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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 massively parallel sequencing (sometimes called next-generation sequencing) panel reveals a pathogenic variant in the MSH6 gene. 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 Lynch syndrome, a heritable cancer predisposition syndrome.

Impact of the genomic result

  • Lynch syndrome arises from a pathogenic constitutional (germline) variant of one of the genes involved in DNA mismatch repair (MLH1, MSH2, MSH6 or PMS2), or from inactivation of MSH2 owing to deletion in the neighbouring EPCAM gene.
  • Individuals with Lynch syndrome have an increased lifetime risk of a variety of cancers, most commonly colorectal cancer and endometrial cancer, as well as ovarian, pancreaticobiliary, gastric, small intestinal, brain, urinary tract, skin and other cancers.

What do you need to do?

Management of the current cancer

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

Management of the patient's risk of further primary cancers

  • This should be considered on an individual basis, and should take into account the overall prognosis from the patient’s 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 if the genomic diagnosis is confirmed prior to therapeutic surgery in patients with early stage colorectal cancer. This is the case particularly in younger patients with Lynch syndrome caused by MLH1 or MSH2 pathogenic variants, in whom risk of second or 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 into consideration, as well as risk of recurrence of the first colorectal cancer and life expectancy.
  • Surveillance for colorectal cancer by screening colonoscopy in any residual bowel should be undertaken every two years (from 25 years of age for those with MLH1 and MSH2 variants, and from 35 years of age for those with MSH6 and PMS2 variants). 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; however, a significant proportion of cancers arising in the context of Lynch syndrome do not arise from a defined polyp stage, but rather from MMR-deficient crypts.
  • Daily aspirin has been shown to reduce the risk of colorectal cancer and certain other cancers in Lynch syndrome. The optimal dose remains to be established (see the ongoing CAPP3 study). Current UK Cancer Genetics Group guidelines recommend a dose of 150mg once a day 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 and fallopian tubes with or without ovaries after the age of 35 (note that those with PMS2 variants are not thought to be at significantly increased risk of ovarian cancer);
    • the role of prostate cancer screening with prostate specific antigen (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 with likely pathogenic or pathogenic variants in MSH2 or MSH6 (males with these variants should be counselled regarding symptom awareness);
    • there should be prompt investigation of any symptoms (such as gynaecological, urinary, gastrointestinal or dermatological symptoms); and
    • 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. This means that first-degree relatives are at 50% risk of inheriting it.
  • Refer the case to clinical genetics to discuss cascade screening of relatives at risk.

Recessive conditions associated with pathogenic variants in MMR genes

  • Individuals with 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 (such as café-au-lait macules and 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 MLH1.
    • CMMRD only arises when individuals inherit biallelic variants in the same MMR gene.
    • Individuals who 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 has approved the use of preimplantation genetic testing (previously known as preimplantation genetic diagnosis) for couples in whom one or both intended parents have a likely pathogenic or pathogenic variant in a gene associated with Lynch syndrome.

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

Note that 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 and are not present in the patient’s normal tissue have no implications for the patient’s future cancer risk, nor that of their relatives.

Tagged: Colorectal cancer, Constitutional mutations

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  • Last reviewed: 07/12/2023
  • Next review due: 07/12/2024
  • Authors: Dr Alison Berner
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh, Dr Amal Singh