POT1 mutation spectrum in tumour types commonly diagnosed among POT1-associated hereditary cancer syndrome families

Abstract

BackgroundThe 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.MethodsWe 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.ResultsA 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 >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).ConclusionsThese 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.

Role of POT1 in Human Cancer

“…This figure comprises both missense and truncating mutations (2.3%, n = 10/444), as well as gene copy number amplifications (1.8%, n = 8/444). Similarly, Shen et al found that non-benign POT1 variants were observed in 3.7% of melanoma cases examined ( n = 64/1735) [ 65 ] ( Figure 2 ).…”

“…A recent pan-cancer study of POT1 mutations categorized genetic variants according to the standards of the American College of Medical Genetics and Genomics, and referred collectively to all POT1 variants that are neither “presumed benign” nor “benign” as “non-benign”. By this classification, 2.9% of tumors ( n = 1834/62,368) were found to have non-benign POT1 mutations [ 65 ]. Among the tumor categories with more than 50 cases, angiosarcoma (23.3%, n = 20/86) and cutaneous squamous cell carcinoma (9.1%, n = 20/220) had the highest prevalence of POT1 mutations [ 65 ] ( Figure 2 ).…”

“…By this classification, 2.9% of tumors ( n = 1834/62,368) were found to have non-benign POT1 mutations [ 65 ]. Among the tumor categories with more than 50 cases, angiosarcoma (23.3%, n = 20/86) and cutaneous squamous cell carcinoma (9.1%, n = 20/220) had the highest prevalence of POT1 mutations [ 65 ] ( Figure 2 ).…”

“…Another somatic variant of POT1 (p.Arg432*) has been identified in a small CAS cohort (20%, n = 1/5) [ 95 ]. Shen et al [ 65 ] found that angiosarcoma was 11 times more likely to harbor mutated POT1 than other cancers overall.…”

“…The prevalence of POT mutations defined as neither “presumed benign” nor “benign” was investigated in 62,368 tumors. The figure shows the POT1 mutation burden in some tumor categories that included more than 50 cases (data from [ 65 ]). The number in brackets indicate the total number of cases for each cancer type.…”