Abstract
Purpose – One of the current key dilemmas in the management of metastatic renal cell carcinoma (mRCC) is the manifestation of innate or acquired resistance to anti-angiogenic therapy. Currently there are no biomarkers of therapeutic efficacy for antiangiogenic agents in clear cell renal cell carcinoma (ccRCC). Loss of chromosomal arm 14q has been previously associated with poor outcomes in surgically treated patients. We evaluated the association between 14q loss and therapeutic resistance in metastatic ccRCC (mRCC) and explored the role of candidate effector genes on this chromosome.
Experimental Design – DNA from archival FFPE tumor specimens from 56 mRCC patients treated with sorafenib or bevacizumab was analyzed with Affymetrix 250K Nsp SNP microarrays. We identified the presence of genomic imbalances focusing on the presence of 14q loss. We then evaluated candidate genes in chromosome 14 by qPCR and immunohistochemistry (IHC) in the bevacizumab treated cohort.
Results – 14q loss showed a significant association with worse response (SDPD vs. CRPR) in bevacizumab cohort (Fisher's exact test, p=0.0473), and with shorter progression free survival (PFS) in the sorafenib cohort (p=0.0318). HIF1A mRNA expression was significantly reduced in specimens with loss of 14q and was associated with PFS in the bevacizumab treated cohort (p=0.045). HIF-1alpha protein expression was also reduced in samples with 14q loss.
Conclusions – Our studies demonstrate an association between a specific chromosomal alteration (14q loss) and clinical outcome in patients with advanced renal cell carcinoma treated with antiangiogenic agents. Loss of 14q was also associated to changes in the expression of HIF1A. Low HIF1A expression was strongly correlated with shorter PFS. We hypothesize that loss of 14q could lead to an imbalance in HIF-1α/HIF-2α activity, leading to increased HIF-2α, which has been shown to improve tumor cell viability by upregulating various pro-survival pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3491. doi:10.1158/1538-7445.AM2011-3491
- ©2011 American Association for Cancer Research
Volume 71, Issue 8 Supplement
