Germline Testing in Kidney Cancer

First, the doctors explain basic information about germline mutations and kidney cancer. Although historical data has shown that 5% of kidney cancers are inherited, recent efforts to increase testing through commercial testing and large scale efforts at cancer centers have proven that 8-10% of kidney cancers are inherited. Von Hippel Lindau (VHL) syndrome is the most prototypical kidney cancer predisposition syndrome, but there are other less common ones as well. Extrarenal manifestations of VHL syndrome include pancreatic tumors, pancreatic cysts, pheochromocytomas, retinoblastomas, and CNS hemangioblastomas. These tumors have a variable penetrance, but African Americans and women are more likely to have hereditary RCC. The doctors recommend asking newly diagnosed RCC patients about a broad spectrum of their family history that includes cancer and non-malignant conditions, such as uterine leiomyomata. Dr. Hakimi notes that some patients will confuse germline testing with somatic tumor testing, so urologists will have to explain to patients that the VHL mutation was found in their tumor, not in their blood or saliva.

Extended physical exams to look for syndromic conditions can also be performed. A thorough cutaneous exam to look for fibrofolliculomas, leiomyomas, facial angiofibromas, and cafe-au-lait spots can help indicate the presence of a familial syndrome. According to guidelines, all patients diagnosed with RCC under 46 years of age should be recommended to have germline testing. Dr. Bagrodia mentions that having experienced genetic counselors and setting up thorough dot phrases to send to patients explaining their results is helpful for him. Dr. Singla adds that medical geneticists have the ability to counsel the patients more extensively on the risks and benefits of giving consent to go forward with genetic testing. They can also provide psychosocial support and education for the patients.

The doctors then move on to discuss how germline mutations may lead to different treatment modalities. Precision surgery, or utilizing pretest probability information about a tumor to guide surgical approach, may be possible with germline testing. Additionally, testing may help surgeons to decide whether to perform a retroperitoneal lymph node dissection (RPLND). Next, the doctors discuss belzutifan, which is an oral drug used to treat VHL familial syndrome tumors. Finally, they discuss the use of tumor sequencing for research purposes and share what they are most excited for in the field of RCC research.