Genetic alterations involved in initiation and progression of human pancreatic cancer

• Project/Area Number: 09470049
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human pathology
• Research Institution: Tohoku University
• Principal Investigator: HORII Akira Tohoku University, Graduate school of Medicine, Professor, 大学院・医学系研究科, 教授 (40249983)
• Project Period (FY): 1997 – 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥12,500,000 (Direct Cost: ¥12,500,000); Fiscal Year 1999: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 1998: ¥4,300,000 (Direct Cost: ¥4,300,000); Fiscal Year 1997: ¥4,900,000 (Direct Cost: ¥4,900,000)
• Keywords: tumor suppressor gene / pancreatic cancer / 6q / 12q / 17p / 18q / the DUSP6 gene / the TDG gene / SMAD4遺伝子 / FISH / DNAミスマッチ修復異常招 / 染色体6番長腕 / 染色体12番長腕 / 染色体20番長腕 / IGFIIレセプター / BAX

Research Abstract

1.We previously identified frequently deleted region in human pancreatic cancer in chromosome arms 1p, 6q, 9p, 12q, 17p, and 18q. Among these regions, losses of 12q, 17p, and 18q were found to associated with poor prognosis in human pancreatic cancer. 17p and 18q are the loci for TP53 and SMAD4, respectively.
2.On 6q and 12q, three and two smallest regions of overlap (SROs), respectively, were identified. BAC contigs for one region on 6q and two regions on 12q were constructed, and some genes in these regions were analyzed.
3.DUSP6 on 12q21 and TDG on 12q24 were analyzed. Although no genomic alterations were found, loss or suppressed expression in pancreatic cancer cell lines were observed, suggesting the involvement of suppressed expression of these genes in human pancreatic carcinogenesis.
4.Adenoviral mediated delivery of the SMAD4 gene in pancreatic cancer cell lines with homozygous deletion of SMAD4 did not show any suppression of cell growth. We think that inactivation of the SMAD4 gene is not associated with acceleration of cell growth but associated with some other mechanisms in pancreatic carcinogenesis.
5.We reported that loss of 18q is an early event in pancreatic carcinogenesis. There is a possibility that mutation of the SMAD4 gene is responsible for the initial step of pancreatic carcinogenesis as well as prognosis defining factor. However, there is a possibility of unknown tumor suppressor gene on 18q that is distinct from SMAD4.

Research Products

• [Journal Article] p24/ING1-ALT1 and p47/ING1-ALT2,distinet alternative transcripts of p33/ING1 (2000)
  • Author(s): Saito, A.
  • Journal Title: J.Hum.Genet. 45 Pages: 177-181
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] p24/ING1-ALT1 and p47/ING1-ALT2, distinct alternative transcripts of p33/ING1. (2000)
  • Author(s): Saito, A., Furukawa, T., Fukushige, S., Koyama, S., Hoshi, M., Hayashi, Y., Horii, A.
  • Journal Title: J.Hum.Genet. 45 Pages: 177-181
  • NAID: 10011570238
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Infrequent somatic mutations of the p73 gene in various human cancers. (1999)
  • Author(s): Han, S.
  • Journal Title: Eur.J.Surg.Oncol. 25 Pages: 194-198
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genomic analysis of the thymine-DNA glycosylase(TDG) gene on 12q22-q24.1 in human pancreatic ductal adenocarcinoma (1999)
  • Author(s): Yatsuoka, T.
  • Journal Title: Int.J.Panc. 25 Pages: 97-102
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of three commonly deleted regions on chromosome arm 6q in human pancreatic cancer. (1999)
  • Author(s): Abe, T.
  • Journal Title: Genes Chromosomes Cancer 25 Pages: 60-64
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cloning and characterization of the human UDP-N-acetylglucosamine : α-1,3-D-mannoside β-1,4-N-acetylglucosaminyltransferase IV-homologue(hGnT-IV-H) gene (1999)
  • Author(s): Funukawa, T.
  • Journal Title: J.Hum.Genet. 44 Pages: 397-401
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Infrequent somatic mutations of the p73 gene in various human cancers. (1999)
  • Author(s): Han, S., Semba, S., Abe, T., Makino, N., Furukawa, T., Fukushige, S., Takahashi, H., Sakurada, A., Sato, M., Shiiba, K., Matsuno, S., Nimura, Y., Nakagawara, A., Horii, A.
  • Journal Title: Eur.J.Surg.Oncol. 25 Pages: 194-198
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genomic analysis of the thymine-DNA glycosylase (TDG) gene on 12q22-q24.1 in human pancreatic ductal adenocarcinoma. (1999)
  • Author(s): Yatsuoka, T., Furukawa, T., Abe, T., Yokoyama, T., Sunamura, M., Kobari, M., Matsuno, S., Horii, A.
  • Journal Title: Int.J.Panc. 25 Pages: 97-102
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of three commonly deleted regions on chromosome arm 6q in human pancreatic cancer. (1999)
  • Author(s): Abe, T., Makino, N., Furukawa, T., Ouyang, H., Kimura, M., Yatsuoka T., Yokoyama, T., Inoue, H., Fukushige, S., Hoshi, M., Hayashi, Y., Sunamura, M., Kobari, M., Matsuno, S., Horii, A.
  • Journal Title: Genes Chromosomes Cancer 25 Pages: 60-64
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cloning and characterization of the human UDP-N-acetylglucosamine:a-1,3-D-mannosideb-1,4-N-acetylglucosaminyltransferase IV-homologue (hGnT-IV-H) gene. (1999)
  • Author(s): Furukawa, T., Youssef, E.M., Yatsuoka, T., Yokoyama, T., Makino, N., Inoue, H., Fukushige, S., Hoshi, M., Hayashi, Y., Sunamura, M., Horii, A.
  • Journal Title: J.Hum.Genet. 44 Pages: 397-401
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Loss of chromosome 18q is an early event in pancreatic ductal tumorigenesis. (1998)
  • Author(s): Fukushige, S.
  • Journal Title: Cancer Research 58 Pages: 4222-4226
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genomic analysis of DUSP6,a dual specificity MAP kinase phosphatase, in pancreatic cancer. (1998)
  • Author(s): Furukawa, T.
  • Journal Title: Cytogenetics and Cell Genetics 82 Pages: 156-159
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium. (1998)
  • Author(s): Ouyang, H.
  • Journal Title: Clinical Cancer Research 4 Pages: 1071-1074
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of two common regions of allelic loss in chromosome arm 12q in human pancreatic cancer. (1998)
  • Author(s): Kimura, M.
  • Journal Title: Cancer Research 58 Pages: 2456-2460
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium. (1998)
  • Author(s): Ouyang, H., Furukawa, T., Abe, T., Kato, Y., Horii, A.
  • Journal Title: Clin Cancer Res. 4 Pages: 1071-1074
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of two common regions of allelic loss in chromosome arm 12q in human pancreatic cancer. (1998)
  • Author(s): Kimura, M., Furukawa, T., Abe, T., Yatsuoka, T., Youssef, E.M., Yokoyama, T., Ouyang, H., Ohnishi, Y., Sunamura, M., Kobari, M., Matsuno, S., Horii, A.
  • Journal Title: Cancer Res. 58 Pages: 2456-2460
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Loss of chromosome 18q is an early event in pancreatic ductal tumorigenesis. (1998)
  • Author(s): Fukushige, S., Furukawa, T., Satoh, K., Sunamura, M., Kobari, M., Koizumi, M., Horii, A.
  • Journal Title: Cancer Res. 58 Pages: 4222-4226
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer. (1998)
  • Author(s): Furukawa, T., Yatsuoka, T., Youssef, E.M., Abe, T., Yokoyama, T., Fukushige, S., Soeda, E., Hoshi, M., Hayashi, Y., Sunamura, M., Kobari, M., Horii, A.
  • Journal Title: Cytogenet.Cell Genet. 82 Pages: 156-159
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Frequent gain of copy number on the long arm of chromosome 20 in human pancreatic adenocarcinoma. (1997)
  • Author(s): FukuShige, S.
  • Journal Title: Genes, Chromosomes and Cancer 19 Pages: 161-169
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The insulin-like growth factor II receptor gene is mutated in genetically unstable cancers of the endometrium, stomach and colorectum. (1997)
  • Author(s): Ouyang, H.
  • Journal Title: Cancer Research 57 Pages: 1851-1854
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Infrequent genetic alterations of the PTEN/MMAC1 gene in Japanese patients with primary cancers of the breast, lung, pancreas, kidney, and ovary. (1997)
  • Author(s): Sakurada, A.
  • Journal Title: Japanese Journal of Cancer Research 88 Pages: 1025-1028
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] PTEN1 is frequently mutated in primary endometrial carcinomas. (1997)
  • Author(s): Kong, D.
  • Journal Title: Nature Genet. 17 Pages: 143-144
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Frequent gain of copy number on the long arm of chromosome 20 in human pancreatic adenocarcinoma. (1997)
  • Author(s): Fukushige, S., Waldman, F.M., Kimura, M., Abe, T., Furukawa, T., Sunamura, M., Kobari, M., Horii, A.
  • Journal Title: Genes Chromosomes Cancer 19 Pages: 161-169
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The insulin-like growth factor II receptor gene is mutated in genetically unstable cancers of the endometrium, stomach and colorectum. (1997)
  • Author(s): Ouyang, H., Shiwaku, H.O., Hagiwara, H., Miura, K., Abe, T., Kato, Y., Ohtani, H., Shiiba, K., Souza, R.F., Meltzer, S.J., Horii, A.
  • Journal Title: Cancer Res. 57 Pages: 1851-1854
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Infrequent genetic alterations of the PTEN/MMAC1 gene in Japanese patients with primary cancers of the breast, lung, pancreas, kidney, and ovary. (1997)
  • Author(s): Sakurada, A., Suzuki, A., Sato, M., Yamakawa, H., Orikasa, K., Uyeno, S., Ono, T., Ohuchi, N., Fujimura, S., Horii, A.
  • Journal Title: Jpn.J.Cancer Res. 88 Pages: 1025-1028
  • NAID: 10008081442
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] PTEN1 is frequently mutated in primary endometrial carcinomas. (1997)
  • Author(s): Kong, D., Suzuki, A., Zou, T.-T., Sakurada, A., Kemp, L.W., Wakatsuki, S., Yokoyama, T., Yamakawa, H., Furukawa, T., Sato, M., Ohuchi, N., Sato, S., Yin, J., Wang, S., Abraham, J.M., Souza, R.F., Smolinski, K.N., Meltzer, S.J., Horii, A.
  • Journal Title: Nature Genet. 17 Pages: 143-144
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of poor prognosis with loss of 12q,17p, and 18q, and concordant loss of 6q/17p and 12q/18q in human pancreatic duetal adenocarcinoma
  • Author(s): Yatsuoka, T.
  • Journal Title: Am.J.Gastroent. (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Association of poor prognosis with loss of 12q, 17p, and 18q, and concordant loss of 6q/17p and 12q/18q in human pancreatic ductal adenocarcinoma.
  • Author(s): Yatsuoka, T., Sunamura, M., Furukawa, T., Fukushige, S., Yokoyama, T., Inoue, H., Shibuya, K., Takeda, K., Matsuno, S., Horii, A.
  • Journal Title: Am.J.Gastroent. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yatsuoka T.: "Association of poor prognosis with loss of 12q, 17p, and 18q, and concordant loss of 6q/17p and 12q/18q in human pancreatic ductal adenocarcinoma"Am. J. Gastroent.. (in press).
• [Publications] Saito A.: "p24/ING1 and p47/ING1-ALT2, distinct alternative transcripts of p33/ING1"J. Hum. Genet.. (in press).
• [Publications] Furukawa T.: "Cloning and characterization of the human UDP-N-acetylglucosamine: α-1,3-D-mannoside β-1,4-N-acetylglucosaminyltransferase IV-homologue (hGnT-IV-H) gene"J. Hum. Genet.. 44. 397-401 (1999)
• [Publications] Yatsuoka T.: "Genomic analysis of the thymine-DNA glycosylase (TDG) gene on 12q22-q24.1 in human pancreatic ductal adenocarcinoma"Int. J. Panc.. 25. 97-102 (1999)
• [Publications] Han S.: "Infrequent somatic mutations of the p73 gene in various human cancers"Eur. J. Surg. Oncol.. 25. 194-198 (1999)
• [Publications] Abe T.: "Identification of three commonly deleted regions on chromosome arm 6q in human pancreatic cancer"Genes Chromosomes Cancer. 25. 60-64 (1999)
• [Publications] Abe,T.: "Identification of three commonly deleted regions on chromosome arm 6q in human pancreatic cancer." Genes,Chromosomes & Cancer. (in press).
• [Publications] Yatsuoka,T.: "Genomic analysis of the thymine-DNA glycosylase(TDG)gene on 12q22-q24.1 in human pancreatic ductal adenocarcinoma." International Journal of Pancreatology. (in press).
• [Publications] Han,S.: "Infrequent somatic mutations of the p73 gene in various human cancers." European Journal of Surgical Oncology. (in press).
• [Publications] Fukushige,S.: "Loss of chromosome 18q is an early event in pancreatic duc-tal tumorigenesis." Cancer Research. 58. 4222-4226 (1998)
• [Publications] Ouyang,H.: "The BAX gene,the promoter of apoptosis,is mutated in genetically unstable cancers of the colorectum,stomach,and endometrium." Clinical Cancer Research. 4. 1071-1074 (1998)
• [Publications] Kimura,M.: "Identification of two common regions of allelic loss in chromosome arm 12q in human pancreatic cancer." Cancer Research. 58. 2456-2460 (1998)
• [Publications] Furukawa,T.: "Genomic analysis of DUSP6,a dual specificity MAP kinase phosphatase,in pancreatic cancer." Cytogenetics and Cell Genetics. 82. 156-159 (1998)
• [Publications] Kimura, M.: "Identification of two common regions of allelic loss in chromosome arm 12q in human pancreatic cancer." Cancer Research. (in press).
• [Publications] Ouyang, H.: "The BAX gene,the promoter of apoptosis,is mutated in genetically unstable cancers of the colorectum,stomach,and endometrium." Clinical Cancer Research. (in press).
• [Publications] Kong, D.: "PTEN1 is frequently mutated in primary endometrial carcinomas." Nature Genetics. 17. 143-144 (1997)
• [Publications] Sakurada, A.: "Infrequent genetic alterations of the PTEN/MMAC1 gene in Japanese patients with primary cancers of the breast,lung,pancreas,kidney,and ovary." Japanese Journal of Cancer Research. 88. 1025-1028 (1997)
• [Publications] Ouyang, H.: "The insulin-like growth factor II receptor gene is mutated in genetically unstable cancers of the endometrium,stomach and colorectum." Cancer Research. 57. 1851-1854 (1997)
• [Publications] Fukushige, S.: "Frequent Gain of copy number on the long arm of chromosome 20 in human pancreatic adenocarcinoma." Genes,Chromosomes & Cancer. 19. 161-169 (1997)