BETHESDA, MD USA (UroToday.com) - Dr. Eric Jonasch presented his group’s work at MD Anderson Cancer Center for the Kidney SPORE program. He highlighted four different projects that are ongoing, and they are as follow:
- Modulating proteostasis (“fix broken VHL to refunctionalize it”);
- Novel function of SETD2 pathway;
- Epigenetic drivers of RCC; and
- Targeting AXL signaling in RCC.
He subsequently focused on the RCC tumor ontogeny. RCC comprises 3% of all malignancies. It remains asymptomatic until it reaches advanced stage. Prognosis is proportionate to size in this disease. He poses the question—why is it that clear cell RCCs are virtually never lethal if less than 3cm in size (current standard of care to observe in VHL patients and in some sporadic RCC)? He hypothesizes that lethality-producing events have yet to occur in these smaller tumor, but tumor-initiating events have already occurred. He argues that factors cooperate with biallelic VHL loss to induce ccRCC, but additional events need to happen.
The conundrum in the study of genomic changes in small renal masses was that The Cancer Genome Atlas (TCGA) tissue requirements resulted in a dearth of small renal mass. Therefore, they initially investigated genomic changes in 2 VHL patients with small renal masses.
One VHL patient had a nephrectomy done for a central 6 cm mass and also had 3 additional small renal masses. Another VHL patient had 2 small tumors (3.5 cm on left and another 3.5 cm on right) and underwent partial nephrectomies. Surprisingly, on genomic analysis, over l 000 somatic mutations were seen in these tumors, but none of these mutations overlapped in any of the tumors. Most mutations were “private.” No mutations were seen in SETD2, PBRM1, or BAP1 (which are known drivers of invasiveness). These results were then also studied and confirmed in 2 other patients with sporadic RCC.
In all of these small renal masses, VHL and 3p loss was universal. However, the question remained about other drivers that promote lethality when there are up to 70-150 private mutations in individual tumors They then investigated whether DNA damage may be responsible. They found that RCC samples showed that ATR is activated, whereas ATM is not, suggesting that single-strand breaks dominate.
In conclusion, the group is planning ongoing experiments that will further define the underlying DNA repair defect in RCC. The hope is that these findings will permit development of prevention/early intervention strategies in sporadic and hereditary RCC when the tumors are still small.
Presented by:
Eric Jonasch, MD
University of Texas MD Anderson Cancer Center, Houston, TX USA
Reported by:
Mohammed Haseebuddin, MD* from the 2014 Winter Meeting of the Society of Urologic Oncology (SUO) "Defining Excellence in Urologic Oncology" - December 3 - 5, 2014 - Bethesda, MD USA
*Fox Chase Cancer Center, Philadelphia, PA USA