Abstract
BackgroundA subset of lung adenocarcinomas harboring an EML4-ALK fusion gene resulting in dominant oncogenic activity has emerged as a target for specific therapy. EML4-ALK fusion confers a characteristic histology and is detected more frequently in never or light smokers and younger patients.MethodsTo gain insights into etiology and carcinogenic mechanisms we conducted analyses to compare allelotypes of 35 ALK fusion-positive and 95 -negative tumours using single nucleotide polymorphism (SNP) arrays and especially designed software which enabled precise global genomic profiling.ResultsOverall aberration numbers (gains + losses) of chromosomal alterations were 8.42 and 9.56 in tumours with and without ALK fusion, respectively, the difference not being statistically significant, although patterns of gain and loss were distinct. Interestingly, among selected genomic regions, oncogene-related examples such as 1p34.3(MYCL1), 7q11.2(EGFR), 7p21.1, 8q24.21(MYC), 16p13.3, 17q12(ERBB2) and 17q25.1 showed significantly less gain. Also, changes in tumour suppressor gene-related regions, such as 9p21.3 (CDKN2A) 9p23-24.1 (PTPRD), 13q14.2 (RB1), were significantly fewer in tumours with ALK fusion.ConclusionGlobal genomic comparison with SNP arrays showed tumours with ALK fusion to have fewer alterations in oncogenes and suppressor genes despite a similar overall aberration frequency, suggesting very strong oncogenic potency of ALK activation by gene fusion.
Highlights
A subset of lung adenocarcinomas harboring an EML4-ALK fusion gene resulting in dominant oncogenic activity has emerged as a target for specific therapy
We have revealed that ALK fusion-positive tumours constituted a particular subset in lung adenocarcinomas in terms of clinical characteristics, histology and etiology, as well as molecular changes [7,8]
Distribution of histological subtypes differed between two groups, namely, “acinar” subtype accounted for nearly forty percent in ALK fusion positive group (Table 1)
Summary
A subset of lung adenocarcinomas harboring an EML4-ALK fusion gene resulting in dominant oncogenic activity has emerged as a target for specific therapy. EML4-ALK fusion confers a characteristic histology and is detected more frequently in never or light smokers and younger patients. The adenocarcinoma is the most common form of lung cancer worldwide, different subsets having specific genetic backgrounds of great importance for molecular-targeted therapy. Somatic mutations of the epidermal growth factor receptor (EGFR) are especially prevalent in adenocarcinomas among never smokers, females, and those with Asian ethnicity [1]. Since the tyrosine kinase is involved and activated by gene fusion, this type of malignancy has emerged as a target for anti-tyrosine kinase therapy [4,10,11,12]
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