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Example clinical scenario

A 36-year old man is diagnosed with a locally advanced diffuse gastric cancer. His aunt developed gastric cancer aged 48 years. The patient has two young children. You wish to undertake constitutional (germline) genomic testing given the patient’s young age, family history and his concerns regarding his children’s risk of developing cancer at a young age.

When to consider genomic testing

Constitutional (germline) testing

Constitutional (germline) genetic testing of the CDH1 gene should be undertaken in an individual with diffuse (rather than intestinal subtype) gastric cancer in the following circumstances:

  • diffuse gastric cancer (<50 years);
  • gastric in situ signet ring cells or pagetoid spread of signet ring cells (<50 years);
  • double primary diffuse gastric cancer and lobular breast cancer (both <70 years); or
  • diffuse gastric cancer at any age and
    • a personal history or first-degree relative (FDR) with cleft lip or cleft palate;
    • ≥1 FDR/SDR with diffuse gastric cancer at any age;
      ≥1 FDR/SDR with lobular breast cancer <70 years;
    • lobular breast cancer and ≥FDR/SDR has diffuse gastric cancer (≥ 1 case occurred < 70 years); or
    • two cases of lobular breast cancer<50 years, such as bilateral or multiple ipsilateral tumours.
  • Patients presenting at a young age with intestinal-type gastric cancer with a family history of the disease may be classified as having familial intestinal gastric cancer.
  • Any patient presenting with a Lynch syndrome-related cancer (including gastric cancer) at less than 50 years of age meets the criteria for inherited mismatch-repair (MMR) deficiency testing (R210 inherited MMR deficiency (Lynch syndrome)).
  • Gastric polyposis has been reported in APC-related gastric adenocarcinoma and proximal polyposis of the stomach and other hereditary gastric polyposis syndromes.
  • Patients who are considered for chemotherapy with capecitabine should undergo germline testing of the dihydropyrimidine dehydrogenase (DPYD) gene. Certain variants in the DPYD gene result in a deficiency of the enzyme dihydropyrimidine dehydrogenase and a subsequent reduction in metabolism of fluoropyrimidine chemotherapy drugs (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.

Somatic (tumour) testing

  • Somatic (tumour) testing of diffuse gastric cancers is not currently routine.
  • Somatic testing for NTRK1, NTRK2 and NTRK3 fusion genes as a biomarker for treatment with an NTRK inhibitor is available for any solid tumour patients when all other approved lines of treatment have been exhausted.
  • Other somatic tests may be available in the context of a clinical trial.
  • In the future, somatic (tumour) testing is likely to be expanded to include larger somatic gene panels. Ultimately, it is likely that paired somatic and constitutional (germline) whole genome sequencing will be performed.

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 of the panels best suits the needs of your patient. For those affected by gastric cancer, the options are:
    • R215CDH1 gene testing, associated with hereditary diffuse gastric cancer.
    • R210: can be considered if testing for inherited MMR deficiency (Lynch syndrome) is indicated.
  • A record of discussion (RoD) form is required prior to testing. 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):
  • For DNA-based tests (all the above listed tests), an EDTA blood sample is required. Please refer to your local Genomics Laboratory Hub for details of test request forms and where to send samples.
  • Constitutional (germline) DPD testing is requested using test codes M227.2 and M227.3.
  • Somatic NTRK fusion gene analysis can be requested as test M227.1. This consists of next-generation sequencing structural variant analysis.


For clinicians


For patients

Tagged: Gastric cancer

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  • Last reviewed: 03/05/2022
  • Next review due: 03/05/2023
  • Authors: Dr Samuel Luke Hill
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh