title: Concurrent mutations of coding and regulatory sequences of the Ha-ras gene in urinary bladder carcinomas.
abstract: This report concerns the study of Ha-ras gene mutations and ras p21 expression in primary tumors of the urinary bladder. Polymerase chain reaction-based techniques and computerized image analysis were used. The data obtained were related to tumor grade, DNA ploidy, and tumor invasion. A point mutation (G-->T) at Ha-ras codon 12 was found in 30 of 67 tumors. The mutation frequency was greater in grade III (65%) than in grade II (44%) tumors; no mutations were observed in grade I tumors. The mutation was observed more often in aneuploid (58%) than in diploid (28%) tumors. No other substitution at codon 12 was seen and no codon 61 mutation was detected. The tumors were also tested for the A-->G mutation at position 2719 of Ha-ras intron D. Concurrent codon 12 and intron D mutations were identified in seven high-grade aneuploid tumors; six were invasive. The levels of the ras gene product p21 were approximately 10 times higher in tumors with intron D mutation than in those without. These findings confirm on human bladder tumors the observations of the effect of synchronous exon-intron mutations reported on the bladder cancer cell line T24. Our results are the first demonstration of Ha-ras intron D alterations in human tumor tissues and suggest that concurrent mutations at codon 12 and intron D of this gene within the same tumor may contribute to the aggressive behavior of human bladder carcinomas.
authors.affiliation: Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467.
authors.forename: B
authors.initials: B
authors.lastname: Czerniak
authors.forename: G L
authors.initials: GL
authors.lastname: Cohen
authors.forename: P
authors.initials: P
authors.lastname: Etkind
authors.forename: D
authors.initials: D
authors.lastname: Deitch
authors.forename: H
authors.initials: H
authors.lastname: Simmons
authors.forename: F
authors.initials: F
authors.lastname: Herz
authors.forename: L G
authors.initials: LG
authors.lastname: Koss
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D003062:Codon; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis*; D005091:Exons; D005260:Female; D015870:Gene Expression; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009361:Neoplasm Invasiveness; D011003:Ploidies; D016283:Proto-Oncogene Proteins p21(ras) / Q000032:analysis*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D003062:Codon; D004273:DNA, Neoplasm; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)