ALK Alterations in Adult Renal Cell Carcinoma

Frequency, Clinicopathologic Features and Outcome in a Large Series of Consecutively Treated Patients

William R Sukov; Jennelle C Hodge; Christine M Lohse; Monica K Akre; Bradley C Leibovich; R Houston Thompson; John C Cheville

Disclosures

Mod Pathol. 2012;25(11):1516-1525. 

In This Article

Abstract and Introduction

Abstract

Chromosomal rearrangements involving the anaplastic lymphoma kinase gene (ALK) at 2p23 result in fusion with various partner genes leading to aberrant production of oncogenic protein products in multiple tumor types. Recently, the ALK protein inhibitor crizotinib was shown to be an effective therapy in patients with ALK-rearranged non-small cell lung cancer. The goal of this study was to determine the frequency of ALK alterations in adult renal cell carcinoma (RCC) and define associated clinicopathologic features and outcome. RCCs from a cohort of 534 consecutive surgically treated adult patients were analyzed for alterations of ALK by fluorescence in situ hybridization. ALK rearrangements were identified in 2 of 534 (<1%) RCCs. Both showed similar histologic features and the patients had a poor outcome. ALK copy number gain was identified in 54 (10%) RCCs. In clear cell type RCC (CCRCC), ALK copy number gain was significantly associated with tumor size (P=0.02) and nuclear grade (P<0.001), and with a worse 10-year cancer-specific survival vs similar patients lacking ALK copy number gain (P=0.03). ALK rearrangement is rare in adult RCC but may be associated with distinct histological features and poor outcome. Another potential mechanism to elevate ALK expression, increased ALK gene copy number, was observed in 10% of adult CCRCC, where it is associated with a higher tumor grade and poorer outcome. Additional studies are necessary to determine whether patients RCCs with ALK rearrangement and/or those with an increase in ALK copy number would benefit from ALK inhibitor treatment.

Introduction

Chromosomal rearrangements involving the anaplastic lymphoma kinase gene (ALK) at 2p23 were first recognized in anaplastic large cell lymphoma.[1] The characteristic translocation was shown to result in fusion of the 3′ portion of ALK with the 5′ portion of NPM1 at 5q35 to produce a chimeric oncogene.[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).[3–9]

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.[2] Chromosomal rearrangements resulting in ALK gene fusion lead to aberrant ALK activation by formation of chimeric protein products, which are expressed in a cytoplasmic and/or membranous distribution, depending on the fusion partner. The ALK fusion products have significant oncogenic activity.[10–14] Because of the expression pattern, ALK fusion products have become an enticing chemotherapeutic target. Recently, the ALK inhibitor crizotinib was shown to be an effective therapy in patients with ALK-rearranged non-small cell lung cancers.[15–17]

The present study involved screening RCCs from a large cohort of surgically treated adult patients from a single institution for ALK alterations. The goal was to define the frequency of ALK alterations, including rearrangements and copy number gain, in a comprehensive manner. Additionally, we wished to identify the associated clinical and pathological features as well as any relationship between patient outcome and ALK locus alteration.

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