2000 年度実績報告書

ヒトがんの発生・進展における遺伝子異常の解明、ならびにがん診療への応用

研究課題

研究課題/領域番号	12213010
研究種目	特定領域研究(C)
研究機関	東北大学
研究代表者	堀井明東北大学, 大学院・医学系研究科, 教授 (40249983)
キーワード	膵がん / 遺伝子変異 / 下垂体腺腫 / Wnt / 神経芽細胞腫 / 1p / RIZ / MSI
研究概要	膵癌において高頻度に欠失の見られる領域のうち3か所(12q、17p、18q)の染色体欠失が予後不良と相関することを明らかにし、これらのうち膵の発癌過程で初期変化と考えられる18qにおける標的遺伝子と考えられるSMAD4遺伝子がホモに欠失している膵癌株に正常SMAD4遺伝子を導入しても増殖能は抑制されなかったことをふまえ、膵の前がん病変と位置づけられる粘液産成膵腫瘍(intraductal papillary-mucinous tumor、IPMT)を解析した。その結果、全くSMAD4の異常は見られず、18qにはSMAD4以外にもがん抑制遺伝子が局在する可能性が考えられた。種々の腫瘍におけるWntの経路の異常の関与について検討を加え、下垂体腺腫で非常に高頻度にbeta-cateninの異常が生じていることを検出した。神経芽細胞腫では14qの1100kbの高頻度欠失領域の特定、ならびに1p32の高頻度欠失と同領域の相互転座点の同定を行った。多くの腫瘍において異常が報告されている1p36-p35領域においてBACによるcontigを作成し、同領域の解析を進めた。同領域に局在するRIZ遺伝子を解析し、胃癌、大腸癌、子宮内膜癌などのMSI陽性の癌で高頻度に異常が見られるのみならず、これまでMSI陽性であって標的遺伝子の不明であった膵癌においても異常を同定し、これらの腫瘍における発がんの標的遺伝子である可能性が示唆された。

研究成果

(26件)

すべてその他

すべて文献書誌 (26件)

[文献書誌] Hoshi,M. et al.: "Detailed deletion mapping of chromosome band 14q32 in human neuroblastoma defines a 1.1-Mb region of common allelic loss."Br.J.Cancer. 82. 1801-1807 (2000)
[文献書誌] Ikeda,T. et al.: "Mutational analysis of the CTNNB1 (β-catenin) gene in human endometrial cancer : Frequent mutations at codon 34 that cause nuclear accumulation."Oncol.Rep.. 7. 323-326 (2000)
[文献書誌] Kadota,M. et al.: "Identification of a 7-cM region of frequent allelic loss on chromosome band 16p13.3 that is specifically associated with anaplastic thyroid carcinoma."Oncol.Rep.. 7. 529-533 (2000)
[文献書誌] Saito,A. et al.: "p24/ING1-ALT1 and p47/ING1-ALT2, distinct alternative transcripts of p33/ING1."J.Hum.Genet.. 45. 177-181 (2000)
[文献書誌] Ikeda,T. et al.: "Anticorresponding mutations of the KRAS and PTEN genes in human endometrial cancer."Oncol.Rep.. 7. 567-570 (2000)
[文献書誌] Yatsuoka,T. et al.: "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.. 95. 2080-2085 (2000)
[文献書誌] Semba,S. et al.: "Analysis of the candidate target genes for mutation in microsatellite instability-positive cancers of the colorectum, stomach, and endometrium."Int.J.Oncol.. 16. 731-737 (2000)
[文献書誌] Mayama,T, et al.: "Frequent loss of copy number on the long arm of chromosome 21 in human esophageal squamous cell carcinoma."Int.J.Oncol.. 17. 245-252 (2000)
[文献書誌] Ohira,M. et al.: "Identification and characterization of a 500-kb homozygously deleted-region at 1p36.2-p36.3 in a neuroblastoma cell line."Oncogene,, 2000s. 19. 4302-4307 (2000)
[文献書誌] Nakagawara,A. et al.: "Identification of the homozygously deleted region at chromosome 1p36.2 in human neuroblastoma."Med Pediatr Oncol.. 35. 516-521 (2000)
[文献書誌] Hoshi,M. et al.: "Deletion mapping of 14q32 in human neuroblastoma defines an 1100-kb region of common allelic loss."Med.Pediat.Oncol.. 35. 522-525 (2000)
[文献書誌] Kondo,E. et al.: "Not hMSH2 but hMLH1 is frequently silenced by hypermethylation in endometrial cancer but rarely silenced in pancreatic cancer with microsatellite instability."Int.J.Oncol.,. 17. 535-541 (2000)
[文献書誌] Piao,Z. et al.: "Frequent frameshift mutations of RIZ in sporadic gastrointestinal and endometrial carcinomas with microsatellite instability."Cancer Res.. 60. 4701-4704 (2000)
[文献書誌] Yuki,M. et al.: "Structure, expression and mutational analysis of the hBRAG gene on 10q in the frequently deleted retion in human endometrial cancer."Oncol.Rep.. 7. 1339-1342 (2000)
[文献書誌] Sakamoto,Y. et al.: "Molecular cloning and expression of cDNA encoding chicken UDP-GlcNAc : GlcNAcβ1-6 (GlcNAcβ1-2) Manα1-R [GlcNAc to Man]β1,4N-acetylglucosaminyltransferase VI."J.Biol.Chem.. 275. 36029-36034 (2000)
[文献書誌] Shinoura,N. et al.: "Degree of apoptosis induced by adenovirus -mediated transduction of p53 or p73 alpha depens on the p53 status of glioma cells."Cancer Lett.,. 160. 67-73 (2000)
[文献書誌] Semba,S. et al.: "Frequent nuclear accumulation of β-catenin (CTNNB1) in human pituitary adenoma."Cancer. 91. 42-48 (2001)
[文献書誌] Sun,C., et al.: "Characterization of the mutations of the K-ras, p53, p16, and SMAD4 genes in 15 human pancreatic cancer cell lines."Oncol.Rep.. 8. 89-92 (2001)
[文献書誌] Sakurada,K. et al.: "RIZ, the retinoblastoma protein interacting zinc finger gene, is mutated in genetically unstable cancers of the pancreas, stomach, and colorectum."Genes Chromosomes Cancer. 30. 207-211 (2001)
[文献書誌] Schutte,B.C. et al.: "Report of the sixth international workshop on human chromosome 1 mapping 2000."Cytogenet.Cell Genet.. (in press).
[文献書誌] Youssef,E.M. et al.: "Human BAC contig covering the deleted region in pancreatic cancer at 12q21."DNA Seq.. (in press).
[文献書誌] Makino,N. et al.: "Isolation and characterization of the human gene homologous to the Drosophila Headcase (hdc) gene in chromosome bands 6q23-q24, a region of common deletion in human pancreatic cancer."DNA Seq.. (in press).
[文献書誌] Inoue,H. et al.: "Exclusion of SMAD4 mutation as an early genetic change in human pancreatic ductal tumorigenesis."Genes Chromosomes Cancer. (in press).
[文献書誌] Chen,Y.Z. et al.: "A BAC-based STS-content map spanning a 35-megabase region of human chromosome 1p35-36."Genomics. (in press).
[文献書誌] Kaneko,K. et al.: "Analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene mutations in Japanese patients with chronic pancreatitis."J.Hum Genet.. (in press).
[文献書誌] Kondo,E. et al.: "The interacting domains of three MutL heterodimers in man : hMLH1 interacts with 36 homologous amino-acid residues within hMLH3,hPMS1, and hPMS2."Nucl.Acids Res.. (in press).

2000 年度 実績報告書

ヒトがんの発生・進展における遺伝子異常の解明、ならびにがん診療への応用

研究代表者

堀井 明 東北大学, 大学院・医学系研究科, 教授 (40249983)

研究成果

[文献書誌] Hoshi,M. et al.: "Detailed deletion mapping of chromosome band 14q32 in human neuroblastoma defines a 1.1-Mb region of common allelic loss."Br.J.Cancer. 82. 1801-1807 (2000)

[文献書誌] Ikeda,T. et al.: "Mutational analysis of the CTNNB1 (β-catenin) gene in human endometrial cancer : Frequent mutations at codon 34 that cause nuclear accumulation."Oncol.Rep.. 7. 323-326 (2000)

[文献書誌] Kadota,M. et al.: "Identification of a 7-cM region of frequent allelic loss on chromosome band 16p13.3 that is specifically associated with anaplastic thyroid carcinoma."Oncol.Rep.. 7. 529-533 (2000)

[文献書誌] Saito,A. et al.: "p24/ING1-ALT1 and p47/ING1-ALT2, distinct alternative transcripts of p33/ING1."J.Hum.Genet.. 45. 177-181 (2000)

[文献書誌] Ikeda,T. et al.: "Anticorresponding mutations of the KRAS and PTEN genes in human endometrial cancer."Oncol.Rep.. 7. 567-570 (2000)

[文献書誌] Yatsuoka,T. et al.: "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.. 95. 2080-2085 (2000)

[文献書誌] Semba,S. et al.: "Analysis of the candidate target genes for mutation in microsatellite instability-positive cancers of the colorectum, stomach, and endometrium."Int.J.Oncol.. 16. 731-737 (2000)

[文献書誌] Mayama,T, et al.: "Frequent loss of copy number on the long arm of chromosome 21 in human esophageal squamous cell carcinoma."Int.J.Oncol.. 17. 245-252 (2000)

[文献書誌] Ohira,M. et al.: "Identification and characterization of a 500-kb homozygously deleted-region at 1p36.2-p36.3 in a neuroblastoma cell line."Oncogene,, 2000s. 19. 4302-4307 (2000)

[文献書誌] Nakagawara,A. et al.: "Identification of the homozygously deleted region at chromosome 1p36.2 in human neuroblastoma."Med Pediatr Oncol.. 35. 516-521 (2000)

[文献書誌] Hoshi,M. et al.: "Deletion mapping of 14q32 in human neuroblastoma defines an 1100-kb region of common allelic loss."Med.Pediat.Oncol.. 35. 522-525 (2000)

[文献書誌] Kondo,E. et al.: "Not hMSH2 but hMLH1 is frequently silenced by hypermethylation in endometrial cancer but rarely silenced in pancreatic cancer with microsatellite instability."Int.J.Oncol.,. 17. 535-541 (2000)

[文献書誌] Piao,Z. et al.: "Frequent frameshift mutations of RIZ in sporadic gastrointestinal and endometrial carcinomas with microsatellite instability."Cancer Res.. 60. 4701-4704 (2000)

[文献書誌] Yuki,M. et al.: "Structure, expression and mutational analysis of the hBRAG gene on 10q in the frequently deleted retion in human endometrial cancer."Oncol.Rep.. 7. 1339-1342 (2000)

[文献書誌] Sakamoto,Y. et al.: "Molecular cloning and expression of cDNA encoding chicken UDP-GlcNAc : GlcNAcβ1-6 (GlcNAcβ1-2) Manα1-R [GlcNAc to Man]β1,4N-acetylglucosaminyltransferase VI."J.Biol.Chem.. 275. 36029-36034 (2000)

[文献書誌] Shinoura,N. et al.: "Degree of apoptosis induced by adenovirus -mediated transduction of p53 or p73 alpha depens on the p53 status of glioma cells."Cancer Lett.,. 160. 67-73 (2000)

[文献書誌] Semba,S. et al.: "Frequent nuclear accumulation of β-catenin (CTNNB1) in human pituitary adenoma."Cancer. 91. 42-48 (2001)

[文献書誌] Sun,C., et al.: "Characterization of the mutations of the K-ras, p53, p16, and SMAD4 genes in 15 human pancreatic cancer cell lines."Oncol.Rep.. 8. 89-92 (2001)

[文献書誌] Sakurada,K. et al.: "RIZ, the retinoblastoma protein interacting zinc finger gene, is mutated in genetically unstable cancers of the pancreas, stomach, and colorectum."Genes Chromosomes Cancer. 30. 207-211 (2001)

[文献書誌] Schutte,B.C. et al.: "Report of the sixth international workshop on human chromosome 1 mapping 2000."Cytogenet.Cell Genet.. (in press).

[文献書誌] Youssef,E.M. et al.: "Human BAC contig covering the deleted region in pancreatic cancer at 12q21."DNA Seq.. (in press).

[文献書誌] Makino,N. et al.: "Isolation and characterization of the human gene homologous to the Drosophila Headcase (hdc) gene in chromosome bands 6q23-q24, a region of common deletion in human pancreatic cancer."DNA Seq.. (in press).

[文献書誌] Inoue,H. et al.: "Exclusion of SMAD4 mutation as an early genetic change in human pancreatic ductal tumorigenesis."Genes Chromosomes Cancer. (in press).

[文献書誌] Chen,Y.Z. et al.: "A BAC-based STS-content map spanning a 35-megabase region of human chromosome 1p35-36."Genomics. (in press).

[文献書誌] Kaneko,K. et al.: "Analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene mutations in Japanese patients with chronic pancreatitis."J.Hum Genet.. (in press).

[文献書誌] Kondo,E. et al.: "The interacting domains of three MutL heterodimers in man : hMLH1 interacts with 36 homologous amino-acid residues within hMLH3,hPMS1, and hPMS2."Nucl.Acids Res.. (in press).

2000 年度実績報告書

堀井明東北大学, 大学院・医学系研究科, 教授 (40249983)