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Comparative Genomic Hybridization Studies on Mesothelioma Show a Parallel Fate of 1p21-1p22 and 9p21 Bands and a Chromosomally Stable Sub-Group

Melaiu Ombretta, Bracci Elisa, Cristaudo Alfonso, Bonotti Alessandra, Foddis Rudy, Mutti Luciano, Gemignani Federica, Landi Stefano*

Department of Biology, University of Pisa, Pisa, Italy

Abstract: Malignant Pleural Mesothelioma (MPM) is a cancer whit a poor prognosis. The landscape of the chromosomal rearrangements in MPM was approached by several authors but robust conclusions could not be made, given the limited sample sets analyzed within each study. In order to improve the knowledge on the field, we retrieved and pooled all the results deriving from published studies where comparative genomic hybridization (CGH) was employed. A total of 283 tissues (149 epithelioid, 53 sarcomatoid, 78 biphasic, and 3 unclassified) were analysed, 179 with classical chromosome CGH (cCGH), and 104 with arrayed-CGH (aCGH). Some chromosomal bands were involved in aberrations with a frequency exceeding 20% (-1p21, -9p, -14q, and -22q for the epithelioid, -4, +5p, +8q21àter, -9p, -13, and -14q for the sarcomatoid, and -9p, -14q, and -22q for the biphasic type). We found a statistical significant association between contemporary losses at 9p21 and 1p21-1p22 (21% of the samples showed losses at both bands, P=7.74x10⁻⁸), whose significance should be elucidated with further studies. Candidate cancer genes involved in MPM were suggested. Finally, 15% of epithelioid, 13% of sarcomatoid, and 13% of biphasic MPM tissues did not show any genomic alteration. Only two previous studies suggested a less aggressive behavior of MPM in relation to a low degree of chromosomal alterations. Thus, more work is warranted to understand whether chromosomal rearrangements could be included as prognostic biomarker in the clinical practice.

Keywords: comparative genomic hybridization, mesothelioma, chromosomal instability, tumor suppressor genes, chromosomal gain, chromosomal loss

Received July 08, 2013; Revised September 24, 2013; Accepted December 19, 2013

Citation: Melaiu Ombretta, Bracci Elisa, Cristaudo Alfonso, Bonotti Alessandra, Foddis Rudy, Mutti Luciano, Gemignani Federica, Landi Stefano, Comparative Genomic Hybridization Studies on Mesothelioma Show a Parallel Fate of 1p21-1p22 and 9p21 Bands and a Chromosomally Stable Sub-Group. American Journal of Medical and Biological Research, 1 (4). 149-158. January 2013. doi:10.12691/ajmbr-1-4-8

1. Introduction

Malignant Pleural Mesothelioma (MPM) is a highly aggressive cancer of the pleural cavity, classified in three histological sub-types (epithelioid, sarcomatoid, biphasic). It is caused by asbestos exposure [1,2,3] however SV40 virus infections and the individual genetic susceptibility may play a role [4,5]. Because the latency is assessed to be longer than 30 years after the asbestos exposure, it was estimated that the incidence will increase in the next decades. The prognosis of the MPM is poor, in particular because of the difficulties for an early diagnosis and because it is refractory to conventional therapies [6]. In order to improve diagnosis, therapies, and prognosis a better knowledge of the somatic alterations occurring within neoplastic cells is mandatory. In this context, one of the biological aspects to be studied is the occurrence of chromosomal rearrangements. This can be addressed with the classical chromosome comparative genomic hybridization (cCGH), with the BAC- (bacterial artificial chromosome) array CGH, or with the newest SNP-(single nucleotide polymorphisms) CGH array (aCGH) [7]. cCGH is an efficient approach for detecting and mapping changes in the copy number alterations throughout entire genomes with a single hybridization, although with the resolution limited to the chromosomal band visible with the optic microscope. The most recent techniques of aCGH allow testing a huge number of loci in a single hybridization, with a very high resolution, close to a single exon within a gene [8]. MPM is a rare disease and published studies were carried out on limited series of samples. For this reason, scattered observations were reported without the possibility to make robust conclusions. Thus, the aim of this review was to collect all the published results deriving from independent studies on CGH analyses and to give more robust conclusions on the chromosomal alterations most commonly occurring in this neoplasm.

2. Data Collection

Firstly, we made an extensive literature search. We focused on cCGH and aCGH studies involving human specimens. To systematically collect studies published until September 2013, PubMed (URL: http://www.ncbi.nlm.nih.gov/pubmed/) was searched with keywords related to the study background (we used: “malignant mesothelioma AND comparative genom* hybridization”). Forty-one articles appeared (September 2013) and they were further filtered. The search was limited to English-language publications. Studies not reporting the complete data for each tissue sample and/or cell line, evaluated at a resolution of, at least, the single chromosomal band, were not included. We considered only studies where the complete set of chromosomal bands was provided for each analyzed sample, whereas we did not include studies with processed data or reporting partial karyotypes or data on long term cell lines only. Studies investigating only part of chromosomes, such as those using the fluorescence in situ hybridization or real-time PCR, were also excluded. Finally, fourteen studies (Table 1) accomplished the required criteria. Then, the results from ten studies where cCGH was used were pooled. We accounted the individual gains/losses for each chromosome band: each chromosomal region was evaluated by calculating how often (in %) it was involved in chromosomal rearrangements. The percentages were calculated by dividing the absolute number of events involving the considered region by the total number of analyzed chromosomes collected across the ten studies. This allowed assessing regions frequently subject to chromosomal rearrangements. Then, the results from four aCGH studies were compared graphically, in order to detect the common gained/lost regions. In Figure 1 the results of the pooled analysis obtained from studies employing the cCGH are depicted as “pooled-CGH chromosomes”, where the red and green segments represent gained or lost regions, respectively, occurring at a frequency greater than 10%. Moreover, the results from aCGH were reported independently in the same figure, where each chromosome in each study was graphically aligned with the corresponding “pooled-CGH chromosome”. For each chromosome, we annotated as relevant only the segments showing a high frequency of copy abnormalities in at least four representations out of the five depicted in figure.

Table 1. Studies employing chromosome CGH (cCGH) or array-CGH (aCGH) evaluated in the present review

3. Results

Among ten selected studies, 179 tissues were analyzed with the cCGH. Tissue samples were classified as epithelioid (74), sarcomatoid (48), and biphasic (57) and did not overlap among studies. The most relevant findings are summarized in Table 2 and supplementary figures. It should be observed that some chromosomal regions are gained in a group of specimens, but deleted in others. These "inconsistent" regions could be ascribed to a simple epiphenomenon (they do not correlate with the histological type), because of the genomic instability of the tumour. On the other hand, it should be noticed that some chromosomes, such as 2, 12, 19, 21, and X, are not often subject to rearrangements, probably because clones with alterations within them are selected negatively. When the complete dataset was analyzed, including 104 specimens (75 epithelioid, 5 sarcomatoid, 21 biphasic, and 3 unknown) investigated with aCGH, it could be observed (Figure 1) that several chromosome aberrations are consistent among studies. The most frequent chromosomal aberrations observed were -1p21, -9p, -14q, and -22q for the epithelioid MPM, -4, +5p, +8q21àter, -9p, -13, and -14q for the sarcomatoid MPM, and -9p, -14q, and -22q for the biphasic type (Table 2). The overall landscape of chromosomal abnormalities reported in Figure 1 looks remarkably similar to that reported by a recent work [9] carried out on a panel of long term established MPM cell lines. Among other chromosomal bands involved in MPM, the deletion of 3p21 seemed to be specific for the epithelioid type and it was previously proposed as marker [10]. Considering the rearrangements found among all the epithelioid MPM tissues, gains were about 41.4% of the total events. In the sarcomatoid-type, gains were 36.2%, whereas in biphasic-type they were 33.5%. Thus, the three types of MPM did not seem to differ dramatically for their tendency to accumulate chromosomal rearrangements, in particular chromosomal losses (58.6, 63.8, and 66.5 percent, respectively).

Figure 1. Graphic representation of the results obtained from the pooled analysis of cCGH studies (the “pooled-CGH chromosomes”, b), compared with four aCGH studies. In red and green are represented the gained or lost regions, respectively, occurring at a frequency greater than 10%. a, Didier et al., 2011; c, Ivanov et al., 2009; d, Taniguchi et al., 2006 ; e, Balsara 1999

Graphics overview of the percentages of chromosomal gains and losses (data obtained from pooling 179 tissues analyzed wit cCGH). The top half of each slide represents the gains, and the lower half the losses. Epithelioid MPM are shown in black, the sarcomatoid type in gray, the biphasic in light gray. The y-axis represents the percent of events. Some putative cancer genes were also reported.

Table 2. Most frequent chromosomal aberrations observed in the three histological types of MPM and putative cancer genes located in the corresponding regions (data obtained by pooling 179 human tissues analysed with cCGH)

Moreover, there was a highly statistical significant association between the loss of 9p21 and the losses of chromosomal bands 1p21-1p22. The peak of significance was reached for the contemporary losses of 9p21 and 1p21.1-1p21.2 (7.74x10⁻⁸, chi-square test), but it was of the order of 10⁻⁶ also for 1p22. The significance level was so low to hold any correction for multiple testing at genome-wide level (Bonferroni’s correction). About 21% of samples with chromosome alterations showed a contemporary loss of the two chromosomal bands, whereas about 50% of them retained both bands. This association was highly significant also when samples were selected for the histological type or selected for the type of specimen. Finally, it should be noticed that about 15% of epithelioid, 13% of sarcomatoid, and 13% of biphasic MPM tissues were, apparently, deprived of chromosome abnormalities, suggesting the presence of a phenotype negative for chromosome instability (CIN-negative). MPM is commonly considered a type of tumour with a high level of CIN, therefore these findings do not completely agree with the general knowledge.

4. Discussion

The main results obtained from our analysis are (i) a fine characterization of the most common chromosomal abnormalities in MPM, and (ii) the possible existence of a sub-group of MPM with a CIN-negative phenotype. The band at 3p21, frequently deleted in the epithelioid type, bears at least eleven genes related to cancer. These include BAP1, PHF7, SEMA3G, TNNC1, NISCH, STAB1, NT5DC2, C3orf78, RPL29, DUSP7, and PBRM1. It is important to note here that inactivating mutations within BAP1 were reported to be causative of a rare familial form of MPM [11]. Therefore, it is likely that the deletion of 3p21 confer an important advantage in the clonal evolution of MPM, through the deprivation of the active form of BAP1. However, also RPL29 and DUSP7 were found homozygously deleted in a variety of MPM cell lines, suggesting a potential involvement of these genes in MPM [9]. Allelic losses at one or both arms of chromosome 4 are frequent in cancer. Shivapurkar et al., observed frequent losses at three non-overlapping regions: (a) 4q33-34 (>80%); (b) 4q25-26 (>60%); and (c) 4p15.1-15.3 (>50%) [12]. T1A12, PTPN13, caspases 6 and 3 [13], ING2 (found lost in head-neck carcinoma) [14], FBXW7 (lost in renal carcinoma) [15], NEIL3, IRF2 (described for hepatocellular carcinoma) [16], and miR-218 [17] are among the suggested tumor suppressor genes (TSGs) within the region. However, none of them has never been reported as involved in MPM, therefore the significance of this observation remains to be further elucidated. On the other hand, a role could be played by CCSER1, frequently inactivated or deleted in MPM cell lines [9]. The region 8q2 bears three known cancer genes: EDD1, GRHL2, and MYC. EDD1 and GRHL2 are both able to inhibit death receptor-mediated apoptosis by repressing the expression of FAS and DR5 death receptors. They are often amplified in breast, lung, melanoma, and ovarian cancers [18]. However, they were never reported in the contest of MPM. On the other hand, the expression of c-MYC was found increased in MPM [19]. MYC is a well-characterized proto-oncogene related to the prognosis of several human cancers [20,21]. Moreover, many case-control association studies showed a link between polymorphisms close to MYC and the risk of lung [22], prostate [23], bladder [24], colorectum [25], and breast [26] cancer. MYC could result up-regulated following gains of 8q, potentially leading to an uncontrolled cell proliferation, escape from immune surveillance, and growth factors production [27]. In summary, it is likely that the gain of 8q2 confer an evolutive advantage of MPM clones through the amplification of this gene.

Concerning the losses of chromosome 13 and 14, detailed genetic analyses showed that there are minimal deleted regions within 13q12 [28], and 14q11.1-q12 and 14q23-q24. The first segments harbors LATS2 (large tumor suppressor homolog 2), a gene encoding a serine/threonine kinase capable of inhibit MPM cell lines through YAP and the Hippo tumour-suppressive signaling pathways [29]. Very few information is available on genes within 14q in relation to MPM. Angiopoietin-1 (ANG1) could be one interesting candidate gene, given that patients with advanced-stage MPM showed higher levels of serum Ang-1 than the early-stage MPM patients and the Kaplan-Meier method revealed a significant correlation between Ang-1 levels and survival [30]. Within this chromosome (in 14q3), also ACOT6 and NRXN3, frequently deleted in MPM cell lines, could be proposed as candidate cancer genes for MPM [9]. Another region frequently involved as cytogenetic abnormality in the MPM is in 22q12.2 [31,32,33]. It could be hypothesized that such a change provides a clonal advantage because it leads to the loss of neurofibromin 2 (NF2). Mutations in NF2 occur in approximately half of MPM cases [34,35], and its deletion has been proposed as an early event [36]. Although MPM is not typically present in families affected by type-2 neurofibromatosis (where mutations within NF2 are inherited at germline level) [37], the risk of developing MPM increases if an NF2 patient is exposed to asbestos [38,39].

The biological significance of the concurrent losses at 9p21 and 1p21-1p22 is not clear. It is known that one of the predominant genetic abnormalities in the MPM is the homozygous inactivation of the gene CDKN2A within the 9p21 region, occurring at a frequency of greater than 70% [40,41]. The locus encodes two distinct proteins, p16INK4a and p14ARF, originating from different transcription start sites and translated from mRNA undergone to alternative splicing [42] and it is involved in cell proliferation and senescence of mature cells, through the regulation of both the pRb and p53 pathways [43,44,45]. The frequent deletion of 1p21-1p22 in MPM was already known since late nineties [46]. Detailed analyses defined a 4-cM segment delimited by the loci D1S435 and D1S236. The list of potential TSGs within that region includes also: HFM1, CDC7, HSP90B3P, TGFBR3, BRDT, EPHX4, BTBD8, KIAA1107, C1orf146, GLMN, ABCA4, GFI1, EVI5, RPL5, FAM69A, SNORD21, SNORA66, MTF2, TMED5, CCDC18, LOC100131564, DR1, FNBP1L, BCAR3, miR-760, DNTTIP2, GCLM, and ARHGAP29. Among the listed genes, we found MTF2 having a potential link with CDKN2A. In fact, the Drosophila orthologs of the human MTF2 (i.e. Pcl2) was showed to be an important regulator of CDKN2A gene expression through the Polycomb repressive complex-2 [47]. Thus, this evidence could suggest some hypothesis on the common fate of 9p21 and 1p22 in MPM cells.

Overall, a relatively novel finding is the observation that around 15% of specimens are CIN-negative. One possible reason could be ascribed to the use of a low resolution techniques for most of the specimens considered in the pooled analysis. However, studies where the aCGH was employed [48,49] showed a similar share of CIN-negative samples. Tissue specimens negative for macroscopic chromosomal alterations were scattered throughout the publications, thus it is also reasonable to exclude a bias due to a laboratory effect. The only plausible explanation remains the possibility of massive contamination of genomic DNA from non-malignant cells infiltrating the MPM specimens, for some of the samples. However, in all the manuscripts the tissue collection is described accurately and the specimens were all evaluated by expert pathologists. Thus, taken with caution, present data suggest the existence of a sub-group of MPMs with a CIN-negative phenotype. In one study [50], there seems not to be a prolonged survival for patients showing a CIN-negative MPM. However, in 1992, Tiainen et al. noticed a correlation between survival and chromosome number [51]. According to this study, patients with normal chromosome numbers and no clonal abnormalities, have survived longer (mean survival 17 months) than patients with clonal abnormalities (mean survival 12 months). In summary, the use of CGH could be of support in revealing cancer genes involved in MPM. Moreover, a very promising finding is related to the clinical significance of the chromosomal abnormalities. So far, too few studies were carried out on this subject. In particular, more investigations should be encouraged in order to elucidate the relationship between chromosomal alterations and prognosis in MPM.

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Acknowledgements

This work was made possible thanks to funds of the Associazione Italiana Ricerca Cancro (AIRC) Investigator Grant 2008.

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