POT1mutation spectrum in tumour types commonly diagnosed amongPOT1-associated hereditary cancer syndrome families

Background The shelterin complex is composed of six proteins that protect and regulate telomere length, including protection of telomeres 1 (POT1). GermlinePOT1mutations are associated with an autosomal dominant familial cancer syndrome presenting with diverse malignancies, including glioma, angiosarcoma, colorectal cancer and melanoma. Although somaticPOT1mutations promote telomere elongation and genome instability in chronic lymphocytic leukaemia, the contribution ofPOT1mutations to development of other sporadic cancers is largely unexplored. Methods We performed logistic regression, adjusted for tumour mutational burden, to identify associations betweenPOT1mutation frequency and tumour type in 62 368 tumours undergoing next-generation sequencing. Results A total of 1834 tumours harboured a non-benign mutation ofPOT1(2.94%), of which 128 harboured a mutation previously reported to confer familial cancer risk in the setting of germlinePOT1deficiency. Angiosarcoma was 11 times more likely than other tumours to harbour aPOT1mutation (p=1.4x10(-20)), and 65% ofPOT1-mutated angiosarcoma had >1 mutations inPOT1. Malignant gliomas were 1.7 times less likely to harbour aPOT1mutation (p=1.2x10(-3)) than other tumour types. Colorectal cancer was 1.2 times less likely to harbour aPOT1mutation (p=0.012), while melanoma showed no differences inPOT1mutation frequency versus other tumours (p=0.67). Conclusions These results confirm a role for shelterin dysfunction in angiosarcoma development but suggest that gliomas arising in the context of germlinePOT1deficiency activate a telomere-lengthening mechanism that is uncommon in gliomagenesis.