Renal cell carcinoma survival predicted in genetic variants

December 1, 2009

Single nucleotide polymorphisms of the carbonic anhydrase 9 gene are found frequently in patients with metastatic renal cell carcinoma, and predict prognosis and response to immunotherapy.

Key Points

Orlando, FL-Single nucleotide polymorphisms (SNPs) of the carbonic anhydrase 9 (CA9) gene are found frequently in patients with metastatic renal cell carcinoma, and predict prognosis and response to immunotherapy, according to research presented at the American Society of Clinical Oncology annual meeting.

Identification of reliable predictors of response and survival is necessary to choose metastatic RCC patients most likely to respond to newer targeted drug therapies and cytokine-based immunotherapy.

"Molecular information such as protein or genetic data may improve patient selection," said Steven G. Wong, MD, assistant clinical professor of hematology/oncology at UCLA, who presented the study on behalf of first author Michela de Martino, PhD, a former urologic oncology fellow working with Arie Belldegrun, MD, and colleagues.

The CA9 gene is located on chromosome 9p12-13, a prognostically relevant chromosomal area, Dr. Wong said. It encodes for the CAIX protein, one of the most significant protein markers in metastatic kidney cancer.

"CAIX is not overexpressed in benign renal tissue, as opposed to malignant disease," he said.

In prior studies, high CAIX expression in clear cell RCC predicted a better prognosis after nephrectomy and a greater likelihood of response to interleukin-2-based immunotherapy.

In the study, 54 consecutive Caucasian patients who underwent radical nephrectomy for primary metastatic RCC had DNA extracted from tumor tissue. All exons of the CA9 gene were amplified by polymerase chain reaction and sequenced. CAIX protein expression was evaluated by immunohistochemistry.

The hypothesis was that SNPs of the CA9 gene are associated with CAIX expression, the response to IL-2, and survival.

CA9 SNPs were frequently detected, Dr. Wong reported. The c.210G>A reference SNP was found in 59%, the c.249T>C was found in 15%, the c.1081A>C in 11%, and the c.1584C>A in 33% of patients.

CAIX expression, survival linked

CAIX expression was high (>85%) in 65% of the patients. None of the SNPs was significantly associated with CAIX expression. However, "the c.249T>C SNP predicted overall survival," Dr. Wong said.

The median survival in patients with tumors with this SNP was 27.3 months, compared with 13.6 months in patients with tumors without the SNP (p=.043). Further, 57% of patients with the c.249T>C variant responded to IL-2, compared to 22% without this variant (p=.081).

High CAIX expression was associated with a longer median survival compared to low CAIX expression (25.5 vs. 8.5 months; p<.0001). Some 37% of patients with high CAIX expression responded to IL-2, compared to only 8% of those with low CAIX expression (p=.07).

On multivariate analysis, both c.249T>C and CAIX expression remained independent prognostic factors of overall survival.

The present study is the first to demonstrate such a finding in metastatic RCC and may represent a step forward in the integration of genetic and molecular data for patient treatment selection, Dr. Wong said.