Interact CardioVasc Thorac Surg 2009;9:42-44. doi:10.1510/icvts.2008.201509
© 2009 European Association of Cardio-Thoracic Surgery
Institutional report - Thoracic oncologic |
Chromosomal deletion in patients with malignant pleural mesothelioma
Siyamek Neragi-Miandoaba,* and
David John Sugarbakerb
a St Vincent's Medical Center, Department of Surgery, New York Medical College, School of Medicine, 130 West 12th Street, New York City, NY 10011, USA
b Division of Thoracic Surgery, Department of Surgery, Harvard Medical School, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
Received 31 December 2008;
received in revised form 20 February 2009;
accepted 23 March 2009
*Corresponding author. Tel.: +1 617 9352782.
E-mail address: Sneragi{at}yahoo.com (S. Neragi-Miandoab).
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Abstract
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Malignant pleural mesothelioma (MPM) is associated with frequent deletions of specific chromosomal regions within 1p, 3p, 6q, 9p, 13q, 15q, and 22q. In this retrospective review of our patients with MPM, the tumor tissue of 40 patients (31 male and 9 female) was evaluated for chromosomal deletions and was karyotyped. Chromosomal deletions in regions 1p, 3p, 6p, 9p, 6q, 9q, 22q were observed in 22 of 40 patients (55%). Of this group of 22 patients, 15 (68%) demonstrated deletions in chromosome 6; 12 (54%) exhibited deletions in chromosome 22q; and 13 (59%) had deletions in chromosome 9p. Asbestos exposure was found in only 13 of the 22 patients (59%) with chromosomal deletions. There was no correlation between asbestos exposure and chromosomal deletion (95% CI –0.38–0.23, P=0.63). Chromosomal deletion did not correlate with age (95% CI –0.45–0.14, P=0.29). The majority of patients with chromosomal deletions had epithelial histology (17 of 22 patients; 77%), which was not statistically significant (95% CI –0.14–0.46, P=0.27). Chromosomal deletion is common in tumor tissue of MPM and the inactivation of tumor suppressor genes (TSGs) residing in these chromosomes may contribute to mesothelial cell tumorigenesis.
Key Words: Genetic analysis; Malignant transformation; Genetic susceptibility; Malignant pleural mesothelioma
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1. Introduction
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Malignant pleural mesothelioma (MPM) is an asbestos-related fatal cancer [1, 2]. Its genetic basis is unknown, but it appears to involve multiple types of chromosomal abnormalities [3–5]. Karyotypes can provide valuable information on prognosis based on low mitotic indices or poor chromosome morphology [6]. Further, identifying chromosomal deletions/translocations [7] or loss of heterozygosity (LOH) can reveal epigenetic silencing, possibly caused by chromosomal deletions or point mutations [8].
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2. Method
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This study is a retrospective review of the karyotypes of tumor tissue of patients with MPM. The aim of the study is to look for any chromosomal deletion and its potential correlation with environmental factors. Sixty patients with MPM were initially included in this study. In 20 cases the specimen contained insufficient viable cells and a chromosomal analysis could not be performed; therefore, these patients were eliminated from the evaluation. The final analysis included tumor tissue from 40 patients (31 males and 9 females). Tumor cell lines were established from the resected tumor tissue and cytogenetic analysis was performed on them. The genomic DNA was isolated by standard methods as described in the literature [9]. LOH was scored when complete loss of one allelic band in the tumor cell line DNA was observed. Patients' DNA in normal tissue was not analyzed in this study. The karyotyping was performed at the Department of Pathology at Brigham and Women's Hospital.
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3. Results
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Forty cases had informative karyotyping, of which 22 (55%) had chromosomal deletion. (Table 1 demonstrates the location of chromosomal deletion and the karyotype in each individual case.) The average age of the patients was 61±11 years (range 39–79 years) and the right-to-left pleura ratio was 22:18. Only 13 of 22 patients (59%) with chromosomal deletions had a known history of asbestos exposure. We did not find any statistically significant correlation between asbestos exposure and chromosomal deletion (95% CI –0.3802–0.2395, P=0.63). Twelve patients had asbestos exposure without evidence of chromosomal deletion. Nine patients had chromosomal deletions without known asbestos exposure; three of them had radiation exposure and one of them had SV40 exposure.
Three of four patients with previous radiation therapy showed abnormal karyotyping and chromosomal deletions. Five patients had no asbestos exposure and no chromosomal deletions. Four patients without any history of exposure had chromosomal deletions.
Table 2 demonstrates the relationship between asbestos exposure and chromosomal deletion in a two-by-two table.
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4. Discussion
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LOH has been reported in different genomic regions in patients with MPM [4]. Chromosomal deletions lead to tumorigenesis and inactivation and/or loss of multiple tumor suppressor genes (TSGs). Segments in 1p, 6q, 9p, and 22q are common sites of karyotypic abnormality and allelic loss in MPM [10]. It has been reported that TSGs located within these chromosomes may be involved in the pathogenesis of the disease [11]. Pylkkanen et al. [4] reported frequent deletions of specific sites within chromosomal arms 1p, 3p, 6q, 9p, 13q, 15q, and 22q in MPM tissue. These samples exhibited concurrent allelic losses at multiple tumor suppressor gene sites, with the NF2 gene preferentially affected [4, 11]. Furthermore, TSGs within p16/CDKN2A-p14ARF at 9p21 and NF2 at 22q12 are frequently altered in MPM [4]. The most frequent chromosomal losses and deletions observed in our series were located in 1p, 3p, 6q, 9p, and 22q. Our results are in accord with most of the published data [4, 10]. Pylkkanen et al. [4] studied allelic losses at three known TSG regions (22q/NF2 gene, 9p/p16 gene, and 3p/FHIT gene), as well as in other areas (14q and 6q), which have been shown frequently in MPM. Analysis of chromosome 22q, which included an NF2 marker (NF2CA3), demonstrated that frequent LOH occurs simultaneously at multiple loci.
Recurrent allele loss has been reported at 9p, 3p, 9p, 14q, and 6q [4]. In our series of 22 patients with chromosomal deletions, 12 (54%) had deletions in 22q (location of NF2 gene); 13 (59%) exhibited deletions in chromosome 9p (p16 gene); and 14 (64%) showed deletions at chromosome 3p (location of FHIT gene). Jensen et al. [12] performed genetic analysis on 14 mesothelioma samples to identify regions in the tumor genomes that may carry tumor suppressor genes. The most frequent alteration was a deletion in chromosome 6q. They found three tumor suppressor genes within chromosome 6q involved in the pathogenesis of mesothelioma [12]. Fifteen of 22 patients (68%) with chromosomal deletions in our series had a deletion on chromosome 6q.
Karyotyping is a useful tool to identify chromosomal deletion and the associated mutated/deleted genes. However, considering the genetic complexity and variability of malignant neoplasms, DNA sequencing of the tumor tissue can provide more specific mutational profiles and help individualize therapy [13, 14]. DNA sequencing, a systematic, genome-wide characterization of rearrangements in complex human cancer genomes, would allow us to identify and further stratify genes associated with various types of cancer [15].
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5. Limitations of the study
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Our study is limited by small sample size and the retrospective nature of the study. Further, an evaluation of chromosomal deletion in the patients' normal tissue was not performed. This could reveal whether the chromosomal deletions were the result of neoplastic changes or if the patients developed MPM because they already had chromosomal instability.
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6. Conclusion
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Knowledge about individuals with chromosomal deletions can contribute to identifying individuals at risk for MPM and possibly preventing them from environmental exposure. Our data suggest that loss of TSGs residing within deleted chromosomes is critical in mesothelial cell oncogenesis. Perhaps other unidentified tumor suppressor genes are located on these chromosomes, as well. Further extensive genomic analysis could identify potential targets for new biological drugs for this devastating cancer.
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Abstract
1. Introduction