Chromosomal Imbalances Identify Pathways Associated with Resistance to Antiangiogenic Therapy in Clear Cell Renal Cell Carcinoma.
Federico A Monzon, Karla Alvarez, Leif Peterson, Kanishka Sircar, Pheroze Tamboli, Eric Jonasch. The Methodist Hospital, Houston, TX; The Methodist Hospital Research Institute, Houston, TX; MD Anderson Cancer Center, Houston, TX
Background: Antiangiogenic agents are used to treat metastatic clear cell renal cell carcinoma (ccRCC). Currently there are no biomarkers of therapeutic efficacy with these agents. We have previously shown that chromosome copy number alterations are associated with poor (14q loss) or more favorable outcomes (5q31-ter gain). In this study, we evaluated candidate genes that might be responsible for therapeutic resistance in metastatic ccRCC (mRCC). The genes evaluated were miR-143, an anti-oncomir located in 5q; and HIF-1alpha (HIF1A), a proangiogenic molecule located in 14q and often deregulated in ccRCC.
Design: We obtained archival FFPE tumor specimens from 56 patients with mRCC treated with sorafenib (after tumor removal) or bevacizumab (neoadjuvant treatment). DNA from the FFPE blocks was analyzed with Affymetrix 250K Nsp SNP microarrays. We identified the presence of genomic imbalances and loss of heterozygosity (LOH) to obtain “virtual karyotypes”. We then evaluated candidate genes in gain/lost chromosomal regions by qPCR and immunohistochemistry (IHC) in the bevacizumab treated specimens.
Results: Gain of 5q was strongly associated with longer progression free survival (PFS) in both sorafenib and bevacizumab treated cohorts (HR = 0.25, 95% CI 0.08 to 0.81, P = 0.021 and HR = 0.82 95% CI 0.65- 1, P < 0.0001 respectively). miR-143 showed higher expression in samples with 5q gain but it did not reach statistical significance (P > 0.05). In the bevacizumab cohort, 14q loss showed a significant association with worse response to treatment (CR or PR vs SD or PD, Fisher exact test, P = 0.0473). HIF1A mRNA expression was significantly reduced in specimens with loss of 14q and mRNA levels were associated with PFS (HR = 2.29, 95% CI = 1.01-5.16, P = 0.045). HIF-1alpha protein expression was also reduced in samples with 14q loss.
Conclusions: Our results show that chromosomal imbalances associated with outcomes in ccRCC lead to changes in the expression of miR-143 and 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 and enhanced c-Myc expression, which improves tumor cell viability by altering DNA damage repair mechanisms, and by upregulating various pro-survival pathways.
Category: Genitourinary (including renal tumors)
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 121, Wednesday Morning