UKCGG Unexplained Mismatch Repair Deficiency consensus meeting
Because of potential therapeutic implications, and expanding access to treatment with or clinical trials involving checkpoint inhibition, assessment of mismatch repair status of a wide range of tumours, including typical Lynch Syndrome-associated cancers as well as cancers that are less likely to be associated with Lynch Syndrome, is increasing. This is usually undertaken by immunohistochemistry testing to assess for expression of MMR proteins, or by microsatellite instability testing. As per current best practice guidelines, further testing is usually recommended to clarify the aetiology of dMMR when it is identified. This pathway is complex and multistep and can comprise somatic BRAF testing, tumour-based and/or constitutional MLH1 promoter hypermethylation testing, germline MMR gene testing (which may/may not include long-range PCR of PMS2) and tumour-based MMR gene testing +/- loss of heterozygosity testing. The term "Lynch-like Syndrome" has traditionally been applied where the aetiology of dMMR has not been identified, to direct colonoscopic screening in the proband in whom cancer has been identified, as well as their first-degree family members - to safeguard against a potentially missed germline genetic variant predisposing to colorectal cancer risk in that family. However, while enhanced colonoscopic screening may be appropriate where clinical suspicion of a heritable predisposition to colorectal cancer is high, this may represent over-investigation in those families where the likelihood of dMMR being due to Lynch Syndrome is low, even in the setting of "unexplained dMMR".
Following anecdotal observations of variability in the extent to which aetiology of dMMR was being investigated, and in the management of families where unexplained dMMR cancer has been identified, a UK Cancer Genetics Group national MDT was held on the topic, led by colleagues in South East Scotland Clinical Genetics service.
Further to that meeting, we held a national consensus meeting on 25th April 2023. In advance of the meeting, a survey was circulated to get a snapshot of practice across the UK. At the meeting, we presented the outcome of that survey, as well as an overview of the discussion at the national MDT, and a number of invited expert speakers provided an overview of testing strategies in different tumour types, and an overview of the history of "Lynch like Syndrome".
Thereafter, a number of polls were run in real-time to try to generate consensus about extent of investigation and screening in these families.
Please find agenda and presentation slides here below. A summary of outputs and recording of meeting will follow in due course.