Genotypic classification of colorectal adenocarcinoma. Biologic behavior correlates with K-ras-2 mutation type

Cancer. 1993 Jun 15;71(12):3827-38. doi: 10.1002/1097-0142(19930615)71:12<3827::aid-cncr2820711207>;2-n.


Background: New measures enabling better prediction of biologic behavior of large bowel cancer are highly desirable. One hundred ninety-four consecutive primary, recurrent, and metastatic colorectal adenocarcinomas, accessioned during 1991 at Rhode Island Hospital, were classified according to the presence and specific type of K-ras-2 point mutation.

Methods: An integrated histopathologic-genetic approach was used to detect mutations starting with minute, topographically selected, tissue samples from formaldehyde-fixed, paraffin-embedded specimens.

Results: Each colorectal adenocarcinoma exhibited either no or only one of seven specific types of K-ras-2 mutation. The mutation type of each primary tumor was present consistently in its metastatic deposits. Thirty-five percent of primary colorectal adenocarcinomas were found to be mutated (42 of 119). A significantly higher mutation rate (65%) was seen in lymphogenous-hematogenous metastases as a group (35 of 54; P < 0.005). By contrast, 22% of anastomotic recurrences and transcoelomic metastasis were mutated (4 of 18). Twenty-eight percent of adenocarcinomas with invasion limited to muscularis propria (Tis, T1, T2) were mutated (16 of 57), compared to 41% for more deeply invasive tumors (T3, T4; 26 of 63). When colorectal adenocarcinomas were analyzed by specific K-ras-2 mutation type, it was found that codon 13 mutated tumors did not progress to local or distant metastasis (P < 0.01). Tumors having a codon 12 valine substitution did not metastasize beyond pericolonic-perirectal lymph nodes. In contrast, colorectal cancers with codon 12 aspartic acid substitutions accounted for most of the distant hematogenous deposits (P < 0.01). Tumors with normal K-ras-2 accounted for most intraperitoneal deposits.

Conclusions: Genotyping of colorectal adenocarcinoma by K-ras-2 status can identify subsets of patients likely to pursue indolent and aggressive forms of disease. The integrated histopathologic-genetic approach outlined is feasible for use in diagnostic pathology, providing information that together with clinicopathologic staging may individualize and optimize treatment.

MeSH terms

  • Adenine
  • Adenocarcinoma / classification
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Adenocarcinoma / secondary
  • Aspartic Acid / genetics
  • Biology
  • Codon / genetics
  • Colonic Neoplasms / classification
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / pathology
  • Gene Frequency
  • Genes, ras / genetics*
  • Genotype
  • Guanine
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / secondary
  • Lymphatic Metastasis / genetics
  • Lymphatic Metastasis / pathology
  • Mutation / genetics*
  • Neoplasm Invasiveness
  • Neoplasm Recurrence, Local / classification
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Rectal Neoplasms / classification
  • Rectal Neoplasms / genetics*
  • Rectal Neoplasms / pathology


  • Codon
  • Aspartic Acid
  • Guanine
  • Adenine