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Example clinical scenario

A 72-year-old male is diagnosed with 3cm colorectal tumour at the right hepatic flexure. He undergoes a right hemicolectomy and is found to have a poorly differentiated adenocarcinoma, pT3N0M0, with clear margins and no lymphovascular invasion. 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.

When to consider genomic testing

Constitutional (germline) testing

  • If microsatellite instability (MSI) testing demonstrates instability, if the MSH2, MSH6 or PMS2 IHC results are abnormal, or if the MLH1 promoter hypermethylation test is negative, the patient should be tested for Lynch syndrome by genomic testing of constitutional (germline) DNA.
  • Broader panel-based testing of genes associated with polyposis and other rare hereditary causes of colorectal cancer is available for patients with colorectal cancer if they fulfil one of the following criteria:
    • diagnosis of colorectal cancer:
      • >40 years; and
      • ≥5 adenomatous polyps
    • ≥5 adenomatous polyps <40 years, ≥10 adenomatous polyps <60 years, or ≥20 adenomatous polyps at any age;
    • ≥5 adenomatous polyps <60 years and first-degree relative with ≥5 adenomatous polyps (age <60 years)
    • Serrated polyposis:
      • ≥5 serrated lesions/polyps proximal to the rectum all ≥5 mm in size, with ≥2 ≥10mm in size; or
      • >20 serrated lesions/polyps of any size distributed through the large bowel with ≥5 being proximal to the rectum.
    • hamartomatous polyposis syndromes:
      • ≥5 hamartomatous polyps of the colorectum;
      • ≥2 hamartomatous polyps throughout the GI tract; or
      • ≥1 hamartomatous polyp and a first / second degree relative has hamartomatous polyp.
  • If this patient is mismatch repair (MMR) proficient or negative, then this patient would be eligible for fluoropyrimidine chemotherapy and would therefore require testing for constitutional dihydropyrimidine dehydrogenase (DPD) deficiency.

Somatic (tumour) testing:

  • All patients with colorectal cancer are eligible for testing of MMR or MSI of the tumour.
    • In the context of an intermediate risk stage II colorectal cancer, MMR/MSI status provides important prognostic information and predicts likely benefit from adjuvant chemotherapy.
    • MMR/MSI status may be assessed by an immunohistochemistry (IHC) 4‑panel test for MLH1, MSH2, MSH6 and PMS2 proteins (not a genomic test), or PCR for MSI (a genomic test).
    • If tumour IHC results demonstrate loss of MLH1/PMS2, BRAF analysis should be undertaken. Pathogenic BRAF variants (most commonly BRAF V600E) are common in sporadic MMR-deficient colorectal cancers, but rare in tumours associated with Lynch syndrome.
      • If BRAF testing does not identify a pathogenic variant in an MLH1/PMS2-deficient colorectal cancer, MLH1 promoter hypermethylation testing should be performed.
  • 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?

Constitutional (germline) testing:

  • R210 Inherited MMR deficiency (Lynch syndrome) after working through the tumour-based MSI/MMR IHC pathway; and
  • R211 Inherited polyposis and early onset colorectal cancer, for patients with polyps fulfilling eligibility.

Somatic testing:

  • M1.1 Multi-target NGS panel for patients with colorectal cancer (CRC) eligible for anti-EGFR therapy or where BRAF or MMR genes required for Lynch testing (KRAS, NRAS, BRAF, MLH1, MSH2, MSH6, PMS2, POLD1, POLE, DPYD);
  • M1.2 KRAS hotspot testing in CRC patients eligible for anti-EGFR therapy where NGS panel has failed;
  • M1.3 NRAS hotspot testing in CRC patients eligible for anti-EGFR therapy where NGS panel has failed;
  • M1.4 MSI testing testing in CRC patients where MMR testing has failed;
  • M1.5 MLH1 promoter hypermethylation in CRC patients where this is indicated by the Lynch testing algorithm. This is best done alongside constitutional (germline) DNA to facilitate detection of constitutional hypermethylation of the MLH1 promoter; and
  • M1.6 NTRK rearrangement panel for CRC patients who may be clinically eligible for NTRK inhibitor (advanced disease only).
  • For constitutional (germline) testing for Lynch syndrome, 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.
  • All of the above somatic tests can be performed on formalin-fixed tumour tissue. Testing of tumour tissue for MMR or MSI, as well as subsequent somatic testing, may be done reflexively by your histopathology department, but you may need to follow this up within the multidisciplinary team meeting and clarify patient eligibility.
  • 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 clinicians

For patients

Tagged: Colorectal cancer

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  • Last reviewed: 03/05/2022
  • Next review due: 03/05/2023
  • Authors: Dr Alison Berner
  • Reviewers: Dr Amy Frost, Dr Terri McVeigh, Professor Kate Tatton-Brown