Characterisation of clinical and pathological features associated with isolated PMS2 loss in Lynch Syndrome associated colorectal cancer

Aine Stakelum, Éanna Ryan, Peter Molony, Robert Geraghty, Sean Martin, Ann Hanly, Ronan O’Connell, Rory Kennelly, Kieran Sheahan, Des Winter

Centre for Colorectal Disease, St Vincent’s Hospital, Dublin 4, Ireland


Objectives: Lynch syndrome is the commonest hereditary colorectal cancer syndrome and results from a germline mutation in one of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. Universal screening of all incident CRCs for DNA mismatch repair deficiency (dMMR) is now recommended to identify patients with LS and guide surveillance and treatment options. This study aimed to characterise the clinical and pathological characteristics of a cohort of patients with isolated PMS2 loss.


Methods: Immunohistochemistry for dMMR was performed on all incident CRCs between 2006 and 2018. Data including patient demographics, clinical details, and histological tumour parameters, was extracted from original pathology reports with any missing information being repopulated by review of the original slides.


Results: 3095 colorectal cancers were resected over the 12-year study period and 328 of these displayed mismatch repair deficiency on immunohistochemical staining. Of these, 16 patients (56% male) showed isolated PMS2 loss. Of those patients who accepted genetic testing, 88.9% had a germline mutation in the PMS2 gene. The majority (75%) presented with stage 2 disease with no patients having metastatic disease at diagnosis. Tumours showed a predilection for the right colon (69%) and exhibited a localised inflammatory response with more than half demonstrating a high Klintrup-Makinen score. Patients with isolated PMS2 loss had a favourable prognosis with no recurrences and a 5-year disease-free survival rate of 83%.


Conclusions: Isolated PMS2 loss is a rare presentation of Lynch Syndrome and is associated with favourable survival outcomes.