Detection Of DNA Copy Number Changes And Oncogenic Signaling Abnormalities From Gene Expression Data Reveals MYC Activation In Renal Cell Carcinoma

- Genetic studies of familial renal cell carcinoma (RCC) syndromes identified that c-met (type I papillary RCC) and fumarate hydratase (type II papillary RCC) are mutated and contribute to disease progression and metastasis. Whether these gene alterations are important in cases of sporadic papillary RCC remains controversial. Some investigators have suggested that mutations in c-met and fumarate hydratase are quite rare in sporadic papillary RCC. Here, Furge and colleagues out of the Van Andel Institute, Grand Rapids demonstrate that myc amplification and activation is an important molecular event in the biology of high grade type II papillary RCC.


The authors point out that 60-70% of papillary RCC are type I, typically of low grade and associated with a favorable outcome, whereas type II papillary RCC is associated with higher grade, more aggressive tumors and a worse prognosis. Using Affymetrix technology, the authors performed gene array on samples of RCC including 22 type I papillary, 13 type II papillary, and 31 clear cell RCC. In contrast to clear cell RCC, papillary RCC samples did not demonstrate predominant VHL or hypoxia related pathway signatures. Transcriptional activity was significantly increased on chromosome 8q in the type II papillary samples and gene array data demonstrated a myc activation signature in this group (the myc gene is located on chromosome 8q24). Fluorescent in situ hybridization (FISH) analysis demonstrated amplification of the 8q chromosome 33% of high grade type II papillary tumors, and immunohistochemistry for myc demonstrated increased expression at the protein level in 100% of type II papillary RCC. Myc activation and over expression was associated with higher grade tumors (p=0.01) and a worse survival (p=0.02). Furthermore, inhibition of myc expression in a cell line model of type II papillary RCC using siRNA technology, and pharmacologic inhibition of myc activity with a specific myc inhibitor (10058-F4) both inhibited cellular proliferation. Taken together, these data suggest that the myc pathway is an important mediator of tumor aggressiveness in sporadic type II papillary RCC.


The authors conclude that myc over expression is an important molecular event in type II papillary RCC. It is known that myc over expression is associated with increased genomic instability and it may be that myc activation may be the molecular switch that separates the biologic aggressiveness of type I from type II, despite the possibility of coming from a common ancestor. Myc should be further developed as a therapeutic target in papillary RCC.


Furge K.A, Chen J, Koeman J, Swiatek P, Dykema K, Lucin K, Kahnoski R,Yang X.J, Teh B.T


Cancer Res. 67(7):3171-6, April 2007.


doi: 10.1158/0008-5472.CAN-06-4571


Reported by Contributing Editor Christopher G. Wood, MD.


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