Original Article
K-ras Oncogene Activation as a Prognostic Marker in Adenocarcinoma of the Lung
N Engl J Med 1990; 323:561-565August 30, 1990
- Abstract
- Abstract
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<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. (N Engl J Med 1990; 323:561–5.)
Media in This Article
Figure 1
Determination of Point Mutations in Codon 12 of the K-ras Oncogene in Adenocarcinomas of the Lung.Figure 2
Survival of 69 Patients after Radical Surgery for Adenocarcinoma of the Lung.Article Activity
- Article
THE concept of oncogenes has revolutionized our understanding of cancer, but there have been disappointingly few situations in which the detection of activated oncogenes has proved to be of clinical value. The difficulty in relating activation of oncogenes to the specific clinical or biologic features of a tumor may arise in part from technical problems in demonstrating the activation of oncogenes in small tumor samples. Recent technical advances have resolved these problems in the case of the ras genes.
Oncogenes of the ras family have been found to be activated frequently in human tumors.1 , 2 The three well-characterized members of this family — H-ras, K-ras, and N-ras — code for closely related 21-kd proteins that have a putative role in the transduction of growth signals.1 These proteins acquire transforming potential when an amino acid at position 12, 13, or 61 is replaced as a result of a point mutation in the encoding gene. These activating point mutations can be detected by a highly specific assay employing oligonucleotide hybridization.3 When this assay is used in combination with the polymerase chain reaction,4 very small DNA samples (e.g., DNA isolated from formalin-fixed paraffin-embedded tissue sections) suffice to allow screening for the presence of one of these point mutations.5 , 6
We previously reported that a point mutation in codon 12 of the K-ras oncogene in human lung cancer is specifically associated with a subtype of adenocarcinoma,7 and that such a mutation occurs in about one third of these tumors.8 We report here on 69 patients with adenocarcinoma whose tumors could be completely removed by radical surgery. Analysis of the survival data shows that the patients whose tumors had K-ras codon-12 point mutations had an unfavorable prognosis as compared with the patients who had no such mutation.
Methods
Patient Selection and Tumor Specimens
We studied 23 women and 46 men with adenocarcinoma of the lung. Their ages ranged from 42 to 80 years. Forty-eight patients had stage I tumors (T1–2, N0, M0), 14 had stage II tumors (T1–2, N1, M0), and 7 had stage IIIa tumors (T3, N0, M0 or T1–2, N2, M0).9 Five patients had been found to have tumors of another origin before their lung adenocarcinoma was diagnosed (two patients with chronic myelocytic leukemia, two with squamous-cell head-and-neck cancer, and one with a morphologically and genetically distinct breast cancer10). None of the 69 patients had any signs of distant metastases at the time of initial evaluation of their lung tumor. Patients were included in the study only if their tumors could be resected completely and pathological examination showed no evidence of tumor in the resection margins of the operative specimen.
DNA was isolated from the frozen tumor samples from 35 patients as reported previously7 , 8 and from the formalin-fixed paraffin-embedded material from 34 patients as described below. The former samples had been frozen for up to 62 months, and the latter had been embedded in paraffin for up to 71 months before analysis. All tumors were classified as adenocarcinomas by a single investigator according to the World Health Organization classification of lung tumors.11 The clinical data (see below) for the 69 patients were reviewed after the tumor DNA had been tested for point mutations in K-ras codon 12.
Tissue Preparation and Detection of Ras Oncogene Point Mutations
From each paraffin-embedded tumor sample, 5-μm sections were cut and collected in Eppendorf vials. An additional 5-μm section was stained with hematoxylin and eosin and was used to classify the tumor and to determine the proportion of tumor cells in the specimen. The tumor sections were deparaffinized with xylene and then ethanol and dried in a vacuum desiccator. After sterile water was added, the DNA in the sample was heat denatured and used for amplification in vitro.5 In addition, DNA isolated from 10 25-μm tumor sections according to standard procedures for DNA extraction was also analyzed.6 The polymerase-chain-reaction cycles were performed at 92°C to denature the DNA, at 55°C to anneal the primers, and at 70°C to synthesize DNA, for 1.5 minutes at each temperature, in a Dri-block device (Techne, Cambridge, United Kingdom), with the use of Taq polymerase (Perkin–Elmer–Cetus, Emeryville, Calif.) in buffer as recommended by the manufacturer. Approximately 100-ng portions of DNA isolated from the 25-μm sections were amplified for 30 to 35 cycles, and the DNA in the single 5-μm sections was amplified for an additional 30 cycles. From each reaction, approximately 10 ng of amplified DNA fragments was spotted onto nylon membranes (Hybond, Amersham, United Kingdom) for hybridization analysis.
Point mutations were detected by hybridization with 32P-labeled oligonucleotides specific for the different ras sequences. The oligonucleotide sequences, hybridization conditions, and composition of the 31 probes used have been described previously.3 The DNA extracted from frozen tumor samples was screened for activating point mutations in codons 12, 13, and 61 of all three ras genes, whereas the paraffin-embedded samples were screened only for mutations in codon 12 of K-ras. All samples contained at least 20 percent tumor cells.
Analysis of Clinical Data
For each patient the following characteristics were noted from the medical records after the presence or absence of a K-ras gene mutation had been ascertained in the tumor samples: age, sex, history of smoking, the presence of previous or simultaneous tumors, the pathological assessment of resection margins, the stage and degree of differentiation of the tumor, location of relapse when relevant, duration of disease-free survival, duration of survival, and cause of death.
Statistical Analysis
Survival curves were constructed with the Kaplan–Meier method. Comparisons were made with the log-rank test and the Cox proportional-hazards model. All P values are based on two-tailed statistical analysis; a P value of less than 0.05 was considered to indicate statistical significance.
Results
Detection of Point Mutations in K-ras Oncogenes
Two strategies were followed to determine the point mutations in K-ras: amplification of purified DNA from either frozen or paraffin-embedded tissue and direct amplification of the DNA present in a single 5-μm tissue section. Thirty-five frozen samples were analyzed, and 34 other samples were obtained from formalin-fixed, paraffin-embedded tissues. Of the 34 fixed samples, 29 were examined both by isolation of DNA and by direct amplification of the tissue sections; the results were identical. Nineteen of the 69 tumors were positive for a point mutation in codon 12 of the K-ras oncogene. The normal DNA sequence GGT at codon 12 was altered to TGT in 13 tumors, to GTT in 2, and to GAT in 3; the sequence GCT was found in 1 tumor.
The results of hybridization of DNA that was extracted from 18 paraffin-embedded tumor specimens and amplified are shown in Figure 1Figure 1
Determination of Point Mutations in Codon 12 of the K-ras Oncogene in Adenocarcinomas of the Lung.. All amplified DNA samples hybridized to the normal K-ras allele (probe K12-gly), and several hybridized to one of the mutation-specific oligonucleotides, each oligonucleotide representing one of the possible point mutations in codon 12 of K-ras. No association was found between the K-ras point mutation and the patient's age or sex or the occurrence of previous or simultaneous tumors in any of the 69 patients studied.In our previous study we found a difference in the size of the tumor at the time of diagnosis between the patients who were negative for K-ras point mutations and those who were positive.8 In the present study, the K-ras point-mutation—positive tumors also tended to be smaller than the mutation-negative tumors. When the patients with stage I disease were compared with those with higher stages, the difference with respect to all 69 patients was significant (P = 0.039 by Fisher's exact test) (Table 1Table 1
Characteristics of 69 Patients with Stage I, II, or IIIa Adenocarcinoma of the Lung Who underwent Potentially Curative Resection, According to Status for the K-ras Mutation.). The tumors with K-ras point mutations tended to be less differentiated as well (P = 0.04 by chi-square test for trend). No differences in the location of distant metastases or the site of relapse were observed between the two groups.To determine whether the prognosis of patients whose tumors had an activated K-ras oncogene differed from the prognosis of those whose tumors did not, we analyzed a number of potential prognostic factors in univariate and multivariate models after a median follow-up period of 36 months (range, 11 to 63). In this relatively small group of patients, no significant differences in prognosis were found to be related to sex, smoking history, status of lymph nodes, tumor size, tumor differentiation, or tumor stage.
The presence of a K-ras point mutation in tumor DNA defined a group of patients who had a poor prognosis despite radical resection: 12 of the 19 patients with the mutation relapsed or died within the follow-up period, whereas only 22 of the 50 patients without the mutation relapsed or died within this period (Fig. 2Figure 2
Survival of 69 Patients after Radical Surgery for Adenocarcinoma of the Lung.). The difference in prognosis was reflected in all three end points considered: disease-free survival (P = 0.038), overall survival (P = 0.002) (Fig. 2), and death due to cancer (P<0.001). The difference was consistent after adjustment for the other factors evaluated, such as the disease stage or tumor size and differentiation. Statistical analysis with adjustment for the potential influence of age, tumor size and differentiation, and disease stage showed that a K-ras point mutation was the single most important prognostic factor in patients with the mutation. When analysis was limited to patients with stage I disease or to the patients with stage I or stage II, the presence of K-ras activation retained its prognostic value.Discussion
Activating point mutations in ras genes have been demonstrated in a wide range of human tumors. For unknown reasons, point mutations of the K-ras gene are found predominantly in adenocarcinomas (reviewed by Bos2). For example, about 90 percent of pancreatic cancers contain a K-ras point mutation,5 , 14 as do about 50 percent of colon cancers15 , 16 and 50 percent of thyroid cancers.17 Interestingly, K-ras point mutations are very infrequent or even nonexistent in cancers of the breast or ovary.18 , 19
We have found K-ras point mutations in about one third of adenocarcinomas of the lung.7 , 8 The association between K-ras point mutations and the differentiation of adenocarcinomas has also been found in some model systems; for example, immortalized human bronchial cells harboring viral K-ras formed poorly differentiated lung adenocarcinomas in athymic nude mice.20 Furthermore, lung adenocarcinomas developed with high frequency in transgenic mice carrying an activated H-ras gene.21 The finding that virtually all ras point mutations in lung cancer in humans are found in K-ras but not in H-ras or N-ras may reflect the relatively high expression of K-ras in lung tissue.22
It is of interest that the pattern of K-ras codon-12 point mutations differs among adenocarcinomas of different origin. Whereas guanine—thymidine transversions in the first or second position account for about 80 percent of all point mutations found in the lung cancers in this study, guanine—adenine transitions are much more frequent in colon cancers.5 , 23 In addition, occasional codon-13 point mutations of the K-ras and N-ras oncogenes have been found in colon cancers but not lung cancers. It is tempting to speculate that these differences are related to differences in carcinogen exposure between patients with lung cancer and those with colon cancer — a speculation supported by the results of experimental studies in which different carcinogens induced different point mutations in animal tumors.24
In the retrospective analysis of our series of 69 patients, point mutations in the K-ras gene were associated with shorter survival. The K-ras point mutation was by far the most important single prognostic factor. The patients whose tumors had a mutation had a much poorer prognosis than those whose tumors did not, even though the distribution of the patients in the K-ras point-mutation—positive group according to disease stage was prognostically more favorable than that of the patients in the K-ras point-mutation—negative group (Table 1). The worse outcome in the patients with K-ras point-mutation—positive tumors may thus be considered as an additional indication of the more malignant behavior of these tumors.
The K-ras point mutation may not only be of value as a prognostic marker. Recent reports suggest that tumor cells acquiring ras oncogene point mutations in vitro may become resistant to radiation and to several drugs, including cisplatin.25 , 26 Whether tumors that have those mutations are resistant to radiation or chemotherapy in vivo is not known. We believe that clinical studies are now indicated to compare the response of patients with K-ras point-mutation—positive lung adenocarcinomas with the response of patients with mutation-negative tumors.
Supported by a grant (NKI 87–15) from the Dutch Cancer Society.
We are indebted to Ms. S.G. Evers for excellent technical assistance and to Drs. P.W.C. van Barneveld, J.H.A.M. van den Bergh, J. Berkovits, A. van Bochove, F.J.M. van Breukelen, T.K.G. Deves, N.M. Josephus Jitta, P.R.M. Hekking, J. Prins, T.B.M.C. Sie, P.I. van Spiegel, R.A.L.M. Stallaert, E.T.T. Thjo, and J.P.M. Wagenaar for providing clinical data.
Source Information
From the Divisions of Experimental Therapy (R.J.C.S., S.R.), Pathology (R.E.K., W.J.M.), and Clinical Oncology (O.D., N.v.Z.), the Netherlands Cancer Institute, Amsterdam; the Departments of Pathology (C.J.L.M.M.) and Pulmonary Medicine (A.K., J.S.), Free University of Amsterdam, Amsterdam; the Departments of Pathology (S.S.W.) and Pulmonary Medicine (R.G.J.R.A.V.), St. Antonius Hospital, Nieuwegein; and the Department of Medical Biochemistry, State University of Leiden, Leiden (J.L.B.); all in the Netherlands. Address reprint requests to Dr. Rodenhuis at the Division of Experimental Therapy, H6, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
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