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Clinical Cancer Research Vol. 5, 1139-1146, May 1999
© 1999 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Prognostic Significance of Allelic Imbalances on Chromosome 9p in Stage I Non-Small Cell Lung Carcinoma1

Yoshio Tomizawa, Jun-ichi Adachi, Takashi Kohno, Kunihiro Hamada, Ryusei Saito, Masayuki Noguchi, Yoshihiro Matsuno, Setsuo Hirohashi, Naohito Yamaguchi and Jun Yokota2

Biology Division [Y. T., J. A., T. K., K. H., J. Y.], Pathology Division [M. N., Y. M., S. H.], and Cancer Information and Epidemiology Division [N. Y.], National Cancer Center Research Institute, Tokyo 104-0045, Japan, and First Department of Internal Medicine, Gunma University, School of Medicine, Gunma 371-8511, Japan [Y. T., R. S.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Loss of heterozygosity (LOH) on chromosomes 2q, 9p, 18q, and 22q frequently occurs in advanced non-small cell lung carcinoma (NSCLC). The association of p53 mutations with prognosis is still unclear in NSCLC. Therefore, we investigated the prognostic significance of allelic imbalances (AI) on these chromosomes and p53 mutations in 108 cases of stage I NSCLC by PCR amplification of polymorphic dinucleotide repeat-containing sequences and PCR-single strand conformation polymorphism analysis. AI on 2q, 9p, 18q, and 22q was detected in 22, 38, 29, and 15% of cases, respectively, whereas p53 was mutated in 41% of stage I NSCLC. AI on 9p and 22q and p53 mutations were significantly associated with shortened survival of the patients (P = 0.010, 0.024, and 0.022, respectively). Although gender and smoking history showed more significant associations with prognosis than other clinicopathological and molecular parameters, independent prognostic significance for AI on 9p was observed (P = 0.002) in male patients with a positive smoking history. These results indicate that clinical aggressiveness of early-stage NSCLC can be partly defined by the presence of AI on chromosome 9p in cancer cells, and that AI on 9p could be a clinically useful prognostic indicator for early-stage NSCLC patients.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Lung carcinoma is a major cause of cancer-related deaths in the world. At the time of diagnosis, ~30% of NSCLC3 patients have local diseases, whereas others have diseases spread to lymph nodes and/or with distant metastases. Prognosis of the patients is largely dependent on the stage of the disease. However, even in patients with stage I NSCLC, the 5-year survival rate is 65–75%, and this rate has not changed significantly over the past 20 years (1 , 2) . Because there are only a few prognostic parameters that can estimate survival and supplement the stage designation, it is important to identify a novel marker for high-risk, early-stage patients who would benefit from more aggressive treatment approaches.

Recent advances in the molecular genetics of human cancer have revealed that multiple tumor suppressor genes are involved in human lung carcinogenesis (3) . Previously, we demonstrated that LOH on chromosomes 3p, 13q, and 17p occur in nearly 100% of cases with SCLC (4) . The target genes for inactivation by LOH on 13q and 17p have been identified as being the RB and p53 genes, respectively (5, 6, 7, 8) . As in the case of SCLC, p53 mutations occur frequently in NSCLC (8 , 9) . Although the frequency of alterations in the RB gene in NSCLC is lower than that in SCLC (10) , inactivation of the p16INK4A gene on chromosome 9p21 has been detected frequently in NSCLC without RB alterations (11 , 12) .

We reported previously (13 , 14) that the incidence of LOH on chromosomes 2q, 9p, 18q, and 22q in advanced-stage NSCLC was significantly higher than that in early-stage NSCLC. These results indicated that tumor suppressor genes on chromosomes 2q, 9p, 18q, and 22q play an important role in the acquisition of more malignant phenotypes in NSCLC. However, the clinical implications and prognostic impact of 2q, 9p, 18q, and 22q LOH have not been established. There have been a number of reports investigating the association of p53 abnormalities with prognosis of NSCLC patients; however, the relationship between p53 abnormalities and patients’ prognoses are still controversial.

In this study, as a part of systematic search for molecular prognostic markers in stage I NSCLC, 108 cases of stage I NSCLCs were examined for AI on these four chromosomes and p53 mutations. The presence of AI on 9p in tumors was significantly associated with shortened survival and, thus, may define a subset of NSCLC patients who could be suitable candidates for therapeutic approaches.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Tissues.
One hundred and eight pairs of primary lung tumors and corresponding normal lung tissues were obtained from 108 patients with NSCLCs who underwent curative operation and were not treated with chemotherapy and irradiation therapy at the National Cancer Center Hospital, Tokyo, from March 1985 to December 1994. All cases were classified as being stage I according to the Tumor-Node-Metastasis Classification of Malignant Tumors (15) . These tumors were histologically classified as 68 adenocarcinomas, 28 squamous cell carcinomas, 7 large cell carcinomas, and 5 adenosquamous carcinomas, according to the Histological Typing of Lung Tumors by the WHO (15) . Thirty-three of 108 (31%) patients had died of lung cancer up to December 31, 1997. The median follow-up period in all patients was 53.1 months (range, 5–151 months). Tumors and normal tissues were frozen and stored at -80°C until DNA extraction. Genomic DNA was extracted by proteinase K digestion and phenol/chloroform extraction as described previously (4) .

Microsatellite Loci.
DNA was analyzed by PCR amplification of polymorphic dinucleotide repeat-containing sequences. The following microsatellite loci were examined for AI: DH82 and D2S116 at 2q33, D9S157 and D9S162 at 9p22-p23, IFNA at 9p22, D9S171 and D9S126 at 9p21, D18S454 at 18q12.3-q21.1, D18S851 at 18q21.1-q21.2, D18S858 at 18q21.2, and D22S280 and D22S685 at 22q12.2-q13. Detailed information on polymorphic markers used in this study can be obtained from the Genomic Database (GDB Human Genome Database) except for that of the DH82 locus at 2q33. Sequences for a set of primers to amplify polymorphic dinucleotide repeat-containing sequences at the DH82 locus determined in our laboratory are as follows: 5'-CTGTGGTCATCCCTGAAGT-TA-3' and 5'-GACCTAGACTGTCTATTCAAGT-3' (16) . PCRwas carried out in a 20-µl reaction mixture containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, 125 ng of each primer, 250 µM of each deoxynucleotide triphosphate, 0.25 µl of [{alpha}-32P]dCTP (3000 Ci/mmol, 10 Ci/ml), and 0.1 unit of Taq DNA polymerase (Pharmacia). Thirty-five cycles of 94°C (60 s) for denaturation, 55°C (60 s) for annealing, and 72°C (90 s) for extension were performed to amplify DNA fragments. PCR products were diluted by denaturing buffer, containing 95% formamide, 10 mM EDTA, and dye, 5 times, and denatured at 90°C for 3 min. Two µl of the denatured sample were electrophoresed on a 5% denaturing polyacrylamide gel at 1500 V of constant voltage for 2–4 h, depending on sizes of PCR products, at room temperature. Gels were dried and exposed to X-ray film at -80°C. The exposures of the autoradiograms were within the linear response range of the X-ray film.

PCR-SSCP Analysis.
Eight portions of genomic DNA fragments covering the coding region of the p53 gene, between exon 4 and exon 10, were amplified by PCR with p53-specific oligonucleotide primers as described previously (7) . PCR was carried out by 35 cycles of amplification at 94°C (40 s) for denaturation, 55°C (40 s) for annealing, and 72°C (90 s) for extension, followed by 10 min extension at 72°C with [{alpha}-32P]dCTP (3000 Ci/mmol, 10 Ci/ml). PCR products were diluted by denaturing buffer, containing 95% formamide, 10 mM EDTA, and dye, 10 times, and denatured at 90°C for 3 min. Two µl of the denatured samples were electrophoresed on a 6% neutral polyacrylamide gel with or without 5% glycerol. Electrophoresis was carried out at 40 W of constant power for 2–10 h with cooling by fans. The gels were dried and exposed to X-ray film at -80°C.

Definition of AI.
The signal intensity of polymorphic alleles was quantified and calculated by the scanning densitometer and data analysis system (The Discovery Series, Quantity One, pdi, New York) to ascertain the ratios of allele intensities in tumor DNA as compared with the corresponding normal tissue DNA. Normal samples showed small differences in the percentage of allele ratio because of artificial signal variation (SD, 3.4%; n = 50). Thus, signal ratio in the range of 0.87–1.0 could occur even without AI in a tumor, because mean -2SD per mean +2SD was 0.87. Therefore, a sample was scored as having AI if a signal ratio was <0.8.

Statistical Analysis.
The patients were followed up until December 31, 1997. Survival curves were estimated by the Kaplan-Meier method, and the resulting curves were compared using the log-rank test. P < 0.05 was considered to be statistically significant. The joint effect of covariables was examined using the stepwise Cox proportional hazards regression model. The stepwise procedure was used to select significant independent variables. The Fisher’s exact test was used to examine the association of two categorical variables. Statistical analysis was performed using the SAS statistical package (SAS Institute, Cary, NC).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Association of AI and p53 Mutations with Clinicopathological Findings.
One hundred and eight stage I NSCLCs were examined for AI on chromosomes 2q, 9p, 18q, and 22q with 12 microsatellite markers. The proportions of patients informative for chromosomes 2q, 9p, 18q, and 22q were 77, 94, 94, and 87%, respectively, and the frequencies of AI on these chromosomes were 18 of 83 (22%), 38 of 101 (38%), 30 of 102 (29%), and 14 of 94 (15%), respectively (Table 1)Citation . Partial or interstitial AI of these chromosome arms was not observed in these cases. These tumors were also examined for mutations in exons 4–10 of the p53 gene by PCR-SSCP analysis. p53 mutations were detected in 44 of 108 cases (41%; Table 2Citation ). Representative results showing AI on 9p and p53 mutations are shown Fig. 1Citation .


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  		Table 1 Incidence of AI in stage I NSCLC

 

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  		Table 2 Correlation of clinicopathological data with presence of AI and p53 mutations

 


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  		Fig. 1. Representative results of AI on chromosome arm 9p (D9S126) detected by PCR (A) and mobility shifts of DNA fragments for exons 7–8 of the p53 gene detected by PCR-SSCP analysis (B). Arrowheads, AI and shifted DNA fragments. N, normal tissue; T, tumor.

 
We analyzed the relationships of these imbalances and mutations with several clinicopathological factors and other characteristics (Table 2)Citation . There were no significant correlations of AI on 2q, 9p, 18q, and 22q and p53 mutations with gender, age, smoking history, histological subtypes, grade of differentiation, or tumor size.

Association of AI and p53 Mutations with Survival.
Univariate survival analysis of clinicopathological factors showed that gender, age, smoking history, histology, and tumor size were significantly associated with survival. Although not statistically significant, differentiation was also found to be associated with survival (Fig. 2A–ECitation ; Table 3Citation ). In particular, gender and smoking history showed strong associations with survival (P < 0.001). The results in the present study were almost similar to those in previous studies (17, 18, 19, 20, 21) , although the impact of gender and smoking history on survival in this study were stronger than that in previous studies.



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  		Fig. 2. Kaplan-Meier survival curves for patients with stage I NSCLC classified according to gender (A), age (B), smoking history (C), differentiation (D), tumor size (E), AI on 2q (F), 9p (G), 18q (H), and 22q (I) and p53 (J) mutations.

 

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  		Table 3 Overall survival of patients with stage I NSCLC in relation to molecular and clinicopathological characteristics

 
Next, the association of AI on 2q, 9p, 18q, and 22q and p53 mutations with patients’ survival was analyzed (Fig. 2, F–JCitation ; Table 3Citation ). Kaplan-Meier survival estimates showed that the patients with AI on 2q, 9p, 18q, and 22q and p53 mutations tended to have a poorer prognosis than patients without AI on these chromosomes and p53 mutations. The differences between patients with AI on 9p and 22q and p53 mutations and those without AI on 9p and 22q and p53 mutations, respectively, were statistically significant (P = 0.010, 0.024, and 0.022, respectively). However, the differences between patients with AI on 2q and 18q and those without AI on 2q and 18q did not reach statistical significance.

We attempted to place all molecular and clinicopathological variables in a Cox proportional hazards regression model to define independent risk factors. However, it was not possible to control for gender and smoking by multivariate analysis, because only one death was observed among female patients and none among nonsmoking patients. Therefore, multivariate analysis was limited to male patients with a positive smoking history (n = 71). The prognoses of these 71 cases were significantly poorer than the remaining 37 cases (P < 0.001; Fig. 3ACitation ). In male patients with a positive smoking history, a statistically significant association was observed between the presence of AI on 2q and 9p and shortened survival (P = 0.027 and 0.007, respectively; Fig. 3BCitation ; Table 3Citation ). AI on other chromosomes, p53 mutations, and clinicopathological factors were not significantly associated with prognosis. Furthermore, in multivariate analysis in male patients with a positive smoking history, a variable showing the independent predictive value for survival was AI on 9p (P = 0.002), and the risk ratio of AI on 9p was 7.41. No other variable was an independent factor for survival.



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  		Fig. 3. Kaplan-Meier survival curves for patients with stage I NSCLC classified according to male and smoker versus others (A) and AI on 9p in male and smoker (B).

 
It is likely that intratumoral heterogeneity and/or noncancerous cell contamination in the specimens made it difficult to detect AI. Therefore, 38 tumors without AI at any loci and p53 mutations were excluded from the statistical analysis. In this subgroup, patients with AI on 9p showed significantly poorer prognosis (P = 0.048).


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
It was demonstrated here that gender and smoking history are strongly associated with survival of stage I NSCLC patients. Furthermore, AI on 9p correlates with the prognosis of male patients with a positive smoking history, independently of other clinicopathological factors, AI on other chromosomes, and p53 mutations. This result indicates that AI on 9p could be a useful genetic marker for prognosis of surgically resected stage I NSCLC patients.

The correlation between 9p LOH and prognosis was reported in several types of human cancers. Neuroblastoma (22) and renal cell carcinoma (23) showed correlation of 9p LOH with poor prognosis, whereas breast cancer (24) and head and neck cancer (25) had no correlation with prognosis. In lung cancer, Kishimoto et al. (26) reported that 9p LOH did not correlate with poor prognosis. However, because the disease stage was not considered in that study, it is possible that the negative result might have been caused by confounding of other clinical and molecular factors. To avoid such bias, our study was performed exclusively in stage I NSCLC. It was revealed here that the presence of AI on 9p could be an unfavorable prognostic factor in stage I NSCLC. Recent studies indicated that 9p LOH occurs at the early stage in the pathogenesis of NSCLC (27 , 28) . Thus, early-stage lung cancers with 9p LOH could be more malignant than early-stage lung cancers without 9p LOH. The term AI indicates either loss or gain of a chromosomal region. However, a gain in signal intensity of chromosome 9p was indicated to occur at a very low frequency in NSCLC by comparative genomic hybridization analysis (29) . Thus, it is likely that loss rather than gain is the main event in AI on 9p.

Two candidate tumor suppressor genes, the p15 and p16 genes, have been identified and mapped to chromosome 9p21 (30) . Thus, the p15 and/or p16 genes could be target tumor suppressor genes associated with progression of NSCLC. In fact, mutations and deletions of the p15 and p16 genes have been detected frequently in advanced NSCLC (31) , and aberrant expression of p16 were associated with a worse survival in NSCLC (32) . However, immunohistochemical studies as well as methylation studies indicated that silencing of p16 expression occurs early in the progression of NSCLC, and there were no associations between loss of p16 expression and the clinical stage (33 , 34) . Furthermore, recent studies on deletion mapping of chromosome 9p indicated that several loci proximal and distal to the p15 and p16 genes were homozygously and hemizygously deleted in lung cancer (35, 36, 37, 38, 39) . In this study, 108 cases of NSCLC were examined for AI at five loci on chromosome 9p, which have been mapped in the order of 9pter-D9S157-D9S162-IFNA-D9S171-D9S126-cen (GDB Human Genome Database). The p15 and p16 genes are located between the IFNA and D9S171 loci, whereas the regions distal to the D9S157 locus, around the D9S157 locus, around the D9S171 locus, and around the D9S126 locus were reported as being distinct tumor suppressor loci (35, 36, 37, 38, 39) . Because partial imbalances were not observed in the present study, we could not define the region on chromosome 9p that is critical for acquisition of more malignant phenotypes of NSCLC. Additional studies should focus on the identification of target tumor suppressor genes inactivated by AI on chromosome 9p.

Recently, the International System for Staging Lung Cancer was revised to provide greater specificity for identifying patient groups with similar prognosis (17) . In the revised version, T1N0M0 (T <= 3 cm) and T2N0M0 (T > 3 cm) were further subgrouped to stages IA and IB, respectively, because tumor size significantly correlated with prognosis. In our study, a variable showing the independent predictive value for survival was AI on 9p in stage I NSCLC, and AI on 9p was independent of tumor size in multivariate analysis between AI on 9p and tumor size (data not shown). This result demonstrated that AI on 9p could be a prognostic indicator in stage I NSCLC patients independently from tumor size.

p53 mutations have been found frequently in all major histological types of lung cancer, and there have been a number of reports investigating the associations of p53 abnormalities with prognosis of patients with NSCLC. However, the relationships between p53 abnormalities and patients’ prognosis are still controversial. p53 mutations were significantly correlated with prognosis of stage I NSCLC patients in this study. However, p53 protein expression was not significantly associated with a poorer prognosis of these patients (40) . Therefore, differences in the method to detect p53 abnormalities as well as the differences in disease stage and distribution of histological subtypes might be a cause for the discrepancy of findings among previous studies.

Being male and a positive smoking history showed a strong association with shortened survival. Gender and smoking history were closely correlated with each other (P < 0.001, Fisher’s exact test). Similar results were reported previously (18, 19, 20) . The mechanism by which gender and smoking affect the prognosis of lung cancer patients is not clear at present. However, because it was reported recently that genetic alterations accumulated in the bronchial epithelium of smokers (41) , it is possible that lung cancers in smokers progress more quickly than those in nonsmokers. Because no association was detected between smoking history and genetic alterations in this study, additional studies are necessary to clarify this issue.

In conclusion, this result suggested the hypothesis that AI on chromosome 9p could be a useful marker for prognosis in patients with stage I NSCLC. However, because of the relatively small number of patients studied, further investigations will be required to demonstrate its possible use as a diagnostic and prognostic marker in the management of early-stage NSCLC.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported in part by a Grant-in-Aid from the Ministry of Health and Welfare for the second-term Comprehensive 10-Year Strategy for Cancer Control, and Grants-in-Aid from the Ministry of Health and Welfare and from the Naito Foundation. Back

2 To whom requests for reprints should be addressed, at Biology Division, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. Phone: 81-3-3542-2511, extension 4650; Fax: 81-3-3542-0807. Back

3 The abbreviations used are: NSCLC, non-small cell lung cancer; LOH, loss of heterozygosity; AI, allelic imbalance; SSCP, single-strand conformation polymorphism; SCLC, small cell lung cancer. Back

Received 2/20/98; revised 12/28/98; accepted 2/25/99.


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Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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