Presentation: Patient with a family history of gastrointestinal cancer

A 30-year-old man enquires with his GP about genomic testing, as his father has recently been diagnosed with an MMR-proficient T2N0M0 rectal cancer at the age of 55 years. His late paternal grandaunt also had a right hemicolectomy and chemotherapy for a caecal tumour at 80 years of age.

• A family history that does not meet the moderate- or high-risk criteria for familial colorectal cancer (CRC), in the absence of hereditary cancer syndromes, is not eligible for genomic testing.
  • Moderate risk: one affected first-degree relative diagnosed with CRC under 50 years, or two affected first-degree relatives of any age (in first-degree kinship).
  • High risk: cluster of at least three affected first-degree relatives with CRC diagnosed at any age, across at least two generations.
• A possible diagnosis of Lynch syndrome or polyposis in relatives should be ruled out by performing tumour testing for mismatch repair status and reviewing colonoscopy reports in relatives for features of polyposis.
• Predictive testing should be offered to unaffected individuals whose first-degree relative has known familial mutations.
• Where a family member has a known or suspected hereditary bowel cancer syndrome, such as Lynch or polyposis syndromes, make a referral to your clinical genetics service for further genetic assessment where constitutive gene mutation testing is indicated.
  • Predictive testing for first-degree relatives of patients with a confirmed genetic diagnosis of Lynch syndrome or polyposis syndromes. This is usually performed by clinical genetics or highly specialised services.
  • Discuss predictive testing: genetic counselling will be performed by the clinical genetics service prior to testing.
• Occasionally, constitutional (germline) testing may be indicated in unaffected individuals with Amsterdam criteria families where testing is not possible in the affected individual. Please consult your local genetics service if in doubt.
• Those with a moderate or high risk of familial colorectal cancer and/or suspected inherited bowel cancer syndromes should be referred to a specialist familial CRC clinic, and offered colonoscopic surveillance in line with the BSG/ACPGBI/UKCGG guidelines.

Family history of colorectal cancer

• Establish a ≥3 generation family history of cancers and draw a complete genetic family history (pedigree).
• Identify those with a cancer diagnosis and request a copy of the histopathology report of the closest affected relative. Clarify the mismatch repair (MMR) status of the tumour tissue and whether genomic testing has been performed.
  • Where possible, MMR status should be assessed in the tumour tissue of the closest affected family member.
• Where a family history of polyposis is suspected, a review of endoscopy and histopathology reports confirming a minimum of 10 adenomas and serrated lesions in the first-degree relative is recommended.
  • See Presentation: Person with a family history of polyposis.
• Those with a moderate or high risk of familial colorectal cancer and/or suspected inherited bowel cancer syndromes should be referred to a specialist familial CRC clinic at a secondary or tertiary care centre.

Genomic testing for inherited colorectal cancer

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. 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.
• Genomic testing of unaffected individuals can only be performed by clinical genetics:
  • R242 Predictive testing for known familial variant(s): this is a targeted variant test that will show whether the first-degree relative has the inherited pathogenic variant.
  • R210 Inherited MMR deficiency (Lynch syndrome): this is a small gene panel specific for Lynch syndrome for asymptomatic persons who have a first-degree relative with a Lynch-related cancer, meet the modified Amsterdam family history criteria, and where testing is not possible in the affected individual.
• In specific situations, genomic testing may be appropriate for individuals with histologically confirmed colorectal polyps where individuals with or without family history meet criteria.
  • R211 Inherited polyposis and early onset colorectal cancer – germline test: This is a small panel testing genes specific for inherited polyposis.
• Genomic testing may occasionally be appropriate outside of these criteria. Please discuss with your local Genomic Laboratory Hub.
• For more information about colonoscopic surveillance for those with a moderate or high risk of familial colorectal cancer, please refer to the BSG/ACPGBI/UKCGG guidelines for the management of hereditary colorectal cancer, where:
  • average/low risk: National bowel cancer screening programme;
  • moderate risk: one-off colonoscopy at age 55 years followed by BSG post-polypectomy surveillance guidelines; and
  • high risk: colonoscopy should be performed once every five years from 40 years until 75 years old.
  • Note that a flow chart of the above may be found online.
• Optimising individual modifiable risk factors (such as diet, weight, lifestyle, smoking cessation and minimising alcohol intake) may reduce their overall risk of developing colorectal cancer. Patients should be advised to look out for and report red-flag symptoms, which may require further clinical assessments.

Other inherited gastrointestinal cancers

• Please visit the National Genomic Test Directory for eligibility testing criteria for hereditary diffuse gastric cancer and inherited pancreatic cancer.
• Genomic testing of the unaffected first-degree relative may be appropriate where the affected individual is deceased, the individual with or without a family member meets the criteria for testing, there is available histological tissue and no living affected individual is available for genomic testing. Please discuss this with your local clinical genetics service.

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

• Cancer Genetics Group: UKCGG leaflets and guidelines
• NHS England: National Genomic Test Directory

References:

• Monahan KJ, Bradshaw N, Dolwani S and others. ‘Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG)‘. Gut 2020: volume 69, pages 411–444. DOI: 10.1136/gutjnl-2019-319915

For patients

• Bowel Cancer UK: Bowel cancer screening
• Bowel Cancer UK: Family history
• Cancer Research UK: Screening for people at high risk of bowel cancer
• Macmillan Cancer Support: Inherited bowel cancer