The Chromatin Remodeling Gene, ARID1A, Is a New Prognostic Marker in Clear Cell Renal Cell Carcinoma
Samantha J Wala, Zsuzsanna Lichner, Andreas Scorilas, Nicole MA White, Andrew H Girgis, Lora Rotstein, Kimberly C Wiegand, Ashraf Latif, Christine Chow, David Huntsman, George M Yousef. Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada; University of Toronto, Toronto, Canada; University of Athens, Athens, Greece; British Columbia Cancer Agency and the University of British Columbia, Vancouver, Canada; Genetic Pathology Evaluation Centre, GPEC, Vancouver, Canada
Background: Clear cell renal cell carcinoma (ccRCC) is the most common tumor of the adult kidney with increasing incidence rate over the past years. Exome sequencing revealed that the SWI/SNF members, PBRM1 and ARID1A (encoding for the BAF250 protein), are mutated in ccRCC. It has also been suggested that aberrant chromatin regulation is a key step in kidney cancer pathogenesis.
Design: Samples were collected from consenting patients and were used according to a REB approved protocol. 145 cases of kidney cancer were used for tissue microarray construction. Immunohistochemistry was performed to assess for BAF250 expression. Relationships between continuous variables were assessed by Spearman correlation coefficient. The X-tile algorithm was used to generate an optimal cutoff point for BAF250a and prognostic cutoff point to dichotomize ARID1A mRNA using Monte Carlo p-value <0.05. Cox regression analysis and Kaplain-Meier curves were used for survival analysis. Normalized gene expression, normal kidney and overall survival data were acquired from publicly available databases. Copy-number data were quarried for ARID1A homozygous and hemizygous deletions in ccRCC from The Cancer Genome Atlas, and correlated with matched mRNA expression and survival data.
Results: We detected copy number loss of ARID1A in 16% of ccRCC cases. Immunohistochemistry indicated that 67% of ccRCC had significantly lower expression of BAF250a, the protein product of ARID1A, than the matched normal kidney. In-silico mRNA expression analysis of 404 ccRCC tumors and 167 normal kidney samples confirmed significant downregulation of ARID1A in 68.8% of the cases. We also demonstrated that decreased BAF250a protein and ARID1A mRNA expression correlate with tumor stage and grade; thus expression of both may predict for survival.
Conclusions: Our results indicate that both the protein and mRNA level of ARID1A are statistically significant prognostic markers for ccRCC. BAF250a immunohistochemistry is easy to perform and may serve as an adjuvant prognostic tool in the clinic.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 188, Tuesday Afternoon