Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival.
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.
Shichiri
Masayoshi
M
Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Bunkyo-ku, Tokyo 113-8519, Japan. mschichiri.cme@tmd.ac.jp
Yoshinaga
Keigo
K
Hisatomi
Hisashi
H
Sugihara
Kenichi
K
Hirata
Yukio
Y
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
D018797:Cell Cycle Proteins; D012333:RNA, Messenger; D011494:Protein Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases