Presentation: Patient with renal cell cancer

A 47-year-old man is diagnosed with type II papillary renal cancer. There is no significant family history of cancer. You wish to undertake genomic testing and are considering what constitutional (germline) and/or somatic (tumour) genomic testing is appropriate for him.

Constitutional (germline) testing

• All patients diagnosed with renal cancer of any histology at or before the age of 40 years.
• All patients diagnosed with renal cancer before age 50 and a significant family history (first- or second-degree relative diagnosed with renal cancer before 50 years).
• All patients diagnosed with bilateral or multifocal renal cancer at any age.
• All patients under 50 years of age diagnosed with type II papillary renal cancer.
• Patients with renal cancer and other features of a renal cancer predisposition syndrome.

Somatic (tumour) testing

• Somatic testing of FH or SDHx (SDHA, SDHB, SDHC, SDHD) genes may be offered in cases where immunohistochemistry testing indicates loss of expression of the respective protein and where constitutional genomic testing has not identified an underlying causative constitutional pathogenic variant.
• Somatic testing of VHL, TCEB-1, TSC1/TSC2, MET or BRAF may be indicated to assist in diagnosis when morphology alone is inconclusive.
• Somatic testing for NTRK1, NTRK2 and NTRK3 fusion genes is available for metastatic renal cell cancer patients as a biomarker for treatment with an NTRK inhibitor when all other approved lines of treatment have been exhausted.
• All patients with solid tumours who have exhausted all standards of care testing and treatment are now eligible for whole genome sequencing (WGS) in order to explore clinical trial options.

• Consult the National Genomic Test Directory eligibility criteria to ensure your patient is eligible for testing using the inherited renal cancer panel (R224), which includes a number of genes associated with kidney cancer predisposition syndromes, many of which are associated with increased risks of other cancers and/or non-cancerous features. Many of the genes included on the inherited renal cancer panel may be tested as single gene tests or on overlapping panels.
• For information on the genes that are included on different gene panels for constitutional (germline) testing, see the NHS Genomic Medicine Service signed-off panels resource.
• Kidney cancer predisposition syndromes (and overlapping indications) include:
  • Fumarate hydratase (FH) related tumour syndromes (R365), including hereditary leiomyomatosis and renal cell cancer: autosomal dominant tumour predisposition syndromes associated with increased risks of kidney cancer (particularly type II papillary renal cancer), as well as uterine and cutaneous leiomyomatosis and, rarely, paraganglioma/phaeochromocytoma. Cutaneous and uterine leiomyosarcoma have very rarely been reported in carriers of pathogenic constitutional FH variants.
  • Von Hippel-Lindau (VHL) syndrome (R225): an autosomal dominant tumour predisposition syndrome associated with renal cell carcinoma, retinal angioma, spinal or cerebellar hemangioblastoma, adrenal or extra-adrenal pheochromocytoma, multiple renal and/or pancreatic cysts, endolymphatic sac tumours, papillary cystadenomas of the epididymis or broad ligament, and neuroendocrine tumours of the pancreas.
  • Inherited phaeochromocytoma and paraganglioma (R223): an autosomal dominant tumour predisposition syndrome associated with paraganglioma, phaeochromocytoma and SDH-deficient renal cell cancer.
  • Birt Hogg Dubé syndrome (overlap with R190 Pneumothorax – familial): an autosomal dominant tumour predisposition syndrome associated with an increased risk of kidney cancer (most commonly mixed chromophobe/oncocytic histology), multiple lung cysts and/or pneumothoraces, and cutaneous features (including fibrofolliculomas, acrochordons, angiofibromas, collagenomas).
  • BAP1 tumour predisposition syndrome (overlap with R422 BAP1 associated tumour predisposition syndrome): an autosomal dominant tumour predisposition syndrome associated with increased risks of kidney cancer, uveal and cutaneous melanoma and malignant mesothelioma.
  • Hereditary type 1 papillary renal cancer: an autosomal dominant cancer predisposition syndrome caused by pathogenic constitutional variants in MET with phenotype limited to type 1 papillary kidney cancer predisposition.
  • PTEN hamartoma tumour syndrome (R213): an autosomal dominant syndrome variably associated with macrocephaly, mucocutaneous features, hamartomas and cancer predisposition.
  • Cancers of the renal pelvis/ureter (usually transitional cell cancer) have also been described as part of Lynch syndrome (R210 inherited MMR deficiency). Consider further assessment if the patient has a family history of colorectal, endometrial or other Lynch syndrome associated cancers.
• A record of discussion (RoD) form is required prior to constitutional (germline) genomic testing. If you have not completed a RoD form before and/or do not have access to one, please review this Knowledge Hub article on how to complete an RoD form.
• For DNA based tests (all the above listed tests), an EDTA blood sample is required. Please refer to your local Genomics Laboratory Hub (GLH) for details of test request forms and where to send samples.
• Depending on the details you provide and the test that is chosen, a range of different genomic investigation techniques will be applied to your patient’s/their family’s (if appropriate) DNA. These include (but are not restricted to):
  • Single gene sequencing
  • Gene panel sequencing
  • MLPA
• Rare mechanisms for kidney cancer predisposition include structural variants and chromosomal rearrangements. Where clinical suspicion for a heritable predisposition exists but constitutional (germline) gene testing is uninformative, seek advice from clinical genetics.
• NTRK fusion gene analysis of the tumour requires access to a formalin-fixed tumour sample and can be requested as test M18.6. This consists of NGS structural variant analysis.
• WGS of solid tumours where the patient has exhausted all standards of care testing and treatment is requested as code M232. WGS requires access to a fresh tumour sample and a matched blood (EDTA) sample for germline testing. An RoD form must be completed for this investigation. Please discuss with your local GLH before submitting samples for WGS to confirm the local test pathway details.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory and eligibility criteria (note that somatic (tumour) tests are listed in the directory for cancer, while constitutional (germline) tests are listed in the directory for rare and inherited disease)

References:

• Escudier B, Porta C, Schmidinger M and others. ‘Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up‘. Annals of Oncology 2019: volume 30, issue 5, pages 706–720. DOI: 10.1093/annonc/mdz056
• Haas NB, Nathanson KL. ‘Hereditary Renal Cancer Syndromes‘. Advances in Chronic Kidney Disease 2014: volume 21, issue 1, pages 81–90. DOI: 10.1053/j.ackd.2013.10.001
• Maher ER. ‘Hereditary renal cell carcinoma syndromes: diagnosis, surveillance and management‘. World Journal of Urology 2018: volume 36, issue 12, pages 1,891–1,898. DOI: 10.1007/s00345-018-2288-5

For patients

• National Cancer Institute: Hereditary Kidney Cancer Syndromes patient guide