Rates and outcomes of testing for lynch syndrome in a national colorectal cancer screening programme

1 Background

Lynch Syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC), accounting for 2–4% of all CRC cases [1] . LS is an autosomal dominant condition arising from germline pathogenic mutations in mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS2 or an epigenetic mutation in the EPCAM gene which leads to silencing of MSH2.

Morbidity and mortality from CRC can be significantly reduced in those with LS through close endoscopic surveillance which aims to remove precursor lesions and detect CRC at an earlier stage. Colorectal surveillance has been shown to reduce overall mortality in LS by up to 65% [2] . However, surveillance can only be implemented in those known to have LS and it is thought that up to 95% of those with LS are unaware of their diagnosis [3] . Universal testing of all newly diagnosed CRCs, irrespective of age, clinical or family history, for LS is one way in which the detection of LS can be increased and has been widely endorsed internationally 3456 .

Testing of CRCs for LS aims to detect MMR deficiency using either immunohistochemistry (IHC) for MMR proteins or polymerase chain reaction (PCR) for microsatellite instability (MSI). MMR deficiency or MSI are found in LS associated CRCs but also in 10–15% of sporadic CRCs. Most MMR deficient sporadic CRCs are associated with hypermethylation of the MLH1 promotor region which results in silencing of MLH1 [7] . Therefore, CRCs with loss of MLH1, combined loss of MLH1 and PMS2 or MSI-High, should be tested for BRAF V600E mutation, which correlates with hypermethylation of MLH1, or tested directly for hypermethylation of the MLH1 promoter region [3] . Tumours found to have BRAF V600E mutation or hypermethylation of MLH1 are more likely to be sporadic than caused by underlying LS. If neither are detected individuals should be referred for genetic counselling and testing for a corresponding germline mutation. This is also the case for those with loss of MSH2, MSH6 or isolated loss of PMS2. If no corresponding mutation is found on germline testing double somatic testing of the tumour should be considered. If no evidence of a double somatic mutation is identified in these individuals, they are said to have Lynch-like syndrome and need close endoscopic surveillance also [8] .

BowelScreen is Ireland’s national CRC screening programme. Screening is currently offered to those age 60–69 years with planned expansion to 55–75 years. All individuals age 60–69 years, irrespective of family history, are invited to participate in two yearly cycles. The programme uses faecal immunochemical testing (FIT), with a cut-off threshold of 45 ug/g, and a positivity rate of 5%. Those with a positive FIT, if deemed suitable, are invited for colonoscopy at one of 14 screening sites across the country. 79.5% of individuals with a positive FIT proceeded to colonoscopy. Testing for LS in CRCs diagnosed through BowelScreen is currently at the discretion of each individual screening site as there is no national standardised guideline for universal testing in place. There are also currently no national guidelines or referral pathways for individuals with MMR deficient CRCs.

To our knowledge, the rates and outcomes of testing for LS in our CRC screening population have not been examined previously. The aim of this study was to determine the proportion of CRCs, diagnosed through BowelScreen at two screening sites, that were tested for LS and to examine the outcomes of testing. We also aimed to examine the downstream management of CRCs found to be MMR deficient and rates referral of appropriate individuals to clinical genetic services.