Long term follow-up and advances in genetic technologies result in improved management of families with inherited colorectal cancers

  1. Gareth Evans1,2, Fiona Lalloo2, Kate Green2, Andrew Wallace2, Naomi Bowers2, Emma Woodward1

1University of Manchester, Manchester, United Kingdom. 2Manchester Foundation Trust, Manchester, United Kingdom


Objective:To evaluate tumour mismatch repair deficiency(MMRD) and prevalence of Lynch Syndrome in patients referred to Manchester Centre for Genomic Medicine (population=5.6M).

Methods:Tumour testing utilised MSI or immunohistochemistry for MMRD followed by germline mutation testing and latterly somatic.

Results:2652 index tumours have been tested by IHC forMMRD, 332/2652(12.5%) had protein loss with 225 (8.4%)having MLH1 loss.149 of these have had methylation analysis of which 76 (51%) were hypermethylated. One  was found to have constitutional methylation but only 1/22(4%) samples with germline testing had a constitutional pathogenic variant in MLH1.   BRAF c.1799T>A was only found in about half of the cases with hypermethylation and 3/11(27%) with germline testing had a constitutional pathogenic MLH1 variant . Overall of 104 patients with MLH1 loss and no methylation or BRAF 58(56%) had a constitutional pathogenic variant in MLH1. 44/46 of those with no germline variant underwent tumour somatic testing this identified likely causal somatic variants in 32 (73%). Of 186 patients with tumours showing MSH2/MSH6 loss 107(58%) had germline pathogenic variants in one of the genes. Somatic testing of tumour identified likely pathogenic somatic variants in MSH2/MSH6 in 34/41(83%) with no germline variant found. Tumour testing has also identified 7 germline pathogenic variants in deceased relatives.

Conclusions:Reflex testing of all colorectal cancers is likely to leave many individuals with an uncertain diagnosis with IHC loss no methylation and no germline variant. Somatic mutation testing is extremely effective at reducing this group with likely sporadic somatic MMRD.