Renal cell carcinoma with novel VCL–ALK fusion: new representative of ALK-associated tumor spectrum

Abstract

Renal cell carcinoma represents a model for contemporary classification of solid tumors; however, unusual and unclassifiable cases exist and are not rare in children and young adults. The anaplastic lymphoma kinase (ALK) gene has recently been implicated in subsets of pulmonary, esophageal, breast, and colon cancers. These findings strengthen the importance of molecular classification of carcinomas across different organ sites, especially considering the evolving targeted anticancer therapies with ALK inhibitors. In the current study of six pediatric renal cell carcinomas, two cases exhibited structural karyotypic abnormalities involving the ALK locus on chromosomal band 2p23. Fluorescence in situ hybridization (FISH) studies were positive for an ALK rearrangement in one case, and subsequent 5 0 rapid amplification of cDNA ends analysis of this tumor revealed that the 3 0 portion of the ALK transcript encoding for the kinase domain was fused in frame to the 5 Keywords: ALK; FISH; fusion gene; renal cell carcinoma; translocation; VCL Renal cell carcinoma has an incidence of 209 000 cases per year and is responsible for 102 000 deaths worldwide annually. 1,2 Approximately 80% of all renal carcinoma cases are currently classified as clear cell, papillary, or chromophobe subtypes with discrete molecular abnormalities characteristic for each group. 2-7 Rare subtypes have also been defined by the 2004 World Health Organization classification and include collecting duct, multilocular cystic, mucinous tubular and spindle cell, medullary, and Xp11.2 translocation-and neuroblastoma-associated carcinomas; each of these subtypes constitutes B1% of all primary kidney epithelial tumors and the three latter subtypes are diagnosed predominantly in children. 8,9 Additional

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 rearrangement and overexpression in epithelioid fibrous histiocytoma

“…Modern Pathology (2015) 28, 904-912 ALK in epithelioid fibrous histiocytoma clinically aggressive group of renal cell carcinomas arising in young patients with sickle cell trait, [21][22][23] and SQSTM1-ALK in two cases of ALK-immunoreactive large B-cell lymphoma. 24,25 Activated ALK, usually in the form of highly expressed chimeric oncoproteins, is the main oncogenic driver of these neoplasms, which are hence sensitive to therapeutic inhibition with ALK-specific small molecule inhibitors.…”

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

“…19 Rearrangement of ALK has recently been reported in pediatric RCC. 20,21 However, to our knowledge, no study has yet studied ALK alterations in a large series of adult RCC. The goal of the present study was to comprehensively analyze alterations of the ALK locus, specifically rearrangements and copy number gain, in adult RCC to identify the frequency and nature of ALK alterations and to determine if there was a relationship between these alterations and clinical or pathological findings and/or clinical behavior.…”