SUO 2018: Hereditary Kidney Cancer and Genetic Testing

Phoenix, Arizona ( Dr. Maria Carlo gave a brief overview of the more common and less common renal hereditary cancer syndromes and some guidelines on when should patients be referred for genetic testing. Figure 1 demonstrates the prevalence of germline mutations in renal cell carcinoma (RCC) cases in the cancer genome atlas (TCGA). A total of 6%, 9% and 6% of all clear-cell, papillary, and chromophobe RCC cases, respectively are a germline mutation. The most frequently mutated genes are VHL and BAP1 in clear cell, FH and MET in papillary, and CHEK2, NF1, MSH6 in chromophobe.

UroToday Prevalence of germline mutations in renal cell carcinoma cases in the cancer Genome Atlas
Figure 1 – Prevalence of germline mutations in renal cell carcinoma cases in the Cancer Genome Atlas:

The recommended referral indications for genetic assessment include:

  1. Clear cell RCC with either:
    • Age < 50
    • Bilateral or multifocal tumors
    • >=1 close relative with clear cell RCC
  2. Papillary type 1 or 2
  3. Collecting duct histology
  4. Tubulopapillary histology
  5. Birt-Hogg Dube related histology (Chromophobe, oncocytoma, oncocytic hybrid)
  6. RCC with 2 additional features of Cowden syndrome (PTEN germline mutations)
  7. Angiomyolipomas and one additional feature of tuberous sclerosis:
Next, Dr, Carlo discussed the hereditary Leiomyomatosis and RCC (HLRCC) syndrome, which is associated with germline mutations in FH, encoding for an enzyme in the Krebs cycle. There is also an associated 10-20% lifetime risk of RCC (papillary type 2/HLRCC-associated RCC). It is commonly associated with uterine fibroids (nearly 100% penetrance), and skin leiomyomas. The associated small renal tumors can metastasize and tend to have a poor prognosis. HLRCC is common in patients with advanced non-clear cell RCC, and the pathology is not always informative. The combination of Bevacizumab and erlotinib or everolimus has been assessed in HLRCC-associated RCC. Bevacizumab+erlotinib demonstrate an overall response rate of 65%.

BAP1-hereditary cancer syndrome is associated with germline mutations in BAP1, which encodes a deubiquitinase. It increases the risk of uveal and cutaneous melanoma, renal cell carcinoma, pleural and peritoneal mesothelioma, and possibly other cancers.

Lastly, Dr. Carlo mentioned the hereditary paraganglioma-pheochromocytoma syndrome, which is associated with germline mutations in SDHA, DHB, DHC, SDHD, and SDHAF. These encode for a Krebs cycle enzyme.  In this syndrome, there is an increased risk of pheochromocytoma, GIST tumors and SDH-deficient RCC. The highest risk of RCC is in carriers of SDHB. Patients should be referred for genetic assessment if they have:

  • Pheochromocytoma or paraganglioma
  • RCC with a family history of pheochromocytoma or paraganglioma
  • SDH-deficient RCC

Presented by: Maria Carlo, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New-York, NY

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow, SUO, University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan, at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona