title: Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival.
abstract: Sequence alterations of mitotic checkpoint genes, hBUB1 and hBUBR1, were examined, and their gene transcripts were quantified using on-line, real-time quantitative reverse transcription-PCR in surgically resected human colorectal cancers and their neighboring normal tissues. Our results reveal a new hBUB1 missense mutation (Ala130Ser) but not any hBUBR1 coding sequence mutations. hBUB1 and hBUBR1 mRNA levels were reduced to < 10% of the neighboring normal tissues in 3 of 103 and 3 of 109 carcinomas, respectively, and to < 50% in 7 and 7 carcinomas, whereas the overall expression levels were markedly higher in cancers than in normal tissues. Carcinomas with reduced hBUB1 and/or hBUBR1 mRNA levels, as well as the colon carcinoma harboring the hBUB1 mutation, were associated with lymph node metastasis (P < 0.005) and shorter relapse-free survival after surgery (P = 0.006). Thus, hBUB1 and hBUBR1 may contribute to a specific driving force in tumor metastasis and progression as a result of nonmutational, as well as mutational, inactivation.
authors.affiliation: Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Bunkyo-ku, Tokyo 113-8519, Japan. mschichiri.cme@tmd.ac.jp
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Shichiri
authors.forename: Keigo
authors.initials: K
authors.lastname: Yoshinaga
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hisatomi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sugihara
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hirata
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D003106:Colon / Q000378:metabolism / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000502:physiology; D007680:Kidney Neoplasms / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008938:Mitosis / Q000235:genetics*; D020125:Mutation, Missense; D009367:Neoplasm Staging; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins; D012333:RNA, Messenger; D011494:Protein Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases