Activating mutations in members of the RAS oncogene family (KRAS, HRAS, and NRAS) have been found in a variety of human malignancies, suggesting a dominant role in carcinogenesis. In colon cancers, KRAS mutations are common and clearly contribute to malignant progression. The frequency of NRAS mutations and their relationship with clinical, pathologic, and molecular features remains uncertain. We developed and validated a Pyroseqencing assay to detect NRAS mutations at codons 12, 13, and 61. Using a collection of 225 colorectal cancers from 2 prospective cohort studies, we examined the relationship between NRAS mutations, clinical outcome, and other molecular features, including mutation of KRAS, BRAF, and PIK3CA, microsatellite instability, and the CpG island methylator phenotype. Finally, we examined whether NRAS mutation was associated with patient survival or prognosis. NRAS mutations were detected in 5 (2.2%) of the 225 colorectal cancers and tended to occur in left-sided cancers arising in women, but did not seem to be associated with any of the molecular features that were examined.
*Department of Medical Oncology, Dana-Farber Cancer Institute
‡Department of Pathology, Massachusetts General Hospital
§Channing Laboratory, Department of Medicine, Brigham and Women's Hospital
¶Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston
†EpigenDx, Worcester, MA
∥Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA
This work was supported by the US National Institute of Health (P01 CA87969 to S. Hankinson, P01 CA55075 to W. Willett, P50 CA127003 to C.S.F., K07 CA122826 to S.O., K01 CA118425 to K.M.H.); the Bennett Family Fund; the Entertainment Industry Foundation National Colorectal Cancer Research Alliance. Katsuhiko Nosho was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. Funding agencies did not have any role in the design of the study; the collection, analysis, or interpretation of the data; the decision to submit the manuscript for publication; or the writing of the manuscript.
Natsumi Irahara, Yoshifumi Baba, and Katsuhiko Nosho contributed equally. Charles S. Fuchs, Kevin M. Haigis, and Shuji Ogino are co-senior authors.
Reprints: Kevin M. Haigis, PhD, Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, 149 13th St., 6.010, Charlestown, MA 02129 (e-mail: email@example.com).