<i>POT1</i> mutation spectrum in tumour types commonly diagnosed among <i>POT1</i>-associated hereditary cancer syndrome families.

Abstract

The shelterin complex is composed of six proteins that protect and regulate telomere length, including protection of telomeres 1 (POT1). Germline <i>POT1</i> mutations are associated with an autosomal dominant familial cancer syndrome presenting with diverse malignancies, including glioma, angiosarcoma, colorectal cancer and melanoma. Although somatic <i>POT1</i> mutations promote telomere elongation and genome instability in chronic lymphocytic leukaemia, the contribution of <i>POT1</i> mutations to development of other sporadic cancers is largely unexplored. We performed logistic regression, adjusted for tumour mutational burden, to identify associations between <i>POT1</i> mutation frequency and tumour type in 62 368 tumours undergoing next-generation sequencing. A total of 1834 tumours harboured a non-benign mutation of <i>POT1</i> (2.94%), of which 128 harboured a mutation previously reported to confer familial cancer risk in the setting of germline <i>POT1</i> deficiency. Angiosarcoma was 11 times more likely than other tumours to harbour a <i>POT1</i> mutation (p=1.4×10^-20), and 65% of <i>POT1</i>-mutated angiosarcoma had >1 mutations in <i>POT1</i>. Malignant gliomas were 1.7 times less likely to harbour a <i>POT1</i> mutation (p=1.2×10^-3) than other tumour types. Colorectal cancer was 1.2 times less likely to harbour a <i>POT1</i> mutation (p=0.012), while melanoma showed no differences in <i>POT1</i> mutation frequency versus other tumours (p=0.67). These results confirm a role for shelterin dysfunction in angiosarcoma development but suggest that gliomas arising in the context of germline <i>POT1</i> deficiency activate a telomere-lengthening mechanism that is uncommon in gliomagenesis.