Abstract
The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene has been identified as an oncogene in a subset of non-small cell lung cancers (NSCLC). We used profiling of cancer genomes on an exon array to develop a novel computational method for the global search of gene rearrangements. This approach led to the detection of EML4-ALK fusion in breast and colorectal carcinomas in addition to NSCLC. Screening of a large collection of patient tumor samples showed the presence of EML4-ALK fusion in 2.4% of breast (5 of 209), 2.4% of colorectal (2 of 83), and in 11.3% of NSCLC (12 of 106). Besides previously known EML4-ALK variants 1 (E13; A20) and 2 (E20; A20), a novel variant E21; A20 was found in colorectal carcinoma. The presence of an EML-ALK rearrangement was verified by identifying genomic fusion points in tumor samples representative of breast, colon, and NSCLC. EML4-ALK translocation was also confirmed by fluorescence in situ hybridization assay, which revealed its substantial heterogeneity in both primary tumors and tumor-derived cell lines. To elucidate the functional significance of EML4-ALK, we examined the growth of cell lines harboring the fusion following EML4 and ALK silencing by small interfering RNA. Significant growth inhibition was observed in some but not all cell lines, suggesting their variable dependence on ALK-mediated cell survival signaling. Collectively, these findings show the recurrence of EML4-ALK fusion in multiple solid tumors and further substantiate its role in tumorigenesis.
Highlights
Chromosomal translocations and their corresponding gene fusions play an important role in the initiation of tumorigenesis and have been strongly associated with distinct tumor subtypes [1]
As chromosomal translocations often lead to up-regulation of the fusion gene at the 3′ end, we developed a whole genome search algorithm to recognize potential gene fusion candidates with a discordant expression between 5′ and 3′ exons in one or more samples (Fig. 1)
The probability density distribution of the M scores for all examined genes was similar across colorectal, breast, and non–small cell lung cancers (NSCLC) samples showing the consistency of the scoring metric for different datasets (Supplementary Fig. S1A)
Summary
Chromosomal translocations and their corresponding gene fusions play an important role in the initiation of tumorigenesis and have been strongly associated with distinct tumor subtypes [1]. An increasing number of translocations have been identified in the past two decades using technologies based on fluorescence in situ hybridization Gene expression profiling of tumor samples coupled with a novel bioinformatics approach resulted in identification of a gene fusion between TMPRSS2 and ERG or ETV1 in the majority of prostate cancer samples [7]. The presence of TMPRSS2-ERG fusion in prostate was further confirmed by profiling patient tumor samples on exon arrays [8]. The feasibility of using exon array data for the detection of gene fusions has been shown, a more systematic approach is required when performing a global search for novel gene rearrangements across multiple cancer types
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