Detecting DNA mismatch repair gene mosaicism

Lynch syndrome is caused by germline pathogenic variants in the DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2 and predisposes carriers to colorectal, endometrial, sebaceous skin tumours and other solid cancers including a preponderance to develop multiple primary cancers making the identification of carriers important for effective clinical management and cancer prevention.  Somatic mosaicism is a reported mechanism for several cancer predisposition genes, however, a systematic study of mosaicism in the MMR genes has not been conducted to date.

Currently, tumour sequencing of colorectal, endometrial, or sebaceous skin tumours identifies a subgroup of patients where somatic MMR gene mutations, but not a germline MMR gene pathogenic variant, are identified suggesting this subgroup of tumours has a sporadic rather than inherited (Lynch syndrome) cause.  The hypothesis for this project is that somatic mosaicism underlies a significant proportion of patients where currently only somatic MMR gene mutations are identified.  Identifying patients with previously unidentified Lynch syndrome due to somatic mosaicism will have important consequences for their personalised clinical management as well as for their family members.  The project will involve developing sensitive droplet digital PCR assays to screen for MMR gene variants in multiple tissue sources from an existing patient group in the ANGELS study.

By the end of this project the student will have developed skills in the analysis of tumour sequencing and droplet digital PCR data. The outcomes of this project will inform clinical diagnostic testing for Lynch syndrome and, therefore, has significant clinical and translational significance.