Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

Christophe Rosty, Joanne P Young, Michael D. Walsh, Mark Clendenning, Rhiannon J. Walters, Sally Ann Pearson, Erika Pavluk, Belinda Nagler, David Pakenas, Jeremy R. Jass, Mark A. Jenkins, Aung Ko Win, Melissa C. Southey, Susan Parry, John L. Hopper, Graham G. Giles, Elizabeth Williamson, Dallas R. English, Daniel D Buchanan

Research output: Contribution to journalArticleResearchpeer-review

101 Citations (Scopus)

Abstract

KRAS-mutated carcinomas comprise 35-40% of all colorectal carcinomas but little is known about their characteristics. The aim of this study was to examine the pathological and molecular features of KRAS-mutated colorectal carcinomas and to compare them with other carcinoma subgroups. KRAS mutation testing was performed in 776 incident tumors from the Melbourne Collaborative Cohort Study. O 6 -methylguanine DNA methyltransferase (MGMT) status was assessed using both immunohistochemistry and MethyLight techniques. Microsatellite instability (MSI) phenotype and BRAF V600E mutation status were derived from earlier studies. Mutation in KRAS codon 12 or codon 13 was present in 28% of colorectal carcinomas. Compared with KRAS wild-type carcinomas, KRAS-mutated carcinomas were more frequently observed in contiguity with a residual polyp (38 vs 21%; P<0.001), demonstrated mucinous differentiation (46 vs 31%; P=0.001) and were associated with different MSI status (P<0.001) and with MGMT methylation (47 vs 21%; P=0.001). Compared with tumors demonstrating neither BRAF nor KRAS mutation, KRAS-mutated carcinomas showed more frequent location in the proximal colon (41 vs 27%; P=0.001), mucinous differentiation (46 vs 25%; P<0.001), presence of a contiguous polyp (38 vs 22%; P<0.001), MGMT methylation (47 vs 26%; P=0.01) and loss of MGMT immunohistochemical expression (27 vs 19%; P=0.02). KRAS-mutated carcinomas were distributed in a bimodal pattern along the proximal-distal axis of the colorectum. Compared with male subjects, female subjects were more likely to have KRAS-mutated carcinoma in the transverse colon and descending colon (39 vs 15%; P=0.02). No difference in overall survival was observed in patients according to their tumor KRAS mutation status. In summary, KRAS-mutated carcinomas frequently develop in contiguity with a residual polyp and show molecular features distinct from other colorectal carcinomas, in particular from tumors with neither BRAF nor KRAS mutation.

Original languageEnglish
Pages (from-to)825-834
Number of pages10
JournalModern Pathology
Volume26
Issue number6
DOIs
Publication statusPublished - Jun 2013
Externally publishedYes

Keywords

  • BRAF mutation
  • colorectal cancer
  • colorectal polyp
  • KRAS mutation
  • MGMT
  • molecular pathology
  • survival analysis

Cite this

Rosty, C., Young, J. P., Walsh, M. D., Clendenning, M., Walters, R. J., Pearson, S. A., Pavluk, E., Nagler, B., Pakenas, D., Jass, J. R., Jenkins, M. A., Win, A. K., Southey, M. C., Parry, S., Hopper, J. L., Giles, G. G., Williamson, E., English, D. R., & Buchanan, D. D. (2013). Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features. Modern Pathology, 26(6), 825-834. https://doi.org/10.1038/modpathol.2012.240