Virtual Karyotyping with SNP Arrays Identifies Chromosomal Imbalances as Biomarkers for Tumor Progression in Clear Cell Renal Cell Carcinoma
FA Monzon, K Alvarez, K Sircar, P Tamboli, E Jonasch. The Methodist Hospital, Houston, TX; University of Texas MD Anderson Cancer Center, Houston, TX
Background: As many as 20-30% patients with organ confined clear cell renal cell carcinoma (ccRCC) will develop metastases after nephrectomy. Antiangiogenic agents are a successful therapeutic modalities for metastatic RCC but currently there are no biomarkers of therapeutic efficacy with these agents. Chromosome copy number alterations frequent in renal tumors have been shown to be associated with poor prognosis (9p/14q deletions) or more favorable outcomes (5q31-ter gains). We have previously shown that virtual karyotyping is a reliable diagnostic tool that can help reduce uncertainty in the diagnosis of difficult renal tumors. In this study, the goal was to determine whether chromosomal imbalances identified with SNP arrays could be used as biomarkers for progression in metastatic ccRCC (mRCC).
Design: We obtained archival FFPE tumor samples 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 determined if there was any association between genetic lesions identified by virtual karyotyping and tumor outcome measures.
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). There was a nonsignificant trend toward a higher hazard of progression among patients who had loss of 9p or loss of 14q in the sorafenib cohort. 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).
Conclusions: Our results show that whole genome analysis with virtual karyotypes identifies genetic lesions that are associated with outcomes in metastatic RCC treated with novel anti-angiogenic agents. These results suggest that genomic analysis of renal tumors with SNP arrays can provide important predictive information for patients with mRCC. A larger study to confirm our findings are studies to identify potential mechanisms that explain these associations are underway.
Category: Genitourinary (including renal tumors)
Monday, March 22, 2010 11:30 AM
Platform Session: Section A, Monday Morning