Concurrent mutations of coding and regulatory sequences of the Ha-ras gene in urinary bladder carcinomas

Hum Pathol. 1992 Nov;23(11):1199-204. doi: 10.1016/0046-8177(92)90285-b.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Codon
  • DNA Mutational Analysis
  • DNA, Neoplasm / analysis*
  • Exons
  • Female
  • Gene Expression
  • Genes, ras / genetics*
  • Humans
  • Introns
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Neoplasm Invasiveness
  • Ploidies
  • Proto-Oncogene Proteins p21(ras) / analysis*
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology


  • Codon
  • DNA, Neoplasm
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)