Genotypic classification of colorectal adenocarcinoma. Biologic behavior correlates with K-ras-2 mutation type.
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.
Department of Pathology, Rhode Island Hospital, Brown University, Providence.
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Finkelstein
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Sayegh
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Christensen
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Swalsky
D000225:Adenine; D000230:Adenocarcinoma / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D001224:Aspartic Acid / Q000235:genetics; D001695:Biology; D003062:Codon / Q000235:genetics; D003110:Colonic Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D005787:Gene Frequency; D011905:Genes, ras / Q000235:genetics*; D005838:Genotype; D006147:Guanine; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000145:classification / Q000235:genetics / Q000473:pathology; D012004:Rectal Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology
D003062:Codon; D001224:Aspartic Acid; D006147:Guanine; D000225:Adenine