Chromosome Instability in Human Lung Cancers: Possible Underlying Mechanisms and Potential Consequences in the Pathogenesis
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Oncogene (2002) 21, 6884 – 6897 ª 2002 Nature Publishing Group All rights reserved 0950 – 9232/02 $25.00 www.nature.com/onc Chromosome instability in human lung cancers: possible underlying mechanisms and potential consequences in the pathogenesis Akira Masuda1 and Takashi Takahashi*,1 1Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan Chromosomal abnormality is one of the hallmarks of isms that ensure genetic stability. Chromosome neoplastic cells, and the persistent presence of chromo- abnormalities can be classified broadly into numerical some instability (CIN) has been demonstrated in human (i.e., aneuploidy) and structural alterations (e.g., cancers, including lung cancer. Recent progress in deletion, translocation, homogenously staining region molecular and cellular biology as well as cytogenetics (HSR), double minutes (DMs)) of chromosomes. Such has shed light on the underlying mechanisms and the chromosomal alterations, which are indeed present in biological and clinical significance of chromosome most human tumors, are especially marked in solid abnormalities and the CIN phenotype. Chromosome tumors, including lung cancer, but the underlying abnormalities can be classified broadly into numerical mechanisms and the biological and clinical significance (i.e., aneuploidy) and structural alterations (e.g., dele- have not been elucidated to any satisfactory degree. tion, translocation, homogenously staining region (HSR), However, recent progress in molecular and cellular double minutes (DMs)). However, both alterations biology as well as technical development in cytoge- usually occur in the same cells, suggesting some overlap netics has shed light on these important issues related in their underlying mechanisms. Missegregation of to cancer development and progression, providing chromosomes may result from various causes, including evidence for the involvement of failures in the cell defects of mitotic spindle checkpoint, abnormal centro- cycle checkpoint control and defects in the DNA some formation and failure of cytokinesis, while double-strand break (DSB) repair system in the genesis structural alterations of chromosomes may be caused of chromosome instability (CIN). especially by failure in the repair of DNA double-strand In the present article, we will give a brief overview of breaks (DSBs) due to the impairment of DNA damage chromosomal alterations thus far reported in lung checkpoints and/or DSB repair systems. Recent studies cancer, and then summarize recent progress in the also suggest that telomere erosion may be involved. The understanding of possible underlying mechanisms of consequential acquisition of the CIN phenotype would CIN and its potential involvement in the development give lung cancer cells an excellent opportunity to of lung cancer, with reference to recent findings in the efficiently alter their characteristics so as to be more analysis of other human cancers as well as in those of malignant and suitable to their microenvironment, there- various organisms such as mice and yeast. by gaining a selective growth advantage. Oncogene (2002) 21, 6884 – 6897. doi:10.1038.sj.onc. 1205566 Numerical and structural chromosome abnormalities in human lung cancer Keywords: chromosome instability; cell cycle check- point; DNA double-strand break; telomere; lung Early in the 20th century, Theodor Boveri described cancer abnormal mitosis and chromosomal changes in cancers, and hypothesized that malignancy of the mammalian somatic cells resulted from an abnormal Introduction chromosomal constitution (Boveri, 1914). Later on, Philadelphia chromosome (Ph1) was identified in the High fidelity DNA replication and faithful chromo- majority of chronic myelocytic leukemia (CML), some segregation are fundamentally essential processes supporting Boveri’s hypothesis. To date, a large allowing cells to transmit their genetic information to number of additional non-random chromosomal the descendants. Failures in maintaining genetic translocations have been identified especially in tumors stability may cause their death or such abnormal of hematopoietic lineage (Heim and Mitelman, 1989). phenotypes as malignancy. Cancer cells frequently In contrast, in most malignancies of epithelial origin, exhibit marked chromosome abnormalities, which are including lung cancer, studies on the possible involve- generally considered to reflect defects in the mechan- ment of chromosomal alterations in carcinogenesis were hampered by technical limitations. Conventional karyotyping analysis principally requires the presence *Correspondence: T Takahashi; E-mail: [email protected] of mitotic cells in their preparations, but primary solid Chromosome instability in lung cancer A Masuda and T Takahashi 6885 tumors often provide too few mitotic cells. Further- random losses and gains of particular chromosomal more, the presence of very complex karyotypes in solid portions even in solid tumors. CGH enables precise tumor cells from numerical and structural points of analysis of losses and gains of chromosomal segments view often made it difficult to accomplish the by competitive hydridization between cancer and karyotyping analysis satisfactorily. In human lung normal DNAs on a karyotype spread of normal cells, cancer, nearly all cases show complex karyotypes with and thus does not require the abundant presence of multiple structural and numerical abnormalities (Testa mitotic cells in primary cancer cells (Kallioniemi et al., and Siegfried, 1992; Testa, 1996). Approximately 70 – 1992). CGH studies have revealed novel and histolo- 80% of lung cancer cases carry from a near triploid to gical type-specific gains and losses of chromosome tetraploid ranges of karyotypes with various structural segments in human lung cancers (Schwendel et al., abnormalities including deletion, non-reciprocal trans- 1997; Levin et al., 1994, 1995; Petersen et al., 1997a,b), location and isochromosome. DMs are also observed in addition to those previously reported by conven- in 20 – 30% of small cell lung cancer (SCLC) and 10 – tional cytogenetic approaches. 20% of non-small cell lung cancer (NSCLC). SKY is also a powerful technique, which is based on Fluorescence activated cell sorter (FACS) and image 24-color, whole chromosome-painting assay (Liyanage cytometric analyses can assess any overall increase or et al., 1996; Veldman et al., 1997). SKY makes it decrease in the DNA content of a tumor cell, not only possible to detect subtle karyotypic alterations, which in the mitotic phase, but also in the interphase, even would be otherwise overlooked, as well as to identify with fixed and paraffin-embedded specimens. Numer- the chromosomal origins of abnormalities, which ous studies have been reported on the relationships would have been designated merely as a ‘marker between abnormal DNA content reflecting aneuploidy chromosome’ in conventional karyotyping analysis. and various clinical features including histological type, To date, only a few SKY studies have been reported clinical stage, sensitivity to chemotherapy, and prog- in lung cancers, but these have resulted in the nosis. Although most of such studies have identification of a greater degree of chromosomal demonstrated the presence of markedly abnormal rearrangements than those detected by previous G- DNA contents in 65 – 85% of NSCLC and SCLC, banding and CGH analyses (Luk et al., 2001; Dennis the relationship between aneuploidy and patient and Stock, 1999). survival remains controversial. In this connection, As a consequence, it has become evident that the Choma et al. (2001) recently conducted a meta-analysis losses and gains of chromosomes in lung cancer are not of data obtained with 4033 NSCLC patients in 35 random. It is also notable that although lung cancers previously published studies, demonstrating that do share similar chromosomal abnormalities in patients with tumors with abnormal DNA content common, they also have certain histologic type-specific had a significantly shorter survival duration than those characteristics of chromosomal abnormalities. The with normal DNA content reflecting diploid or short arm of chromosome 3 (3p) was among the first psuedodiploid chromosomes. In contrast, the prognos- to be identified as a non-randomly affected chromoso- tic value of the degree of abnormal DNA ploidy does mal region in lung cancer (Whang-Peng et al., 1982). In not seem to be evident in SCLC (Oud et al., 1989; addition to 3p, it has been reported that chromosomal Jackson-York et al., 1991; Viren et al., 1997). gains are frequent in 5p, the long arm of chromosome Fluorescence in situ hybridization (FISH) analysis 8 (8q), 17q and 19q in NSCLC and 3q, 5p, 8p and Xq with centromeric probes of a specific chromosome(s) in SCLC, whereas chromosome losses are frequent in can obtain information of losses and gains of the 1p, 4q, 5q, 6q, 8p, 9p, 13q and 17p in NSCLC and 5q, specific chromosome in each cell of a whole tissue 13q and 17p in SCLC (Schwendel et al., 1997; Levin et section or cultured cells. Although it has been al., 1994, 1995; Petersen et al., 1997a,b; Michelland et suggested that cancer cells possess persistent CIN al., 1999). based on observations of the karyotypic heterogeneity There is considerable circumstantial evidence for even within the same tumor, it has remained rather the involvement of CIN in the initiation, progression, ambiguous as to whether chromosomes in cancer cells and metastasis of human malignancies. Notable are indeed unstable, which would