K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung.
BACKGROUND
The capability of activated oncogenes to induce malignant transformation of immortalized cells in vitro has suggested that they have a similar role in the pathogenesis of human tumors. We previously found that activation of the K-ras oncogene by a point mutation in codon 12 occurs in about one third of human lung adenocarcinomas.


METHODS
We studied the clinical importance of this oncogene-activation in 69 patients with lung adenocarcinoma in whom complete resection of the tumor was possible. The polymerase chain reaction was used to amplify ras-specific sequences of DNA isolated from frozen or paraffin-embedded tumor samples. Ras point mutations were subsequently detected and classified with the use of mutation-specific oligonucleotide probes.


RESULTS
Nineteen of the tumors harbored a point mutation in codon 12 of the K-ras oncogene. There was no association between the K-ras point mutation and the age at diagnosis, sex, or presence of previous or concurrent neoplasms. Tumors positive for K-ras point mutations tended to be smaller and less differentiated than those without mutations. The K-ras codon-12 point mutation was a strong (and unfavorable) prognostic factor: 12 of the 19 patients with K-ras point-mutation-positive tumors died during the follow-up period, as compared with 16 of the 50 patients with no mutation in the K-ras oncogene (P = 0.002). This difference in prognosis was also reflected in the duration of disease-free survival (P = 0.038) and in the number of deaths due to cancer (P less than 0.001).


CONCLUSIONS
The presence of K-ras point mutations defines a subgroup of patients with lung adenocarcinoma in whom the prognosis is very poor and disease-free survival is not usually long despite radical resection and a small tumor load.
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam.
R J
RJ
Slebos
R E
RE
Kibbelaar
O
O
Dalesio
A
A
Kooistra
J
J
Stam
C J
CJ
Meijer
S S
SS
Wagenaar
R G
RG
Vanderschueren
N
N
van Zandwijk
W J
WJ
Mooi
D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D015996:Survival Rate
D004273:DNA, Neoplasm