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Example clinical scenario

A 42-year-old woman is diagnosed with metastatic colorectal cancer. There is no significant family history of cancer. Immunohistochemistry demonstrates loss of expression of the MSH6 protein. Somatic (tumour) testing via a multi-target next-generation sequencing (NGS) panel reveals a MSH6 gene pathogenic variant (mutation). Constitutional (germline) testing confirms that this variant is not only present in the tumour but also constitutionally (in the patient’s germline), meaning that the patient has a heritable cancer predisposition syndrome: Lynch syndrome.

What do you need to do?

Management of the current cancer

Identification of a constitutional (germline) MMR gene pathogenic variant (that is therefore also present in the tumour genome) means that the patient may be eligible for treatment with immunotherapy in the metastatic setting.

More information on clinical trials can be found below and in our ‘Clinical trials in cancer’ Knowledge Hub article.

Management of the patient's risk of further primary cancers

  • This should be considered on an individual basis and take into account the overall prognosis of the patient from their metastatic disease, including treatment intent.
  • Individuals with proven Lynch syndrome who have already been affected by colorectal cancer are at high risk of metachronous cancer. Subtotal colectomy may be considered where the genetic diagnosis is confirmed prior to therapeutic surgery in patients with early stage colorectal cancer, particularly in younger patients with Lynch syndrome caused by MLH1 or MSH2 pathogenic variants, where risk of second/subsequent cancers in the residual bowel is highest.
    • The potential risks and morbidity associated with this must be balanced against potential benefit of risk reduction, taking lifetime risk of second or subsequent primary cancers as well as risk of recurrence of the first colorectal cancer, and life expectancy into consideration.
  • Surveillance for CRC by screening colonoscopy in any residual bowel should be undertaken every two years (from 25 years of age for MLH1/MSH2 and from 35 years of age for MSH6/PMS2 mutation carriers). Data has shown that this approach reduces the risk of colorectal cancer-related mortality in patients with Lynch syndrome.
    • Should polyps be identified, they can be treated at the time of endoscopy, but a significant proportion of cancers arising in the context of Lynch syndrome do not arise from a defined polyp stage, but rather from mismatch repair deficient crypts.
  • Daily aspirin has been shown to reduce the risk of colorectal cancer (CRC) and certain other cancers in Lynch syndrome. The optimal dose remains to be established (see ongoing CAPP3 study). Current UKCGG guidelines recommend a dose of 150mg OD pending formal outcome of this study, but individuals greater than 70kg in weight may benefit from a higher dose.
  • Screening for extracolonic cancers has not been shown to impact overall mortality, however the following should be considered to reduce cancer risk:
    • Screening for H. pylori and eradication, to reduce stomach cancer risk.
    • Women who have completed their family may consider risk-reducing surgery to remove the uterus, fallopian tubes +/- and ovaries, after the age of 35. (Note: PMS2 carriers are not thought to be at significantly increased risk of ovarian cancer)
    • The role of prostate cancer screening with PSA and MRI in male individuals with Lynch syndrome is uncertain, but recent evidence from the IMPACT study supports the role of targeted PSA screening in men who carry likely pathogenic/pathogenic variants in MSH2 or MSH6. Male carriers of such variants should be counselled regarding symptom awareness.
    • Prompt investigation of any symptoms (gynaecological, urinary, gastrointestinal, dermatological, etc).
    • Individuals with Lynch syndrome should be provided with advice regarding modifiable risk factors, including diet, smoking and alcohol intake.

Management of the family's risk

  • Lynch syndrome is an autosomal dominant condition.
  • First-degree relatives are at 50% risk of inheriting Lynch syndrome.
  • Refer to clinical genetics to discuss cascade screening of relatives at risk.

Recessive disorders associated with pathogenic variants in MMR genes

  • Individuals that carry pathogenic variants in both copies of MSH6 (biallelic variants) are affected by a condition known as congenital mismatch repair deficiency (CMMRD), a recessive condition associated with cutaneous features (café au lait spots, pilomatricomas) and predisposition to haematological, brain and solid organ cancers, with risk typically starting from childhood.
    • CMMRD can also be caused by biallelic variants in PMS2 or more rarely in MSH2, or in MLH1.
    • CMMRD only arises when individuals inherit biallelic variant in the same mismatch repair gene.
    • Individuals that inherit monoallelic variants in different MMR genes will have Lynch syndrome but will not be affected by CMMRD.

Family planning implications

The Human Fertilisation and Embryology Authority have approved the use of pre-implantation genetic diagnosis for couples where one or both intended parents are carriers of a likely pathogenic/pathogenic variant in a gene associated with Lynch syndrome.

Other options may include prenatal testing (invasive, or non-invasive if the potential father is the carrier) with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children in adulthood.

Note: the above advice is only relevant when a constitutional (germline) heterozygous variant in an MMR gene is identified. Variants that have been confirmed to be somatic (tumour-only) in origin that are not present in the patient’s normal tissue have no implications for the patient’s future cancer risk, nor that of their relatives. For more information, see this constitutional vs somatic mutations Knowledge Hub article.

Tagged: Colorectal cancer, Constitutional mutations

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  • Last reviewed: 05/05/2022
  • Next review due: 05/05/2023
  • Authors: Dr Alison Berner
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh