, Hiromi Sakamoto

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研究成果: Article › 査読

104 被引用数 (Scopus)

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Background & Aims Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen (PSCA), but the loci of the other 2 were not investigated. Methods We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants. Results A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 (MUC1) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10^-13; odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 (P = 1.43 × 10^-11; OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38). Conclusions MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer.

本文言語	English
ページ（範囲）	892-902
ページ数	11
ジャーナル	Gastroenterology
巻	140
号	3
DOI	https://doi.org/10.1053/j.gastro.2010.10.058
出版ステータス	Published - 2011 3月

ASJC Scopus subject areas

肝臓学
消化器病学

UN SDG

この成果は、次の持続可能な開発目標に貢献しています

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10.1053/j.gastro.2010.10.058

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引用スタイル

Saeki, N., Saito, A., Choi, I. J., Matsuo, K., Ohnami, S., Totsuka, H., Chiku, S., Kuchiba, A., Lee, Y., Yoon, K., Kook, M., Park, S. R., Kim, Y., Tanaka, H., Tajima, K., Hirose, H., Tanioka, F., Matsuno, Y., Sugimura, H., ... Sakamoto, H. (2011). A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer. Gastroenterology, 140(3), 892-902. https://doi.org/10.1053/j.gastro.2010.10.058

Saeki, N, Saito, A, Choi, IJ, Matsuo, K, Ohnami, S, Totsuka, H, Chiku, S, Kuchiba, A, Lee, Y, Yoon, K, Kook, M, Park, SR, Kim, Y, Tanaka, H, Tajima, K, Hirose, H, Tanioka, F, Matsuno, Y, Sugimura, H, Kato, S, Nakamura, T, Nishina, T, Yasui, W, Aoyagi, K, Sasaki, H, Yanagihara, K, Katai, H, Shimoda, T, Yoshida, T, Nakamura, Y, Hirohashi, S & Sakamoto, H 2011, 'A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer', Gastroenterology, vol. 140, no. 3, pp. 892-902. https://doi.org/10.1053/j.gastro.2010.10.058

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title = "A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer",

abstract = "Background & Aims Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen (PSCA), but the loci of the other 2 were not investigated. Methods We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants. Results A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 (MUC1) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10-13; odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 (P = 1.43 × 10-11; OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38). Conclusions MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer.",

keywords = "Cancer Prevention, Genome-Wide Association Study, Risk Genotype, Stomach Cancer",

author = "Norihisa Saeki and Akira Saito and Choi, {Il Ju} and Keitaro Matsuo and Sumiko Ohnami and Hirohiko Totsuka and Suenori Chiku and Aya Kuchiba and Yeonsu Lee and Kyongah Yoon and Myeongcherl Kook and Park, {Sook Ryun} and Youngwoo Kim and Hideo Tanaka and Kazuo Tajima and Hiroshi Hirose and Fumihiko Tanioka and Yoshihiro Matsuno and Haruhiko Sugimura and Shunji Kato and Tsuneya Nakamura and Tomohiro Nishina and Wataru Yasui and Kazuhiko Aoyagi and Hiroki Sasaki and Kazuyoshi Yanagihara and Hitoshi Katai and Tadakazu Shimoda and Teruhiko Yoshida and Yusuke Nakamura and Setsuo Hirohashi and Hiromi Sakamoto",

note = "Funding Information: Funding Supported in Japan by the program for promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NiBio); in Aichi, supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, Culture and Technology of Japan and by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan ; and, in Korea, part of the study was supported by grant 0710340 from the National Cancer Center, Korea . ",

year = "2011",

month = mar,

doi = "10.1053/j.gastro.2010.10.058",

language = "English",

volume = "140",

pages = "892--902",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "3",

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TY - JOUR

T1 - A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer

AU - Saeki, Norihisa

AU - Saito, Akira

AU - Choi, Il Ju

AU - Matsuo, Keitaro

AU - Ohnami, Sumiko

AU - Totsuka, Hirohiko

AU - Chiku, Suenori

AU - Kuchiba, Aya

AU - Lee, Yeonsu

AU - Yoon, Kyongah

AU - Kook, Myeongcherl

AU - Park, Sook Ryun

AU - Kim, Youngwoo

AU - Tanaka, Hideo

AU - Tajima, Kazuo

AU - Hirose, Hiroshi

AU - Tanioka, Fumihiko

AU - Matsuno, Yoshihiro

AU - Sugimura, Haruhiko

AU - Kato, Shunji

AU - Nakamura, Tsuneya

AU - Nishina, Tomohiro

AU - Yasui, Wataru

AU - Aoyagi, Kazuhiko

AU - Sasaki, Hiroki

AU - Yanagihara, Kazuyoshi

AU - Katai, Hitoshi

AU - Shimoda, Tadakazu

AU - Yoshida, Teruhiko

AU - Nakamura, Yusuke

AU - Hirohashi, Setsuo

AU - Sakamoto, Hiromi

N1 - Funding Information: Funding Supported in Japan by the program for promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NiBio); in Aichi, supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, Culture and Technology of Japan and by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan ; and, in Korea, part of the study was supported by grant 0710340 from the National Cancer Center, Korea .

PY - 2011/3

Y1 - 2011/3

N2 - Background & Aims Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen (PSCA), but the loci of the other 2 were not investigated. Methods We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants. Results A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 (MUC1) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10-13; odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 (P = 1.43 × 10-11; OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38). Conclusions MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer.

AB - Background & Aims Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen (PSCA), but the loci of the other 2 were not investigated. Methods We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants. Results A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 (MUC1) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10-13; odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 (P = 1.43 × 10-11; OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38). Conclusions MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer.

KW - Cancer Prevention

KW - Genome-Wide Association Study

KW - Risk Genotype

KW - Stomach Cancer

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DO - 10.1053/j.gastro.2010.10.058

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JO - Gastroenterology

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