Mutation analysis of Beta2-Microglobulin identifies a subset of deficient mismatch repair (dMMR) colorectal cancers which are protected from disease recurrence.


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Susan Richman1,Paul Barrow2,Andrew Wallace3,Kelly Handley4,Gordon Hutchins5,David Kerr6,Laura Magill4,Gareth Evans3,Richard Gray6,Phil Quirke5,James Hill2
1Leeds Teaching Hospitals NHS Trust,2Manchester Royal Infirmary,3Central Manchester University Hospitals NHS Trust,4University of Birmingham,5University of Leeds,6University of Oxford

Abstract

Background

Stage II and III colorectal cancers (CRCs) harbouring deficient mismatch repair (dMMR), have a better prognosis compared with tumours displaying proficient mismatch repair (pMMR). Beta2-Microglobulin (B2M), a component of the HLA Class I complex, is often mutated in dMMR CRC and may afford protection from metastatic progression. We investigated this hypothesis by determining B2M mutation status and B2M protein expression relative to recurrence rates in patients in the stage II QUASAR clinical trial.

 

Method

A subset of dMMR and pMMR tumours were selected for study. Mutation analysis of dMMR (n=121) and pMMR (n=108) tumours was carried out by Sanger sequencing of all three coding exons of B2M. B2M protein expression was profiled by immunohistochemistry. Both parameters were correlated with disease recurrence rates.

Results

The presence of pathogenic B2M mutations was significantly higher in dMMR tumours (39/121; 32%) than in pMMR cases (3/104; 2.9%) (p<0.0001). Within the dMMR subgroup, none the 39 B2M-mutant tumours recurred, compared to 18% (14/77) of the B2M-wildtype tumours (p<0.005). Furthermore, none of the dMMR B2M-mutant tumours displayed extramural vascular invasion (EMVI), compared to 16% (12/74) of B2M-wildtype tumours. Protein expression was assessable in 88 tumours with known B2M mutation status, and complete loss of B2M expression seen in 87% (20/23) tumours containing a pathogenic mutation.

Conclusion

 B2M mutations were detected in a third of dMMR tumours, with none of these patients showing disease recurrence. The mechanism underlying this protective effect remains unclear, but impaired antigen presentation by these tumour cells may activate Natural killer (NK) cells to destroy circulating tumour cells. B2M mutation status has potential clinical utility as a prognostic biomarker in stage II dMMR CRC.