Recurrent chromosome translocation has been accepted to play an important role in the pathogenesis of hematological malignancies, but not of solid tumours. Recently, however, chromosome rearrangements in solid tumours such as prostate cancer and non-small cell lung cancer have been reported
. ALK fusion was originally described in anaplastic large-cell lymphoma as a chimeric protein NPM-ALK resulting from a translocation. More recently, evidence has accumulated that the EML4-ALK fusion gene defines a novel subclass of lung adenocarcinomas with distinct clinicopathological features
[7–9], so that it has emerged as a target for therapy. We focused here for the first time on allelic imbalance of tumours with ALK fusion with a novel technique which has already shown the involvement of loss of A20 function in the pathogenesis of a subset of B-cell lymphomas
 and gain of function of C-CBL tumour suppressor in myeloid neoplasms
. Applying this methodology, we demonstrated that lung adenocarcnomas with ALK fusion feature less amplification of loci with oncogenes and fewer deletions of loci related to tumour suppressor genes, although global chromosome aberrations were similar between tumours with and without ALK fusion. suggesting that the fusion gene is a driver mutation, not just a passenger mutation.
Genetic instability was here categorized into two groups for simplicity, at the chromosomal level and at the nucleotide level. We earlier found the former to play a more important role in lung carcinogenesis, the frequency of LOH (loss of heterozygosity) being higher in less-differentiated tumours
. ALK fusion positive tumours are more common among non-smokers and the younger population, similar to those with EGFR mutations. We had expected fewer chromosome aberrations in ALK fusion-positive tumours because tumours arising in such people usually harbor less LOH and a lower TP53 mutation rate than smokers
[36–38]. Contrary to our expectation, the global copy number changes at the chromosomal arm level did not differ between the two groups, although significant differences of alteration frequency at the individual chromosomal arms were seen. In addition, only ALK fusion-negative tumours showed an increase of the frequency of chromosome arm gain with the advancement of disease stage. Furthermore, at the smaller-genomic scale level, ALK fusion-positive tumours were less amplified at the loci containing EGFR family genes, 7p11.2 (EGFR), 17q12 (ERBB2) and other loci, 1p34.3 (MYCL), 7p21.1, 8q24.21 (MYC), 16p13.3 and 17q25.1. EGFR and ERBB2 play important roles by dimerizing when their ligands binds to produce downward growth signals to the tumour cells. Mutations and activation of these genes may drive carcinogenesis
, and increased expression is associated with a poor prognosis in NSCLCs
[40–43]. ALK fusion positive tumours are speculated to be less dependent on the actions of oncogenes and tumour-suppressor genes induced by copy number changes. Our results may also indicate that there is common and frequent chromosome abnormality in lung adenocarcinomas independent of ALK fusion, such as the 5p15.33 region, including TERT.
As for genomic loss, 9p21.3 (CDKN2A), 9p23-p24.1 (PTPRD) and 13q14.2 (RB1) were significantly less frequently deleted in ALK fusion-positive tumours. Homozygous deletion was seen only at 9p21.3 including CDKN2A and limited to EGFR-mutated tumours among ALK fusion-negative neoplasms as reported in the literature
 and also seen in ALK-fusion positive ones. That deletion of 9p23-24.1 and 13q14.2 including tumour suppressor genes was rare in ALK fusion-positive tumours suggests that they can grow even if the functions of these suppressor genes are retained.
Of all the selected loci, 5p15.33 containing TERT (telomerase reverse transcriptase isoform 2) showed the highest frequency of recurring gain regardless of ALK fusion. The enzyme is important for telomere regeneration and maintenance resulting in a growth advantage and Zhang et al. reported that the locus is a frequent target of amplification during tumourigenesis
. Copy number gain of this locus significantly correlates with telomerase activity
 and is one of the most consistent alterations in the early stages of non-small cell lung cancer
. In addition, increased susceptibility to lung cancer development associated with a SNP polymorphism of this locus has been reported
[48, 49]. The fact that most human tumour cells have telomerase activity indicates that its acquisition is vital for carcinogenesis and cell immortalization, and it might explain the reason why lung adenocarcinomas with or without ALK fusion shows similar frequency of copy number gain of this locus.
Our results have some therapeutic relevance. The fact that there are less involvement of other oncogenes and tumor suppressor genes may be related to dramatic responses to targeted drugs because of intact cellular processes including apoptosis pathways. In this regard, there is an interesting paper by Camidge et al.
, demonstrating the inverse relationship between fused and isolated red copy number on FISH might suggest the ALK fusion positive tumor was a “near-diploid” subtype of non-small cell lung cancer. Comparing closely, however, between their and our results, our study clearly revealed the overall frequency of chromosome aberrations are similar between ALK fusion positive and negative tumors, suggesting not “near-diploid”. But, certainly, we need more investigations on genomic instability of ALK fusion positive tumors.
It is well known that smoking causes genomic changes with allelic imbalance
. As shown in Table
1, smokers dominate never smokers in the group without fusion whereas the fusion-positive group has more never smokers than smokers. Since the tumors without ALK fusion include EGFR-mutated tumors, most of which are from never smokers, the ALK fusion-negative group is certainly heterogeneous. In due course, a study that describes comparisons of allelotypes of non-smoker’s tumors between with ALK fusion and with EGFR mutation should be warranted.