Presentation: Patient with hepatocellular carcinoma

A 57-year-old man with a history of chronic liver disease presents with progressive upper abdominal pain and weight loss. A CT scan reveals a 5cm mass within the liver, and a liver biopsy confirms a diagnosis of hepatocellular carcinoma. There is no significant family history of cancer. You wish to undertake genomic testing and are considering which constitutional (germline) and somatic (tumour) genomic tests are available and appropriate for him.

Constitutional (germline) testing

• Constitutional (germline) testing of BAP1 should be offered to patients with hepatocellular carcinoma if they have a personal history of another BAP1-associated cancer, or at least one first-degree relative with a BAP1-associated cancer. BAP1-associated cancers include:
  • uveal melanoma;
  • cutaneous melanoma;
  • basal cell cancer;
  • BAP1-inactivated melanocytic tumours;
  • malignant mesothelioma (lung or peritoneal);
  • renal cell carcinoma;
  • meningioma;
  • cholangiocarcinoma; and
  • hepatocellular carcinoma.
• A history of chronic liver disease should be investigated appropriately, and constitutional (germline) genomic testing should be considered if investigations indicate an underlying diagnosis of hereditary haemochromatosis or alpha-1-antitrypsin deficiency.
• If treatment with fluoropyrimidine chemotherapy is considered, testing for variants in the DPYD gene associated with dihydropyrimidine dehydrogenase (DPD) deficiency is required. DPD deficiency can result in significant fluoropyrimidine treatment toxicities.

Somatic (tumour) testing

• If all routine treatment options have been exhausted, somatic (tumour) testing for gene rearrangements involving NTRK1, NTRK2 and NTRK3 can be performed.
• Entrectinib and larotrectinib are NTRK inhibitor therapies. They are approved for the 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.
• 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.
• In the future, somatic (tumour) testing is likely to be expanded to include larger somatic gene panels.

• Consult the National Genomic Test Directory to ensure your patient is eligible for testing. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different gene panels for constitutional (germline) testing, see the NHS Genomic Medicine Service Signed Off Panels Resource.
• Testing for DPYD variants associated with DPD deficiency is undertaken on constitutional (germline) DNA, via the National Genomic Test Directory code M222.6.
• Although most constitutional (germline) genomic tests require completion of a record of discussion form, it is not required for DPYD variant testing.
• For 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.
• 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 and/or their family’s DNA. These include (but are not restricted to):
  • single gene sequencing;
  • gene panel sequencing;
  • multiplex ligation-dependent probe amplification (MLPA); and
  • methylation testing.
• NTRK1, NTRK2 and NTRK3 fusion gene analysis can be requested via test code M222.2. This consists of massively parallel sequencing (sometimes called next-generation sequencing) structural variant analysis and is performed on a sample of tumour tissue.
• WGS of solid tumours, in cases in which the patient has exhausted all standards-of-care testing and treatment, is requested as test code M232. WGS requires access to a fresh tumour sample and a matched EDTA blood sample for constitutional (germline) testing. A record of discussion 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

• European Society for Medical Oncology: Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up
• NHS England: National Genomic Test Directory (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: Entrectinib for treating NTRK fusion-positive solid tumours
• NICE: Larotrectinib for treating NTRK fusion-positive solid tumours

For patients

• Cancer Research UK: DPD deficiency
• Cancer Research UK: Liver cancer
• Macmillan Cancer Support: Liver cancer