|
Mutations of the K-ras oncogene result in constitutive activation of this signal transduction pathway and consequently, unregulated proliferation and impaired differentiation.
Activating K-ras mutations are present in greater than 50% of colorectal adenomas and carcinomas, and the vast majority occur at codon 12 of the oncogene. K-ras abnormalities are one of the earliest events in the stepwise progression of colorectal neoplasms, being detectable even in histologically unremarkable epithelium and aberrant crypt foci adjacent to cancers. The clinical significance of K-ras mutations is somewhat controversial, although some studies have shown lower median survival times in patients with mutation-positive tumors. Amongst other gastrointestinal malignancies, K-ras mutations are one of the most common genetic abnormalities in pancreatic and bile duct carcinomas, detectable in greater than 75% of tumors. K-ras mutations are also frequent in adenocarcinomas of the lung, but are uncommon in other histologic subtypes. In limited stage adenocarcinomas, the presence of K-ras mutation is independently associated with more aggressive disease and decreased patient survival. Amongst the gynecological malignancies, endometrial carcinomas harbor K-ras mutations in up to a third of cases; in postmenopausal women with endometrial carcinomas, K-ras mutations appear to be an independent risk factor for adverse prognosis. Some studies have suggested that the presence of K-ras mutations in endometrial hyperplasia specimens may identify a group of patients with a high probability for progression.
An immunohistochemical assay for detecting the levels of mutant K-ras protein p21ras in archival tissue specimens has become available only recently, and studies with this antibody are still in their infancy. Like p53, the accumulation of intratumoral cytoplasmic p21ras correlates in most instances with an underlying K-ras gene mutation. Hopefully, retrospective and prospective studies with the p21ras antibody will validate the utility of this assay for prognostication purposes, besides bypassing the future need for performing expensive genetic analyses to establish K-ras mutation status.
For more information
contact Dr Raheela Ashfaq
at Veripath OncoDiagnostics
at 214.645.7053 or Raheela.Ashfaq@UTSouthwestern.edu
Selected references:
1. Bell SM et al. Prognostic value of p53 overexpression and K-ras gene mutations in colorectal cancer. Gastroenterology 104:57; 1993
2. Ito K et al. K-ras point mutations in endometrial carcinoma: effect on outcome is dependent on age of patient. Gynecol Oncol 63:238; 1996
3. Nelson HH et al. Implications and prognostic value of K-ras mutation for early-stage lung cancer in women. J Natl Cancer Inst 91:2032; 1999
4. Pajkos G et al. The prognostic value of the presence of mutations at the codons 12,13 and 61 of K-ras oncogene in colorectal cancer. Anticancer Res 20:1695; 2000
|
