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Example clinical scenario

A 55-year-old woman is admitted with abdominal pain, weight loss and shortness of breath. Imaging reveals multiple sites of metastatic disease but no obvious primary tumour. After a liver biopsy the patient is diagnosed with unfavourable (subtype) carcinoma of unknown primary (CUP). You wish to undertake genomic testing and are considering which constitutional (germline) and/or somatic (tumour) genomic testing is available and appropriate for her.

When to consider genomic testing

Constitutional (germline) testing

  • Patients who are considered for palliative chemotherapy with capecitabine should undergo constitutional (germline) testing of the dihydropyrimidine dehydrogenase (DPYD) gene. Certain variants in this gene result in a deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD) and a subsequent reduction in metabolism of fluoropyrimidine-based chemotherapies such as 5FU and capecitabine. This results in serious and sometimes life-threatening toxicity, including diarrhoea, mucositis and skin reactions, if these chemotherapy agents are given at standard doses.
  • No targeted constitutional (germline) genomic testing is specifically recommended for patients with CUP, but patients are eligible for paired constitutional and somatic (tumour-based) whole genome sequencing (WGS).

Somatic (tumour) testing

  • The mutational profile of unfavourable CUP has been investigated in a number of clinical trials. TP53 variants are found in approximately 50% of unfavourable CUPs. Beyond this, CUPs demonstrate a very heterogeneous mutational landscape, with a diverse set of potentially actionable genetic alterations.
  • Initial data from the CUPISCO randomised trial, which assessed the clinical utility of massively parallel sequencing (sometimes called next-generation sequencing)-based management approaches in CUP, indicates a favourable impact on progression-free survival associated with a molecularly directed treatment approach. However, overall survival data are pending.
  • Somatic (tumour) testing for NTRK1, NTRK2 and NTRK3 fusion genes is available within the NHS for CUP patients as a biomarker for treatment with an NTRK inhibitor when all other approved lines of treatment have been exhausted.
  • Patients with CUP are eligible for NHS WGS at any time after diagnosis.
  • Large-panel massively parallel sequencing somatic (tumour) testing for CUP may be available within clinical trials.

What do you need to do?

Constitutional (germline) testing

  • Patients being considered for palliative chemotherapy with capecitabine should undergo constitutional (germline) DPYD testing using test code M226.3.
  • For constitutional (germline) DNA-based tests (all the above listed tests), an EDTA blood sample is required. Please refer to your local Genomic Laboratory Hub (GLH) for details of test request forms and where to send samples.

Somatic (tumour) testing

  • NTRK fusion gene analysis can be requested as test M226.1. This consists of massively parallel sequencing structural variant analysis.
  • WGS of CUP is requested as code M226.4. WGS requires access to a fresh tumour sample and a matched blood (EDTA) sample for constitutional (germline) testing. A record of discussion form must be completed for this investigation. Please discuss the case 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


For patients

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  • Last reviewed: 11/12/2023
  • Next review due: 11/12/2024
  • Authors: Dr Ellen Copson
  • Reviewers: Dr Sarah Ellis, Dr Terri McVeigh