A wealth of cytogenetic data has demonstrated that numerous somatic genetic changes are involved in the pathogenesis of human lung cancer. Despite the complexity of the genomic changes observed in these neoplasms, recurrent chromosomal patterns have emerged. In this review, we summarize chromosomal alterations identified in small cell and non-small cell lung cancer, using classical and molecular cytogenetic techniques. These analyses have uncovered a set of chromosome regions implicated in lung cancer development and progression. However, many of the target genes remain unknown. Newer technology, such as array-CGH, when combined with cDNA microarrays and tissue microarrays, will facilitate the integration of genomic and gene expression data and pave the way toward a molecular classification of lung carcinomas. The molecular implications of consistent chromosome imbalances found in lung cancer to date are also discussed.
Consistent chromosome changes are thought to be indicative of critical molecular events involved in tumorigenesis. Some of these chromosome alterations, primarily balanced reciprocal translocations, are associated specifically with certain leukemias, lymphomas, and sarcomas (Heim and Mitelman, 1995; Sandberg, 1990). In many of these malignancies, a specific rearrangement is the only cytogenetic abnormality present. In contrast, in lung carcinomas and other common epithelial tumors, the karyotypes frequently exhibit multiple chromosome aberrations indicative of genome instability. Balanced translocations are rare, and in most instances the alteration results in a genomic imbalance, i.e. a net gain or loss of genetic material.
Primary lung tumor specimens often have a low mitotic index, making it difficult to obtain metaphase cells suitable for detailed karyotypic analysis. Moreover, the karyotypes often contain many extra chromosomes and unidentified (marker) chromosomes, which complicates efforts to identify consistent changes. The application of comparative genomic hybridization (CGH) analysis (Kallioniemi et al., 1992) and other molecular cytogenetic techniques to the study of lung carcinomas has led to the identification of recurring genomic imbalances in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). The chromosomal regions involved are thought to encompass genes that contribute to the development or progression of lung cancer.
In this review, we summarize cytogenetic findings reported in SCLC and NSCLC. The molecular implications of consistent chromosome imbalances found in lung tumors are also discussed.
Karyotypic changes in SCLC
Reports describing complete karyotypes of primary SCLCs have been limited to only a few cases (de Fusco et al., 1989; Miura et al., 1992; Sozzi et al., 1987). The karyotypic changes are usually quite extensive, and the modal chromosome numbers are typically in the triploid range. Mapping of the chromosome sites of clonal rearrangements seen in a total of 33 fresh SCLC specimens and early passage SCLC cell lines revealed clustering of breakpoints in chromosomes 1, 3, 5 and 17 (Testa et al., 1997). Recurrent losses of the short arm (p) of chromosomes 3 and 17 and long arm (q) of chromosome 5 were prominent changes.
Non-random losses of 3p were first reported by Whang-Peng et al. (1982b), and this finding was confirmed by numerous investigators (reviewed in Testa et al., 1997). Among the 18 SCLC tumors and cell lines that we analysed, cytogenetic evidence for loss of 3p was found in 16 cases (Miura et al., 1992; Testa and Graziano, 1993). The structural changes affecting 3p consisted mainly of terminal or interstitial deletions, unbalanced derivative chromosomes involving partial loss of 3p, and isochromosomes resulting in loss of entire 3p. One of the remaining two cases had allelic losses of 3p that were not evident from the karyotype. Loss of heterozygosity (LOH) analyses demonstrated that almost all SCLC tumors exhibit allelic losses from 3p (Brauch et al., 1987; Kok et al., 1987; Naylor et al., 1987). The consistent allelic loss at 3p strongly supports the hypothesis that one or more tumor suppressor genes (TSGs) important in the pathogenesis of SCLC reside within this chromosomal region. Several distinct regions of 3p loss have been identified by high-density allelotyping, i.e. 3p25–26, 3p24, 3p21.3, 3p14.2 and 3p12, suggesting that several different TSGs reside in 3p (reviewed in Sekido et al., 2001). The region 3p21.3 has been examined extensively for putative TSGs, because homozygous deletions have been found in several lung cancer cell lines. Homozygous deletions have also been reported in at least three other regions of 3p in either uncultured lung tumors or cell lines (Todd et al., 1997).
Several candidate genes in deleted regions of 3p have been identified, including the β-retinoic acid receptor gene (Kok et al., 1997), the protein-tyrosine phosphatase-γ gene, the semaphorin IV and A(V) genes (Roche et al., 1996; Sekido et al., 1996), the von Hippel Lindau tumor suppressor gene, VHL (Latif et al., 1993), and the fragile histidine triad gene, FHIT (Sozzi et al., 1996). Although several putative TSGs located at 3p21 have been reported, none appears to be consistently mutated in lung cancer. However, recent investigations have revealed frequent epigenetic inactivation of the RAS effector homologue, RASSF1, which is located at 3p21.3 (Dammann et al., 2000). RASSF1 is located in a 120 kb region of minimal homozygous deletion, and three transcripts have been identified, one of which (transcript A) was missing in all SCLC cell lines examined (Dammann et al., 2000). Loss of expression is correlated with methylation of the CpG-island promoter sequence of RASSF1A (Dammann et al., 2000). The FHIT gene, located at 3p14.2, spans the common fragile site FRA3B and encodes a diadenosine triphosphate hydrolase (Ohta et al., 1996). Abnormal FHIT messenger RNA transcripts have been reported in ∼80% of SCLCs, and most of these tumors exhibited loss of FHIT alleles (Sozzi et al., 1996). Moreover, FHIT protein is absent in many lung carcinomas and in some preneoplastic lesions (Sekido et al., 2001). Transfection of wild-type FHIT in lung cancer cells induces apoptosis and inhibits their tumorigenicity in nude mice, supporting the contention that FHIT functions as a TSG (Ji et al., 1999).
Cytogenetic losses of chromosome 5 appear to overlap within the region 5q13–21 (Miura et al., 1992), suggesting that this region may contain a TSG contributing to SCLC tumorigenesis. Several cell regulatory genes are located at band 5q13, including the gene encoding the p85α regulatory unit of phosphatidylinositol-3 kinase and the colorectal TSG, APC. However, no mutations or homozygous deletions of these genes have been documented in SCLC. Loss of chromosome 13 is a common event in SCLC. We observed numerical loss or structural rearrangements of chromosome 13 in 14 out of 18 (78%) SCLC cases (Miura et al., 1992; Testa and Graziano, 1993). Interestingly, ∼80% of SCLC tumors exhibit absent or very low levels of expression of the TSG RB1 (Harbour et al., 1988), suggesting that in many SCLCs, cytogenetic changes could unveil an inactivated RB1 gene on the remaining, karyotypically normal copy of chromosome 13. Loss of 17p is frequently observed in SCLC, with losses overlapping at 17p13 (Testa et al., 1997). The p53 gene, TP53, is located at band 17p13.1 and has been shown to be a frequent target for molecular alteration in lung cancer (Nigro et al., 1989; Takahashi et al., 1989).
In addition to chromosomal losses, extrachromosomal double minutes (dmin) and intrachromosomal homogeneously staining regions (hsr), two cytogenetic manifestations of gene amplification, have been observed in SCLC, particularly in cell lines derived from these tumors (Testa and Graziano, 1993; Whang-Peng et al., 1982a). An especially high incidence of dmin and hsr have been reported in heavily pre-treated SCLC patients with extensive distant metastases (Wurster-Hill et al., 1984). Amplification of various members of the MYC family of oncogenes is relatively common in SCLC (Nau et al., 1985, 1986). However, such amplification appears to be less common (∼10%) in primary SCLC specimens (Wong et al., 1986). Fluorescence in situ hybridization (FISH) analysis has revealed that amplified MYC genes reside within the dmin or hsr (Brennan et al., 1991; Testa et al., 1997). Dmin or amplification of one of the MYC family genes occurs at a higher frequency in tumors from previously treated SCLC patients than from untreated patients (Brennan et al., 1991; Testa et al., 1997).
Karyotypic changes in NSCLC
In NSCLCs, karyotypic changes typically are extensive, with multiple numerical and structural changes, and the karyotypes are often near-triploid (reviewed in Testa et al., 1997). Prominent numerical changes include losses of chromosomes 9 and 13 and, in males, loss of the Y. Gain of chromosome 7 is also a frequent numerical change. Trisomy 7 has been proposed to be a very early change in NSCLC and may be found in premalignant lung tissue in a subset of patients (Lee et al., 1987).
NSCLCs generally exhibit multiple unbalanced rearrangements. We previously summarized the breakpoints of clonal chromosome rearrangements seen in 185 primary NSCLC specimens (Testa et al., 1997). The most common sites of chromosomal breakage were at or near the heterochromatic centromere regions of chromosomes 1, 3, 5, 6, 7, 8, 9, 11, 13, 14, 15 and 17. Other regions of chromosomes 1, 3, 6, 7, 9p, 11 and 19 were also prone to rearrangement. Loss of genetic material due to numerical loss or unbalanced structural changes affects virtually all chromosomes, although some chromosome arms are affected more frequently. Among 70 NSCLCs we karyotyped (Feder et al., 1998; Testa et al., 1994), the chromosome arm most frequently contributing to losses was 9p (59 out of 70 tumors, 84%). Other chromosome arms lost in at least 60% of cases included 3p, 6q, 8p, 9q, 13q, 17p, 18q, 19p, 21q, 22q and the short arms of each of the acrocentric chromosomes. The chromosome arms most frequently involved in gains were 7p and 7q, each observed in ∼60% of cases. Extra copies of chromosome arms 1q, 3q, 5p, 11q and 12q were also common.
Loss of all or part of 3p was identified in approximately 75% of the NSCLC cases we karyotyped, and the minimally deleted region was 3p21. LOH from 3p has been reported in more than 50% of NSCLC cases and, like in SCLC, is thought to be an early genetic change in disease development (reviewed in Sekido et al., 2001). Allelic loss at 3p21 has been reported in all major types of lung cancer (Brauch et al., 1987; Kok et al., 1987), and homozygous deletions have been reported in three squamous cell lung tumors within a region of 3p21 that had previously been described only in lung cancer cell lines (Todd et al., 1997). As in SCLC, both RASSF1A and FHIT have been implicated in NSCLC. RASSF1A promoter hypermethylation was observed in more than 60% of NSCLC cell lines and in 30% of primary NSCLC tumors (Burbee et al., 2001). Abnormal FHIT mRNA transcripts have been reported in 40% of NSCLCs (Sozzi et al., 1996).
As noted above, 9p was the most frequently deleted chromosome segment in our NSCLC series, and loss of 9p has been proposed as a critical change in this neoplasm (Lukeis et al., 1990). Deletions of 9p are thought to target the CDKN2A (INK4a)/ARF locus, which is located at 9p21 and is frequently altered in many types of cancer. In contrast to the frequent loss of the RB1 gene in SCLC, the p16INK4a gene has been reported to be inactivated in more than 60% of NSCLC tumor specimens and cell lines, but rarely in SCLCs (Shapiro et al., 1995). This reciprocal relationship between RB1 inactivation and p16INK4a expression defines a fundamental distinction between NSCLC and SCLC. The critical alteration of p16INK4a results from homozygous deletion, mutation, or promoter hypermethylation (Sanchez-Cespedes et al., 1999). Aberrant methylation of p16INK4a is an early event in lung cancer and represents a potential biomarker for early diagnosis and monitoring of chemoprevention trials (Belinsky et al., 1998).
Chromosome rearrangement of 17p resulting in loss of genetic material is a particularly frequent finding in NSCLCs (Testa et al., 1997). DNA analyses have demonstrated that loss of alleles from 17p is a common occurrence in NSCLC (Weston et al., 1989). As in SCLC, the cytogenetic and molecular evidence suggests that loss of 17p containing a normal TP53 allele could unmask a mutant allele on the remaining, cytogenetically normal copy.
Other recurrent cytogenetic changes reported in NSCLCs include isochromosomes, which result in duplication of one chromosome arm and loss of the other arm, and dmin (reviewed in Testa et al., 1997). Common isochromosomes include i(5p) and i(8q). Other recurrent isochromosomes are i(1q), i(3q), i(6p), i(7p), i(13q) and i(14q). Dmin have been reported in about 10% of NSCLCs, and we have demonstrated amplification of either MYC or EGFR in several NSCLCs by Southern blot and/or FISH analysis (Testa et al., 1997). In two series of NSCLC specimens screened by Southern blot analysis, amplification of MYC was documented in three out of 36 (8%) and four out of 25 (16%) cases (Gemma et al., 1988; Yokota et al., 1988).
Comparative genomic hybridization (CGH) analysis
CGH analysis represents a valuable approach for overcoming the considerable technical difficulties encountered in the study of chromosome changes in lung cancers. Over the last decade, CGH analysis has been used to identify recurrent chromosomal alterations (gains, losses and amplifications) in a wide variety of human tumor types, and a consistent pattern of genomic imbalances has begun to emerge for each tumor type. In lung carcinomas, CGH analysis has revealed recurrent copy number decreases supportive of previous karyotypic and LOH data, and this work has also uncovered several previously unrecognized, recurrent sites of chromosomal loss. In addition, CGH studies have identified increased chromosome copy number at sites of known oncogenes/growth regulatory genes implicated in lung tumorigenesis. Moreover, these studies have permitted the identification of novel sites representing entry points for the identification of amplified DNA sequences contributing to a proliferative growth advantage in these aggressive neoplasms.
Genomic imbalances in SCLC
Figure 1 summarizes CGH findings in 45 human SCLC specimens reported in the literature (Levin et al., 1995; Petersen et al., 1997; Ried et al., 1994). The genomic imbalances are plotted for gains and losses for every chromosome band over the entire set of autosomes and the X chromosome. The most frequent sites of chromosome loss are 3p, 5q and 13q, each observed in 90% of cases, similar to findings reported by karyotypic analysis. However, several recurrent abnormalities that had not been highlighted in previous karyotypic studies of SCLC, including loss of 4q, 10q and 16q, and gains of 3q and 5p, were each identified in 60–70% of cases. Gains of 8q and 19q were also observed in ∼40% of the tumors. Frequent amplification at 19q13.1 was also reported in one series (Ried et al., 1994). Amplification at chromosome bands 1p32, 2p23 and 8q24.1, sites of MYCL, MYCN and MYC, respectively, were also observed.
Each of the reports of CGH analyses of SCLCs identified a recurrent region of chromosomal loss at 10q24–26, suggesting that a putative TSG important in the pathogenesis of SCLC may reside at this location. The PTEN/MMAC1 gene is located at 10q23.3 and is deleted or mutated in a wide variety of human malignancies such as carcinomas of the prostate, breast, and kidney. Alterations of PTEN have been reported in ∼20% of SCLC cell lines and in 10% of primary SCLC samples (Yokomizo et al., 1998). However, none of the 23 NSCLC specimens and cell lines tested displayed alterations of PTEN/MMAC1, suggesting that the inactivation of this gene contributes to the pathogenesis of SCLC but not NSCLC.
In another CGH study, involving 18 SCLC cell lines (Levin et al., 1994), DNA copy number abnormalities included previously identified increases at 1p22–32 (MYCL), 2p23–25 (MYCN) and 8q24 (MYC) and decreases at 17p13 (TP53), 13q14 (RBI), and 3p. In addition, novel DNA copy number increases were detected at 5p, 1q24, and Xq26, and novel decreases were identified at 22q12–13, 10q26, and 16p11.2. Interestingly, DNA copy number increases at 1p22–32, 2p24–25, and 3q22–25 and a decrease on 18p, were found to occur preferentially in SCLC cell lines of the ‘variant’ phenotype. This suggests that these sites harbor genes whose overexpression or inactivation contributes to the radiation resistance or aggressive growth phenotype characteristic of this subtype of SCLC.
Genomic imbalances in NSCLC
CGH analysis has revealed a wide array of genomic imbalances in NSCLC. Data from a total of 166 primary NSCLC specimens reported in four separate studies (Bjorkqvist et al., 1998; Luk et al., 2001; Pei et al., 2001; Petersen et al., 1997) are depicted in Figure 2. Among all histological types of NSCLC, prominent imbalances include gains of chromosome arms 1q, 3q, 5p and 8q and losses of 3p, 8p, 9p, 13q, and 17p (Figure 2). Losses of 4q, 5q, and 13q were prominent changes in the study by Petersen et al. (1997), but were infrequently observed in the other studies. Over-representation of chromosome arms 3q, 5p, and 8q were observed at high copy numbers in many cases and were common to all four series. Consistently over-represented regions included chromosome bands 1q21–31, 3q26-qter, 5p13–14, and 8q23-qter. The most frequent site of DNA amplification was 3q26. Other recurrent sites of amplification included 8q24, 3q13, 3q28-qter, 7q11.2, 8p11–12, 12p12, and 19q13.1–13.2. The most frequently under-represented segments common in the four series were 3p, 8p, and 17p. The minimally under-represented regions were 3p14–21, 8p21–23, and 17p12–13. These regions of DNA copy number decreases are also common sites of allelic loss, further implicating these chromosome regions as locations of TSGs.
CGH analysis of NSCLC has highlighted several genomic imbalances that are significantly associated with histological subtypes and biological phenotypes. Specifically, when CGH findings in lung squamous cell carcinomas (SCCs) were compared with those in adenocarcinoma (ACs), several statistical differences have been found, prominent among them being gain of 3q24-qter, seen in 55–85% of SCCs compared to 25–30% of ACs (Bjorkqvist et al., 1998; Luk et al., 2001; Pei et al., 2001; Petersen et al., 1997). Earlier evidence for an association between 3q gain and lung SCC of the lung was provided by Brass et al. (1996) who reported amplification of 3q26 in three out of nine lung SCCs analysed by reverse chromosome painting. Moreover, increased copy number at 3q26-27 has also been reported as a recurrent change in a variety of other tumors including cervical carcinoma, in which gain of 3q has been associated with the transition from severe dysplasia to invasive carcinoma (Heselmeyer et al., 1996). One potentially relevant gene at 3q26 whose product may contribute to the control of cell proliferation and malignant transformation is PIK3CA. The PIK3CA gene encodes the catalytic subunit of phosphatidylinositol-3 kinase, a critical component of several signal transduction pathways, including those of epidermal growth factor and platelet-derived growth factor. CGH analysis has also detected a higher frequency of 1q22–32 gains in lung ACs than in lung SCCs (Luk et al., 2001; Petersen et al., 1997). Similarly, karyotypic analysis of lung tumors has revealed a higher frequency of 1q gain in ACs than in SCCs (Testa et al., 1994).
Other differences between SCC and AC have been reported in lung cancer, although the findings are not consistent among studies. For example, Petersen et al. (1997) observed a significantly higher incidence of gain of 12p and loss of 2q in SCCs than in ACs, whereas Pei et al. (2001) reported a significantly higher frequency of gain of 20p13 and loss of 4q in SCC. Several correlations between certain genomic imbalances and other clinical parameters have also been noted. For example, 20q13 gain has been linked with invasiveness in lung ACs (Petersen et al., 1997), and gains of 7q and 8q have been associated with higher-stage tumors and either positive nodal involvement or higher tumor grade (Pei et al., 2001).
Cytogenetic analyses have established that numerous somatic genetic changes are involved in the pathogenesis of lung carcinomas. Despite the complexity of the genomic alterations observed in most lung tumors, the pattern and biological implications of recurrent chromosome alterations have begun to emerge. Chromosomal losses are frequently observed, and some of these changes encompass sites of known TSGs, whose loss and/or inactivation are thought to play a fundamental role in lung tumorigenesis. On the other hand, dmin/hsr and other high-level copy number increases result in the amplification of known or suspected oncogenes, which may impact the tumor phenotype or provide a proliferative growth advantage associated with disease progression.
CGH analysis has helped to unravel the patterns and clinical implications of chromosome changes in lung cancer. However, although some recurrent imbalances have been consistently observed in studies of NSCLC, several notable differences are apparent. For example, loss of 4q, 5q, and 13q were prominent changes in the study by Petersen et al. (1997) but were infrequently observed in other studies summarized above (Bjorkqvist et al., 1998; Luk et al., 2001; Pei et al., 2001). Whether the differences observed in NSCLC are a reflection of the type of computer analysis software, the threshold limits used to designate a gain or loss, or the patient population is unclear at this time. It is noteworthy, however, that three studies that used commercially available software generally showed a similar pattern and frequency of various genomic imbalances. The fourth study (Petersen et al., 1997), which used custom-made software, detected a greater number and higher frequency of imbalances than in the other three series. Until standardization of metaphase-CGH software can be achieved, the clinical value of such analyses will be difficult to establish. Moreover, metaphase-CGH has limited resolution (10–20 megabases), prohibiting precise identification of the specific genetic loci targeted by recurrent genomic imbalances. A relatively large set of chromosome regions have been implicated in lung cancer development and progression. However, many of the target genes remain unknown. For these reasons, there has been much excitement recently regarding the application of a new technology, array-CGH, an important new genomic tool that permits high-resolution analysis (e.g. at ⩽1 megabase resolution) of chromosomal gains, losses, and DNA amplification within entire tumor genomes (Snijders et al., 2001). These arrays permit the use of evenly distributed DNA clones, including those representative of known cancer genes, for direct copy number assessment. Thus, we are at the beginning of a new era. The combined application of array-CGH, cDNA microarrays, and tissue microarrays will facilitate the integration of genomic and expression data and pave the way toward a molecular classification of lung carcinomas.
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This work was supported by NCI grants CA-58184 and CA-06927, by an appropriation from the Commonwealth of Pennsylvania, and by a gift from the Ann Ricci Memorial Fund. The authors thank Donna Black for assistance with the tabulations used in the preparation of the Figures.
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Balsara, B., Testa, J. Chromosomal imbalances in human lung cancer. Oncogene 21, 6877–6883 (2002). https://doi.org/10.1038/sj.onc.1205836
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