TY - JOUR T1 - <em>POT1</em> mutation spectrum in tumour types commonly diagnosed among <em>POT1</em>-associated hereditary cancer syndrome families JF - Journal of Medical Genetics JO - J Med Genet SP - 664 LP - 670 DO - 10.1136/jmedgenet-2019-106657 VL - 57 IS - 10 AU - Erica Shen AU - Joanne Xiu AU - Giselle Y Lopez AU - Rex Bentley AU - Ali Jalali AU - Amy B Heimberger AU - Matthew N Bainbridge AU - Melissa L Bondy AU - Kyle M Walsh Y1 - 2020/10/01 UR - http://jmg.bmj.com/content/57/10/664.abstract N2 - Background The shelterin complex is composed of six proteins that protect and regulate telomere length, including protection of telomeres 1 (POT1). Germline POT1 mutations are associated with an autosomal dominant familial cancer syndrome presenting with diverse malignancies, including glioma, angiosarcoma, colorectal cancer and melanoma. Although somatic POT1 mutations promote telomere elongation and genome instability in chronic lymphocytic leukaemia, the contribution of POT1 mutations to development of other sporadic cancers is largely unexplored.Methods We performed logistic regression, adjusted for tumour mutational burden, to identify associations between POT1 mutation frequency and tumour type in 62 368 tumours undergoing next-generation sequencing.Results A total of 1834 tumours harboured a non-benign mutation of POT1 (2.94%), of which 128 harboured a mutation previously reported to confer familial cancer risk in the setting of germline POT1 deficiency. Angiosarcoma was 11 times more likely than other tumours to harbour a POT1 mutation (p=1.4×10−20), and 65% of POT1-mutated angiosarcoma had &gt;1 mutations in POT1. Malignant gliomas were 1.7 times less likely to harbour a POT1 mutation (p=1.2×10−3) than other tumour types. Colorectal cancer was 1.2 times less likely to harbour a POT1 mutation (p=0.012), while melanoma showed no differences in POT1 mutation 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 germline POT1 deficiency activate a telomere-lengthening mechanism that is uncommon in gliomagenesis. ER -