ASCO GU 2018: Homologous Repair Deficiency in VHL-mutated Clear Cell Renal Cell Carcinoma
Dr. Pilie and colleagues studied several tumors with whole exome sequencing, all of which had bi-allelic VHL loss. All of these tumors were early-stage tumors that already displayed high mutational burdens. They identified mutations in several apoptotic, DNA-damage response, and oncogenic gene pathways, all of which led to genomic instability.
Importantly, further analysis of these tumors and the TCGA data found that 67% of ccRCC tumors display deficiencies in homologous repair (HR) of DNA, and VHL-mutated tumors were more likely to be HR deficient. HR deficiency may indicate that these tumors are more susceptible to DNA damage and loss of viability. HR deficient signatures were significantly higher in early stage tumors, and these signatures also predicted better OS in multivariate analysis.
This may indicate that HR deficiency is a marker for tumor susceptibility to DNA damage and lack of viability -- characteristics which are lost the as the stage of the tumor increases. VHL loss clearly leads to genomic instability, and HR deficient (low-stage) tumors have improved OS compared to non-deficient counterparts. This opens the possibility of using the HR deficiency signature to identify patients who may benefit from DNA-damage repair inhibitors in future clinical studies. By identifying a possible pathway through which tumors increase in aggressiveness over time (by losing their HR deficient signature), we may now have a better understanding of how to attack these tumors before they lose their treatment susceptibility.
Presented by: Patrick Glen Pilie, MD; MD Anderson Cancer Center
Written by: Shreyas Joshi, MD, Fox Chase Cancer Center, Philadelphia, PA at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA