Renal cell carcinoma with novel VCL-ALK fusion

New representative of ALK-associated tumor spectrum

Larisa V. Debelenko, Susana C. Raimondi, Najat Daw, Bangalore R. Shivakumar, Dali Huang, Marilu Nelson, Julia A. Bridge

Research output: Contribution to journalArticle

135 Citations (Scopus)

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′ rapid amplification of cDNA ends analysis of this tumor revealed that the 3′ portion of the ALK transcript encoding for the kinase domain was fused in frame to the 5′ portion of vinculin (VCL, NM-003373). The new fusion gene is predicted to have an open reading frame of 4122 bp encoding for a 1374-aa oncoprotein; its expression was shown by immunoblotting with anti-VCL and anti-ALK antibodies in tumor tissue lysates. Immunohistochemistry with the same antibodies demonstrated cytoplasmic and subplasmalemmal localization of the oncoprotein determined by its N-terminal VCL portion. FISH with a custom-designed VCL-ALK dual-fusion probe set confirmed the presence of the fusion in neoplastic cells and demonstrated the potential clinical utility of this approach for detecting VCL-ALK in routinely processed tissue. The five remaining pediatric renal cell carcinomas did not show ALK rearrangement by FISH or ALK expression by immunohistochemistry. The data identify the kidney as a new organ site for ALK-associated carcinomas and VCL as a novel ALK fusion partner. The results should prompt further studies to advance the molecular classification of renal cell carcinoma and help to select patients who would benefit from appropriate targeted therapies.

Original languageEnglish (US)
Pages (from-to)430-442
Number of pages13
JournalModern Pathology
Volume24
Issue number3
DOIs
StatePublished - Mar 1 2011

Fingerprint

Renal Cell Carcinoma
Neoplasms
Fluorescence In Situ Hybridization
Oncogene Proteins
anaplastic lymphoma kinase
Immunohistochemistry
Pediatrics
Neoplasm Antibodies
Vinculin
Carcinoma
Gene Fusion
Esophageal Neoplasms
Immunoblotting
Colonic Neoplasms
Open Reading Frames
Young Adult
Lung Neoplasms
Phosphotransferases
Complementary DNA
Breast Neoplasms

Keywords

  • ALK
  • FISH
  • VCL
  • fusion gene
  • renal cell carcinoma
  • translocation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Debelenko, L. V., Raimondi, S. C., Daw, N., Shivakumar, B. R., Huang, D., Nelson, M., & Bridge, J. A. (2011). Renal cell carcinoma with novel VCL-ALK fusion: New representative of ALK-associated tumor spectrum. Modern Pathology, 24(3), 430-442. https://doi.org/10.1038/modpathol.2010.213

Renal cell carcinoma with novel VCL-ALK fusion : New representative of ALK-associated tumor spectrum. / Debelenko, Larisa V.; Raimondi, Susana C.; Daw, Najat; Shivakumar, Bangalore R.; Huang, Dali; Nelson, Marilu; Bridge, Julia A.

In: Modern Pathology, Vol. 24, No. 3, 01.03.2011, p. 430-442.

Research output: Contribution to journalArticle

Debelenko, LV, Raimondi, SC, Daw, N, Shivakumar, BR, Huang, D, Nelson, M & Bridge, JA 2011, 'Renal cell carcinoma with novel VCL-ALK fusion: New representative of ALK-associated tumor spectrum', Modern Pathology, vol. 24, no. 3, pp. 430-442. https://doi.org/10.1038/modpathol.2010.213
Debelenko, Larisa V. ; Raimondi, Susana C. ; Daw, Najat ; Shivakumar, Bangalore R. ; Huang, Dali ; Nelson, Marilu ; Bridge, Julia A. / Renal cell carcinoma with novel VCL-ALK fusion : New representative of ALK-associated tumor spectrum. In: Modern Pathology. 2011 ; Vol. 24, No. 3. pp. 430-442.
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