2 Clinical need and practice

The problem addressed

2.1 Testing colorectal tumours using either microsatellite instability (MSI) or immunohistochemistry (IHC) testing for mismatch repair (MMR) proteins can identify people in whom the cancer may have occurred because of Lynch syndrome. Further testing for people at risk of Lynch syndrome can confirm this diagnosis. As well as colorectal cancer, people with Lynch syndrome have an increased risk of other cancers (such as endometrial, ovarian, stomach, small intestine, hepatobiliary tract, urinary tract, brain and skin cancer). After a diagnosis of Lynch syndrome, for some cancer sites, risk-reducing strategies can be offered to prevent or allow early diagnosis of associated cancers.

2.2 Currently, testing for Lynch syndrome is typically offered to people considered to be at high risk of having Lynch syndrome. Risk factors include a family history of cancer and age younger than 50 years at the onset of colorectal cancer. Expanding testing to all people with colorectal cancer may increase the detection of Lynch syndrome and, because Lynch syndrome is an inherited condition, identify families who could benefit from cascade genetic testing to determine if other family members have Lynch syndrome. This could lead to increased surveillance and consequently improved patient outcomes through earlier diagnosis and treatment, if cancer is present.

2.3 The purpose of this assessment is to evaluate the clinical and cost effectiveness of using molecular testing strategies, which involve MSI testing and IHC for MMR proteins, to assess how likely it is that a person with colorectal cancer has Lynch syndrome. This assessment considers the use of the molecular testing strategies to identify people who are at risk of Lynch syndrome for genetic testing and, if Lynch syndrome is confirmed, direct cascade testing for relatives.

The condition

2.4 Lynch syndrome is an inherited genetic condition caused by mutation in 1 of 4 DNA MMR genes: MLH1, MSH2, MSH6 or PMS2. Mutations in another non‑MMR gene, known as EPCAM, which is next to the MSH2 gene, can also cause Lynch syndrome.

2.5 MMR genes encode proteins that are involved in recognising and repairing errors in DNA sequence, which occur when DNA is replicated during cell division. Mutations in MMR genes can lead to impaired functioning of the MMR system and a failure to repair DNA errors. Over time, this allows mutations to accumulate, potentially leading to cancer.

2.6 Lynch syndrome accounts for about 3.3% of colorectal tumours, and the condition is estimated to lead to over 1,100 colorectal cancers a year in the UK. An estimated 175,000 people in the UK have Lynch syndrome, a large proportion of whom will be unaware that they have the condition. In addition to colorectal cancer, people with Lynch syndrome are also at increased risk of other cancers.

The diagnostic and care pathways


2.7 In current practice, testing for Lynch syndrome in people with colorectal cancer is usually targeted using criteria based on family history and age of cancer onset to determine people at high risk.

2.8 There is currently no NICE guidance on the population to be tested or the testing strategy for Lynch syndrome. The guidelines of the British Society of Gastroenterology (BSG) and the Association of Coloproctology for Great Britain and Ireland (ACPGBI) for colorectal cancer screening and surveillance in moderate and high risk groups (2010) recommend that people with a lifetime risk of between 10% and 100% of developing colorectal cancer are referred to a regional genetics centre for genetic counselling and appropriate mutation analysis.

2.9 In 2009, after a review of Lynch syndrome testing, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group's report on genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives recommended offering laboratory testing to all such people with colorectal cancer, regardless of age or family history. The 2013 European revised guidelines for the clinical management of Lynch syndrome (HNPCC) also recommended systematic testing of all people with colorectal cancer (or at least all those up to the age of 70) for loss of MMR function by testing for MSI in tumour DNA or IHC for MMR proteins.

2.10 The Royal College of Pathologists includes MMR protein IHC as a core dataset item for people under the age of 50 diagnosed with colorectal cancer. The Independent Cancer Taskforce also recommended in its report, Achieving world-class outcomes – a strategy for England 2015–2020, that all people under the age of 50 be offered a genetic test for Lynch syndrome when bowel cancer is diagnosed.

Treating colorectal cancer in people with Lynch syndrome

2.11 The NICE guideline on colorectal cancer provides recommendations on treating colorectal cancer. Clinicians in the NHS also use the European Society for Medical Oncology (ESMO) guidelines for diagnosis, treatment and follow-up of early colon cancer to guide treatment decisions.

2.12 The 2013 European HNPCC's revised guidelines for managing Lynch syndrome also note the substantial risk of a second colorectal cancer after partial colectomy and that the quality of life after partial or subtotal colectomy are similar. Therefore, the option of subtotal colectomy, including its advantages and disadvantages, should be discussed with all people with Lynch syndrome and colorectal cancer, especially younger patients.

Management and surveillance of Lynch syndrome

2.13 The 2013 European HNPCC's revised guidelines for managing Lynch syndrome recommend that people with a Lynch syndrome mutation take aspirin because this can reduce the incidence of cancer in Lynch syndrome mutation carriers.

2.14 The 2013 European HNPCC's revised guidelines for managing Lynch syndrome recommend that people with a Lynch syndrome mutation have a colonoscopy every 1 to 2 years. The BSG and ACPGBI's guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (2010) recommend that people with a Lynch syndrome mutation are offered total colonic surveillance at least every 2 years from the age of 25.

  • National Institute for Health and Care Excellence (NICE)