Presentation: Patient with uveal melanoma

A 49-year-old man is diagnosed with uveal melanoma, with staging investigations revealing metastases in the liver. There is no significant family history of cancer. You wish to undertake genomic testing and are considering what constitutional (germline) and somatic (tumour) genomic testing is available and appropriate for him.

Constitutional (germline) testing

• Patients with uveal melanoma are eligible for constitutional (germline) single gene testing for BAP1 variants if they have uveal melanoma and a personal history of, or first-degree relative who has had, another BAP1-related tumour.
• Patients with a history of uveal melanoma and renal cell cancer are eligible for constitutional (germline) genomic testing of BAP1 alongside a number of other renal cell cancer predisposition genes as part of a multigene panel (R224 Inherited renal cancer).
• Uveal melanoma may rarely be associated with other inherited cancer disorders, including heritable TP53-related tumour syndromes (Li-Fraumeni syndrome) and neurofibromatosis type 1. Constitutional (germline) testing of relevant genes should be considered if the personal/family history is consistent with one of these syndromes.

Somatic (tumour) testing

• Patients with uveal melanoma are eligible for MLPA or equivalent dosage testing of chromosomes 1p, 3, 6 and 8 if this will aid diagnosis, prognosis and/or management.
  • Loss of chromosome 3 is associated with metastatic death in uveal melanoma.
  • Loss or gain of chromosomes 1p, 6q, 8p and 8q are associated with poor prognosis in uveal melanoma.
• Patients with uveal melanoma are eligible for a multi-target next-generation sequencing (NGS) panel to check for mutations in BRAF, NRAS and NF1 if this will aid diagnosis/management. BRAF hotspot testing can be performed as an alternative.
  • Targeted treatments (such as BRAF or MEK inhibitors) are not approved for use in uveal melanoma (unlike cutaneous melanoma).
  • Patients with metastatic disease should be considered for clinical trials wherever possible, which mutation testing can help to inform. MEK inhibitor and tyrosine kinase inhibitor clinical trials are in progress.
• In select patients eligible for an NTRK inhibitor (for example, entrectinib) in the event of an NTRK rearrangement, a multi-target NGS panel to check for NTRK1, NTRK2 or NTRK3 structural variants can be requested.
  • Entrectinib is approved for treatment of NTRK fusion-positive tumours if the patient has no other satisfactory treatment options and the patient has not previously received an NTRK inhibitor.
• Testing for the presence of GNA11 and/or GNAQ mutations (common in uveal melanoma) can be helpful diagnostically to confirm a melanoma of primary uveal origin (rather than cutaneous) in metastatic disease if testing is available locally.
• Further somatic (tumour) tests may be available in trial settings, and all available trials should be considered in first-line management of metastatic disease.
• All patients with solid tumours who have exhausted all standards of care testing and treatment are 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. You can also refer to this spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• 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.
• Decide which tests best suits the needs of your patient. For patients affected with uveal melanoma, the options are:
  • R422 BAP1 associated tumour predisposition syndrome (see Panel App) or R224 inherited renal cancer.
  • You may consider testing for other inherited cancer syndromes if the history is suggestive and the patient is eligible.
  • M187.1 for somatic (tumour) chromosome 1p, 3, 6 and 8 MLPA testing.
  • M187.2 for somatic BRAF hotspot testing.
  • M187.3 for somatic testing of BRAF, NRAS and NF1 via a multi-target NGS panel.
  • M187.4 for somatic testing of NTRK1, NTRK2 and NTRK3 structural variants via a multi-target NGS panel in select patients eligible for an NTRK inhibitor in the event of an NTRK rearrangement.
• For constitutional (germline) testing, a record of discussion (RoD) form is required. If you have not completed an RoD form before and/or do not have access to one, please review this Knowledge Hub article on how to complete an RoD form.
• 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 tests include (but are not restricted to):
  • Single gene sequencing
  • Gene panel sequencing
  • MLPA
• For constitutional DNA-based 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. All the somatic tests listed above can be performed on formalin-fixed tumour samples.
• 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 EDTA blood sample for germline testing. An RoD must be completed for this investigation – see how to complete an RoD form. 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. See this article for more information.)

References:

• Carvajal RD, Schwartz GK, Tezel T and others. ‘Metastatic disease from uveal melanoma: treatment options and future prospects‘. British Journal of Ophthalmology 2016: volume 101, pages 38–44. DOI: 10.1136/bjophthalmol-2016-309034
• Nathan P, Cohen V, S Coupland and others. ‘Uveal Melanoma UK National Guidelines‘. European Journal of Cancer 2015: volume 51, issue 16+, pages 2,404–2,412. DOI: 10.1016/j.ejca.2015.07.013

For patients

• Melanoma Focus: Uveal melanoma national guidelines