Example clinical scenario
A 52-year-old man is diagnosed with metastatic cutaneous melanoma, with staging investigations revealing metastases in the liver and lungs. There is no significant family history of cancer. You wish to undertake genomic testing and are considering what constitutional (germline) and/or somatic (tumour) genetic testing is available/appropriate for him.
When to consider genomic testing
Constitutional (germline) testing
- Constitutional (germline) genetic testing for familial melanoma is possible via a familial melanoma small panel (including BAP1, CDK4 and CDKN2A).
- Individuals are eligible for constitutional (germline) genetic testing for familial melanoma if at least one of the following criteria is met:
- ≥2 melanomas and/or melanomas in situ aged <30 years;
- melanoma and/or melanoma in situ and ≥2 relatives (first/second/third-degree relatives) with melanoma and/or melanoma in situ;
- melanoma and/or melanoma in situ and ≥1 first-degree relative with melanoma in situ; one individual has multiple melanomas in situ;
- ≥1 melanoma and/or melanoma in situ or melanoma in situ and atypical moles and ≥1 first degree relative with pancreatic cancer aged <60; or
- atypical moles and ≥2 relatives (first/second-degree relatives) with melanoma and/or melanoma in situ.
- Testing should be targeted at those where a genetic diagnosis will guide management of the patient and/or their family.
- If the affected individual is deceased, constitutional (germline) genomic testing can proceed using a sample of tissue if one of the above criteria is met and no living affected individual is available for genetic testing and appropriate tissue is available.
Somatic (tumour) testing
- All patients with cutaneous melanoma at high risk of recurrence (stage 2C or 3) or metastatic disease (stage 4) are eligible for a multi-target next-generation sequencing (NGS) panel to check for mutations in BRAF, KIT and NRAS. In rare cases where this cannot be delivered by panel testing, BRAF hotspot testing can be performed as an alternative.
- Around half of all melanomas have BRAF mutations – most commonly V600E. Patients with a BRAF mutation are eligible for targeted treatment with a BRAF inhibitor plus MEK inhibitor (for example, dabrafenib/trametinib), both in the metastatic (first or second line after immunotherapy) and adjuvant settings.
- Somatic NRAS mutations (in 15%-20% of cutaneous melanomas) are associated with resistance to BRAF inhibition. MEK inhibition alone has some limited activity in NRAS-mutated melanoma. Immunotherapy remains the first-line treatment of choice.
- Somatic KIT mutations (in 2%-8% of all melanomas, most commonly in acral and mucosal melanomas) are being investigated in trial settings for response to tyrosine kinase inhibition (for example, imatinib or nilotinib).
- 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.
- GNA11 and GNAQ mutations (common in uveal melanoma) can be used diagnostically to confirm a uveal melanoma primary (rather than cutaneous) in metastatic disease if testing is available locally.
- In cases of equivocal melanocytic lesions of the skin, copy number variant analysis of the following gene loci can be requested to aid diagnosis: MYB (6q24), RREB1 (6p25), CCND1 (11q13), MYC (8q24) and CDKN2a (9p21).
- In the future, somatic testing is likely to be available and expanded to include larger somatic gene panels. Ultimately, paired somatic and constitutional whole genome sequencing (WGS) will be performed.
- All patients with solid tumours who have exhausted all standards of care testing and treatment are eligible for WGS in order to explore clinical trial options.
What do you need to do?
- 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 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 suit the needs of your patient. For patients with cutaneous melanoma, the options are:
- R254 Familial melanoma: which is a constitutional (germline) panel for familial melanoma, if the patient meets the criteria for constitutional testing. An up-to-date list of the genes included in this panel is available here.
- M7.1: for somatic (tumour) testing of BRAF, KIT and NRAS via a multi-target NGS panel in all stage 2C, 3 or 4 patients.
- M7.2: for somatic BRAF hotspot testing in rare cases where panel testing cannot be delivered.
- M7.3: 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.
- Somatic testing of equivocal melanocytic lesions of the skin to aid diagnosis is requested as follows:
- M7.5 MYC &6cen CNV by FISH testing
- M7.6 RREB1 (6p25) CNV by FISH testing
- M7.7 CCND1 (11q13) CNV by FISH testing
- M7.8 MYC & 8cen CNV by FISH testing
- M 7.9 CDKN2a &9cen CNV by FISH testing
- M7.10 CNV for MYB, RREB1, CCND1, MYC, CDKN2a by microarray testing
- 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 include (but are not restricted to):
- For constitutional (germline) 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.
- For the somatic (tumour) tests listed above, access to a formalin-fixed tumour sample is required.
- 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.
- ESMO: Clinical practice guidelines for cutaneous melanoma
- 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)
- NICE: Guidance for melanoma assessment and management
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