Metastatic papillary renal cell carcinoma (pRCC) is invariably lethal. Receptor tyrosine kinase inhibitors such as sunitinib malate are demonstrated to prolong survival but resistance is inevitable and clinical responses greater than one year are very rare. Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare inherited disorder caused by germline mutation to the fumarate hydratase (FH) gene and characterized in part by FH-deficient pRCC tumors that are particularly aggressive. We present a remarkable case of FH-deficient metastatic pRCC who has experienced an 8 year complete response to receptor tyrosine kinase inhibitors sunitinib malate and pazopanib. We performed exome sequencing on her primary and metastatic tumors and reveal relevant genomic alterations including amplification of the growth factor effector GRB2, and mutations to critical DNA damage repair genes that are not normally perturbed in pRCC or indeed renal cell carcinoma (RCC) in general. We posit that defects to these genes and pathways could influence the response of RCC to RTK inhibitors, and that other RCC patients with strong response to therapy should be evaluated for similar genomic aberrations.
- DNA damage repair
- fumarate hydratase
- hereditary leiomyomatosis and renal cell cancer