Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non–Small Cell Lung Cancers

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. (Mol Cancer Res 2009;7(9):1466-76)

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

“…In some instances (FGFR2, ALK or NTRK1), overexpression of the TK gene was associated with amplification or translocation of the corresponding locus. The same genetic alterations have been previously reported in CRC cells and patients [26][27][28] , thus validating our approach. Our data further suggest that overexpression of TK sustains primary resistance to EGFR blockade, and could be used to identify patients unlikely to respond to cetuximab or panitumumab.…”

“…We decided to focus on TKs for which targeted agents are in clinical trial or are already approved for treatment, namely ALK, FGFR2, KIT, NTRK1, NTRK2, RET and PDGFRA. This analysis revealed that the overexpression of NTRK1 and FGFR2 is associated to molecular alterations, such as gene translocation (NTRK1) or gene amplification (FGFR2; Supplementary Figs 5 and 6), previously described in cellular models and in cancer patients [26][27][28] , thus validating the experimental approach. The other TK outlier genes were not previously reported in CRC cells.…”

Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK–Positive Anaplastic Large Cell Lymphoma

“…3), and at low frequency in other types of tumor, such as rhabdomyosarcoma (RMS; ref. 4), extramedullary plasmacytoma (5), renal cell carcinoma (6), thyroid cancer (7), basal cell carcinoma (8), breast cancer, and colorectal cancer (9,10). Moreover, aberrant activation or overexpression of full-length ALK has an oncogenic role in neuroblastoma (11,12) and glioblastoma multiforme (13,14).…”

ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients

“…2 Recurrent rearrangements of ALK have since been described with numerous partner genes in anaplastic lymphoma and other hematolymphoid malignancies as well as in solid tumors such as inflammatory myofibroblastic tumors, esophageal squamous cell carcinoma, breast carcinoma, colonic adenocarcinoma, lung adenocarcinoma and, recently, pediatric renal cell carcinoma (RCC). [3][4][5][6][7][8][9] The ALK protein is a membrane-associated tyrosine kinase belonging to the insulin receptor superfamily. Outside of the embryonic state, ALK expression is normally confined to the central nervous system.…”