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Clinical Cancer Research Vol. 5, 17-23, January 1999
© 1999 American Association for Cancer Research

Advances in Brief

Deletions of Chromosome 4 at Multiple Sites Are Frequent in Malignant Mesothelioma and Small Cell Lung Carcinoma1

Narayan Shivapurkar, Arvind K. Virmani, Ignacio I. Wistuba, Sara Milchgrub, Bruce Mackay, John D. Minna and Adi F. Gazdar2

Hamon Center for Therapeutic Oncology Research [N. S., A. K. V., I. I. W., J. D. M., A. F. G.] and Departments of Pathology [A. K. V., S. M., A. F. G.], Internal Medicine [J. D. M.], and Pharmacology [J. D. M.], University of Texas Southwestern Medical Center, Dallas, Texas 75235, and Department of Pathology, M. D. Anderson Cancer Center, Houston, Texas 77030 [B. M.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Recent allelotyping studies suggest that allelic losses at one or both arms of chromosome 4 are frequent in several tumor types. Cytogenetic studies of malignant mesothelioma (MM) and comparative genomic hybridization analyses of small cell lung carcinoma (SCLC) suggest that chromosome 4 deletions may also play a role in these tumor types, although these results have not been confirmed by allelotyping. In an effort to more precisely identify and map the locations of putative tumor suppressor gene(s) on chromosome 4 involved in the pathogenesis of these tumors, we performed loss of heterozygosity studies using 16 polymorphic microsatellite markers. After precise microdissection of archival surgical cases, we studied DNA obtained from 20 MMs, 21 SCLCs, and 20 non-SCLCs (NSCLCs). In addition, DNA from 14 SCLC and 17 NSCLC cell lines and corresponding B lymphoblastoid lines were studied. In MM and SCLC, we observed frequent losses at three nonoverlapping regions: (a) 4q33–34 (region R1; >80%); (b) 4q25–26 (region R2; >60%); and (c) 4p15.1–15.3 (region R3; >50%). Losses at these sites occurred at lower frequencies in NSCLC (>20–30%). Data from tumors and cell lines were similar. In MM and SCLC, the most frequently observed pattern was loss at all three regions. However, in NSCLC, the most frequent pattern was loss at R3 alone. Our study has delineated three nonoverlapping regions of frequent deletions on chromosome 4 in MM and SCLC, suggesting that there may be three putative suppressor genes on chromosome 4, the inactivation of which may be important in the pathogenesis of these tumor types.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
MM3 is a rare neoplasm that is usually associated with asbestos exposure and is known as an aggressive tumor that is essentially unresponsive to standard medical and surgical therapies (1) . The use of asbestos in many products earlier in this century and a latency period of 30–45 years for MM may be responsible for the recent rise in the incidence of MM in the United States (2 , 3) . Unlike lung cancers, smoking is not an important factor in the pathogenesis of MM (2) .

The delineation of genetic alterations that occur in MMs may be important for both the development of molecular markers for early detection and the prediction of response to chemotherapy. It is now well recognized that tumorigenesis is a multistep process resulting from the accumulation of sequential genetic alterations (4) . In addition to oncogene activation, the inactivation of tumor suppressor genes has been shown to play an important role in tumorigenesis (4) . Knudson’s two-hit model established the paradigm for recessive tumor suppressor genes, whereas both alleles of the affected gene must be inactivated to contribute to the tumor phenotype (5) . Allelic deletion manifested as LOH at polymorphic loci is recognized as a hallmark of tumor suppressor genes inactivated by point mutations or some other mechanism. Using this strategy, previous studies have provided evidence for the presence of putative suppressor genes on chromosomes 1p, 3p, 6q, 9p, and 22q in the development of MMs (6, 7, 8, 9) . The diagnostic distinction between malignant pleural epithelial mesothelioma and metastatic adenocarcinoma is often difficult, and there is a considerable interest in identifying markers that might be of use in the differential diagnosis (10 , 11) .

Evidence for tumor suppressor genes on chromosome 4 has been provided by several studies. Recent allelotyping studies have documented allelic loss on one or both arms of chromosome 4 in several neoplasms including bladder, cervical, colorectal, hepatocellular, and esophageal cancers and squamous cell carcinomas of the head and neck and skin (12, 13, 14, 15, 16, 17, 18) . Phenotypic tumor suppression has been observed with the introduction of chromosome 4 into human glioma cells (19) . Thus, chromosome 4 likely contains one or more tumor suppressor genes that are frequently inactivated in several types of cancer.

A previous cytogenetic study has reported partial or complete loss of chromosome 4 as one of the frequent karyotypic changes in MMs (20) . CGH studies have shown frequent losses on chromosome 4 in SCLC (21 , 22) . Another CGH study has also provided evidence for losses on chromosome 4 in adenocarcinomas and squamous cell carcinomas of the lung (23) . However, the location of the putative oncogenes has not been confirmed or more precisely localized by allelotyping studies. The present study was undertaken to examine the presence and location of regions of common deletion involving chromosome 4 in MM and to compare the pattern with those of NSCLC and SCLC. Using a precise microdissection methodology; DNA from archival paraffin-embedded tissue sections from MMs, NSCLCs, and SCLCs; and cell lines from NSCLC and SCLC, we studied the incidences of LOH on both the p and q arms of chromosome 4.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Tumors and Cell Lines.
Paraffin-embedded archival material from surgical resections of 20 MMs, 21 SCLCs, and 20 NSCLCs (10 adenocarcinomas and 10 squamous cell carcinomas) acquired from Parkland Memorial Hospital (Dallas, TX), M. D. Anderson Cancer Center (Houston, TX), and the Armed Forces Institute of Pathology (Washington, D.C.) were used for this study. Paired lung cancer and lymphoblastoid cell lines (14 SCLC cell lines and 17 NSCLC cell lines) were also studied. Further details about these cell lines have been published elsewhere (24) . They are available from the American Type Culture Collection (Manassas, VA).

Microdissection and DNA Extraction.
Areas of malignant cells were identified by pathological review of all of the cases of MM, SCLC, and NSCLC. These areas were precisely microdissected under microscopic visualization, avoiding contamination by normal cells (25) . Stromal cells from the microdissected slides provided a source of constitutional DNA. Approximately 500-1000 tumor and stromal cells were microdissected from each case. The dissected cells were digested using the proteinase K method described previously (25) , and 5 µl of the DNA samples were used directly for each multiplex PCR reaction.

LOH Analyses.
Microsatellite analysis was used to determine the frequency and pattern of allelic loss on chromosome 4 using 11 polymorphic markers on 4q and 5 markers on 4p. Primer pairs that were used to identify specific dinucleotide and tetranucleotide repeat polymorphisms in genomic DNA were obtained from Life Technologies, Inc. (Gaithersburg, MD). The primer sequences used for LOH studies were obtained from the Genome Database. The relative order of these markers was ascertained from the Genethon map of chromosome 4 (26) .

Two rounds of PCR (multiplex PCR followed by uniplex PCR) were performed to amplify each marker used in this study (27) . A 10°C "touch down" strategy (28) was used spanning the primers annealing temperature followed by 25 cycles at the optimal annealing temperature. The final product was separated on a 6% denaturing polyacrylamide gel and subjected to autoradiography. LOH was scored by visual detection of complete absence of the upper or lower allele of informative cases.

Statistical Analysis.
Fisher’s exact two-tailed test was used for statistical evaluation of the differences between the percentage of LOH from two different groups. Probability values of P < 0.05 were regarded as statistically significant.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Microsatellite analysis was used to determine the frequency of allelic loss from chromosome 4 in MMs, SCLCs, and NSCLCs. A summary of the overall frequency of LOH at each locus, which was calculated as the number of cases with LOH: the number of informative cases (percentage), is shown in Table 1Citation . The patterns of LOH and the frequency of LOH at each locus in MMs and SCLCs, which was calculated as the number of cases with LOH:the number of informative cases (percentage), are shown in Fig. 1Citation .


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  		Table 1 Frequency of LOH on chromosome 4 in MM, SCLC, and NSCLC

 


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  		Fig. 1. Patterns of LOH in MMs (a) and SCLCs (b) exhibiting deletions of 4q and 4p. The cases have been grouped into three groups based on the extent of deletions. The case numbers are shown at the top. The microsatellite markers used and the chromosomal arm on which they are located are shown at the left. (D4S1652 to D4S392, q arm; D4S174 to D4S179, p arm.). Markers are placed in the predicted order from 4pter–qter. The number of cases with LOH:the number of informative cases (percentage) values are shown on the right. Vertical lines to the left of the markers indicate hot spots. •, allelic loss; {circ}, retention of heterozygosity; , uninformative.

 
The overall frequencies of allelic loss at any chromosome 4 site in MM and SCLC were high, with 16 of 20 (80%) MMs and 19 of 21 (90%) SCLCs showing LOH at one or more informative markers. The chromosome 4 deletions in six cases of MM and eight cases of SCLC were extensive, with loss of most of the q arm or both the p and q arms, but in the majority of the cases, the deletions were more localized (Fig. 1)Citation . The extent of the partial deletions was used to identify three discrete minimal regions of nonoverlapping deletions. (two regions on 4q and one region on 4p; Fig. 1Citation ). The patterns of LOH in MMs, SCLCs (tumor and cell lines), and NSCLCs (tumors and cell lines) with partial deletions that define three minimal areas of deletions are shown in Fig. 2Citation .



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  		Fig. 2. Patterns of LOH in MM (tumors) and SCLC and NSCLC (tumors and cell lines) that define three minimal areas of deletion. (R1 and R2 on 4q, b; R3 on 4p, a) Tumor numbers correspond with the case numbers of MMs, SCLCs (Fig. 1)Citation , and NSCLCs. Cell line numbers are numbers that were arbitrarily given to identify a cell line and do not correspond to specific tumors of that subtype. SCLC cell lines are shown as follows: CL4, NCI-H1450; CL5, NCI-H1672; CL9, NCI-H2195; CL10, NCI-H1607; and CL11, NCI-H2028. NSCLC cell lines are shown as follows: CL15, NCI-H1395; CL17, NCI-H1770; CL19, NCI-H2009; CL20, NCI-2087; and CL23, SCC-44. The microsatellite markers used and their chromosomal locations are shown at the left. Markers are placed in the predicted order from 4pter–pter. •, allelic loss; {circ}, retention of heterozygosity; , uninformative.

 
On 4q, the region between D4S408 and D4S171 (4q33–34) was one such minimal region of deletion (designated R1), with allelic loss in 15 of 16 cases (95%) of MM and 15 of 15 cases (100%) of SCLC (Figs. 1Citation and 2Citation ). The other minimal region of deletion on 4q (designated R2) was observed between markers D4S175 and D4S194 (4q25–26), with allelic loss in 11 of 17 cases (65%) of MM and 12 of 17 cases (71%) of SCLC. On 4p, the minimal region of deletion (designated R3) was observed between markers D4S1546 and D4S404 (4p15.1–15.3), with regional allelic loss in 10 of 16 cases (63%) of MM and 9 of 15 cases (60%) of SCLC (Figs. 1Citation and 2Citation ). Fig. 3Citation demonstrates 12 informative markers for two cases (one SCLC and one MM). Loss of the entire chromosome is seen in MM case 1 (Fig. 3Citation , top), whereas in SCLC case 14 (Fig. 3Citation , bottom), three discontinuous regions of loss are illustrated.



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  		Fig. 3. Autoradiographs demonstrating 12 informative markers for MM case 1 (top) and SCLC case 14 (bottom). In MM case 1, loss of one entire chromosome is illustrated. In SCLC case 14, three discontinuous regions of loss are seen (R1, R2, and R3; as indicated in Fig. 2, a and bCitation ). In contrast to MM case 1, the regions of loss are discrete, with retention of heterozygosity at the intervening markers. DNAs were assayed as described in "Materials and Methods" using the microsatellite markers indicated. Arrowheads, LOH; N, normal; T, tumor.

 
In NSCLC tumors, the mean frequencies of LOH on chromosome 4 were lower, with frequencies of 5 of 12 (41%), 6 of 18 (33%) and 4 of 16 (25%) at R1, R2, and R3, respectively. These LOH frequencies were statistically lower (P < 0.05) than those at corresponding regions in MM and SCLC tumors (Table 1)Citation . The 20 NSCLC tumors consisted of equal numbers of squamous cell and adenocarcinomas; however, because of the relatively small number of cases, statistically significant differences between them were not detected.

Four cases of MM (cases 17–20) and two cases of SCLC (cases 20 and 21) showed no losses at any of a relatively modest number of informative loci on chromosome 4. It is difficult to determine whether there were small deletions in the critical regions, or whether these cases lacked deletions. Thus, it is possible that analyses of the other, more informative cases resulted in an overestimate of the frequency of losses at the critical regions R1–R3.

Comparison between LOH data from paraffin-fixed archival tumors from lung cancers and their respective cell lines showed a good overall correlation for both SCLC and NSCLC (Table 1)Citation . The LOH data identified the same three hot spots in SCLC cell lines as in the tumors (Fig. 2)Citation , whereas lower frequencies of LOH but presence of the same minimal regions of deletions were detected in NSCLC cell lines. Table 2Citation shows a comparison of the data on the distribution of LOH at the different regions of chromosome 4 in the three tumor types. In MM and SCLC, the most frequent pattern was loss at all three regions, and 66–74% of these tumor types had allelic loss at more than one region. In NSCLC, most samples (72%) lost only one region, especially R3, and none lost all three regions.


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  		Table 2 Patterns of allelic loss on chromosome 4

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Because of previously published data based on cytogenetic and CGH studies, we performed allelotyping to identify the critical regions of allelic loss on chromosome 4 in MM and compared the data with those obtained from lung cancers. During a genome-wide allelotyping of lung cancer cell lines (24) using only two polymorphic markers (one on each chromosome 4 arm) that were previously found to be frequently deleted in bladder cancer (14) , we found moderate frequencies (47–67%) of loss in SCLC and NSCLC. To our knowledge, the present study represents the first attempt to allelotype chromosome 4 in MM and lung cancers using multiple polymorphic microsatellite markers.

In MM and SCLC, we observed frequent losses at three nonoverlapping sites located on the q (two regions) and p (one region) arms of chromosome 4. Losses at these sites occurred at lower frequencies in NSCLC. The most frequently deleted region was at 4q33–34 (region R1). The frequency of allelic loss at this region (94%) was higher than loss at any other chromosomal region previously reported for MM (7, 8, 9, 10) . Of interest, SCLC showed a similar high frequency of allelic loss (100%) in this region, but NSCLC showed a lower frequency of allelic loss (41%). Other investigators have also identified this region, which appears to be about 14cM long, as one of the critical regions of deletion in bladder, cervical, and esophageal cancers and squamous cell carcinomas of the head and neck and skin (12, 13, 14, 15, 16, 17, 18) . Our data suggest the location of a tumor suppressor gene at 4q33–34 that is commonly altered in MM and SCLC (and in other cancers) but is less frequently altered in NSCLC.

High frequencies of LOH at two other regions of chromosome 4 were noted. One region (R2) included the markers D4S194, D4S1586, and D4S175 (4q25–26). Previous studies have shown a common region of deletion at or near this site in squamous cell carcinomas of the head and neck and skin (17 , 18) . Another region that is targeted in MM and SCLC is between markers D4S1546 and D4S404 (4p15.1–15.3). This region appears to be about 3 cM long and was previously found to be frequently deleted in bladder cancer (14) . In MM and SCLC, the most frequently observed pattern was loss at all three regions. However, in NSCLC, the most frequent pattern was loss at R3 alone.

Our results suggest that inactivation of at least three putative tumor suppressor genes located on both arms of chromosome 4 may play important roles in the pathogenesis of MM and SCLC. The finding of three deletion hot spots on chromosome 4 common to MM and SCLC is of interest, particularly because there are major differences in their pathogenetic mechanisms. Asbestos exposure is the major etiological factor for mesothelioma, whereas heavy smoking is the major risk factor for SCLC. Of particular interest, NSCLC had lower frequencies of loss at these three regions. The diagnostic distinction between epithelial MMs and metastatic adenocarcinomas has always caused clinical and pathological problems, and differences in the patterns of allelic loss may help in the identification of pleural-based malignancies. Although previous cytogenetic and allelotyping studies have clearly shown distinct regions of allelic loss on chromosome 1p, 3p, 6q, 9p, and 22q in MM (6, 7, 8, 9) , no substantial qualitative or quantitative differences between MM and NSCLC have been reported. Our previous findings reported neurofibromatosis type 2 gene mutations in a subset of mesotheliomas and their absence in SCLC and NSCLC cell lines (29) .

Of interest, a recent CGH analysis compared findings between MM and NSCLC (30) . Its results showed loss at 4q as the most frequent change in MM. However, the authors could not detect such alterations in NSCLC. A previous CGH study (23) has provided evidence for the occasional loss on chromosome 4 in adenocarcinomas and squamous cell carcinomas of the lung. CGH is not as sensitive as allelotyping for precisely mapping the location of putative suppressor genes. Nevertheless, the CGH findings reported previously (30) are in agreement with our observations.

In summary, deletions of chromosome 4 are frequent in MM and SCLC but occur at lower frequencies in NSCLC. Our data identified three distinct regions of loss on chromosome 4 that may play important roles in the pathogenesis of MM and SCLC.


   ACKNOWLEDGMENTS
 
We thank Dr. William Travis (Armed Forces Institute of Pathology, Washington, D.C.) for providing some of the paraffin-embedded archival materials used in this study and Dr. Asha Rathi for assistance in preparation of the manuscript.


   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 Supported by Specialized Program of Research Excellence Grant 1-P50-CA70907 from the National Cancer Institute (Bethesda, MD). Back

2 To whom requests for reprints should be addressed, at Hamon Center for Therapeutic Oncology Research, NB8.106, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-8593. Phone: (214) 648-4921; Fax: (214) 648-4924; E-mail: gazdar{at}simmons.swmed.edu Back

3 The abbreviations used are: MM, malignant mesothelioma; SCLC, small cell lung carcinoma: NSCLC, non-small cell lung carcinoma; LOH, loss of heterozygosity; CGH, comparative genomic hybridization. Back

Received 7/30/98; revised 10/22/98; accepted 11/ 2/98.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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A. Dallol, N. F. Da Silva, P. Viacava, J. D. Minna, I. Bieche, E. R. Maher, and F. Latif
SLIT2, a Human Homologue of the Drosophila Slit2 Gene, Has Tumor Suppressor Activity and Is Frequently Inactivated in Lung and Breast Cancers
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T. Fujii, T. Dracheva, A. Player, S. Chacko, R. Clifford, R. L. Strausberg, K. Buetow, N. Azumi, W. D. Travis, and J. Jen
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I. I. Wistuba, M. Tang, A. Maitra, H. Alvarez, P. Troncoso, F. Pimentel, and A. F. Gazdar
Genome-wide Allelotyping Analysis Reveals Multiple Sites of Allelic Loss in Gallbladder Carcinoma
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L. Girard, S. Zöchbauer-Müller, A. K. Virmani, A. F. Gazdar, and J. D. Minna
Genome-wide Allelotyping of Lung Cancer Identifies New Regions of Allelic Loss, Differences between Small Cell Lung Cancer and Non-Small Cell Lung Cancer, and Loci Clustering
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I. I. Wistuba, J. Berry, C. Behrens, A. Maitra, N. Shivapurkar, S. Milchgrub, B. Mackay, J. D. Minna, and A. F. Gazdar
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K. M. Fong, Y. Sekido, and J. D. Minna
MOLECULAR PATHOGENESIS OF LUNG CANCER
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E. G. Butchart
Contemporary Management of Malignant Pleural Mesothelioma
Oncologist, December 1, 1999; 4(6): 488 - 500.
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T. Kohno and J. Yokota1
How many tumor suppressor genes are involved in human lung carcinogenesis?
Carcinogenesis, August 1, 1999; 20(8): 1403 - 1410.
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N. Shivapurkar, S. Sood, I. I. Wistuba, A. K. Virmani, A. Maitra, S. Milchgrub, J. D. Minna, and A. F. Gazdar
Multiple Regions of Chromosome 4 Demonstrating Allelic Losses in Breast Carcinomas
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