Prognostic value of specific KRAS mutations in lung adenocarcinomas

• Published in: Cancer epidemiology, biomarkers & prevention Vol. 6; no. 10; pp. 841 - 847
• Main Authors: Siegfried, J M, Gillespie, A T, Mera, R, Casey, T J, Keohavong, P, Testa, J R, Hunt, J D
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-10-1997
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - mortality; Codon; DNA Mutational Analysis; DNA, Neoplasm - analysis; Electrophoresis, Polyacrylamide Gel; Female; Genes, ras - genetics; Humans; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Male; Mutation; Polymerase Chain Reaction; Prognosis; Retrospective Studies; Survival Analysis
• ISSN: 1055-9965; 1538-7755

Adenocarcinomas of the lung remain a significant public health problem. Locally defined (stage I) tumors are considered amenable
to resection with curative intent. However, only about 45% of these patients survive for 5 years. The median survival for
more advanced tumors is drastically lower. Much research has been focused on identifying a valid genetic biomarker of prognosis.
Mutations of the proto-oncogene KRAS have been identified by some groups as being a valid prognostic indicator for adenocarcinoma
of the lung. To evaluate the effect of KRAS gene mutation on the survival of patients with lung adenocarcinoma, 181 archival
tumors were examined by PCR and denaturing gradient gel electrophoresis. Mutations in either codon 12 or 13 were found in
31.5% of the samples. The most common mutation was a G-->T transversion in codon 12, representing 66.7% of the mutations.
No difference was observed in the survival of patients with a KRAS mutation versus those whose tumors contained wild-type
KRAS. This lack of difference was also observed when the analysis was restricted to those with stage I tumors or when patients
with stage I or II disease were grouped together. However, certain amino acid substitutions, including cysteine, arginine,
and aspartate, indicated a significantly poorer prognosis, whereas hydrophobic amino acid substitutions showed a significantly
better prognosis than wild-type (P = 0.04). Sample sizes were small for this analysis due to the number of possible mutations.
As expected, the stage of tumor at resection was the most significant predictor of outcome. Based on this study of 181 patients
from two major medical centers located in different cities, we conclude that KRAS mutation status is not a satisfactory predictor
of prognosis in lung adenocarcinoma, but the substitution of a polar or charged amino acid for the wild-type glycine residue
may be a negative prognostic indicator.