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. 2020 Oct;57(10):664-670.
doi: 10.1136/jmedgenet-2019-106657. Epub 2020 Jan 14.

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

Erica Shen  1 , Joanne Xiu  2 , Giselle Y Lopez  3   4 , Rex Bentley  3   4 , Ali Jalali  5 , Amy B Heimberger  6 , Matthew N Bainbridge  7 , Melissa L Bondy  8 , Kyle M Walsh  9   3   4
Affiliations

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

Erica Shen et al. J Med Genet. 2020 Oct.

Abstract

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 >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.

Keywords: POT1 mutation; atrx; hereditary cancer syndrome families; telomere; tert.

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Conflict of interest statement

Competing interests: JX is an employee of Caris Life Sciences, Inc. ABH holds stock in, and is a paid advisory board member for, Caris Life Sciences, Inc. No other authors have identified potential conflicts of interest relevant to the manuscript.

Figures

Figure 1:
Figure 1:
Summary of reported POT1 mutations in POT1-associated hereditary familial cancer syndromes.
Figure 2:
Figure 2:
Summary of POT1 mutations in angiosarcoma. Deleterious mutations were found on both the DNA oligonucleotide/oligosarccharide and the TPP-1-binding domains of POT1. Variants are listed with complete HGVS nomenclature in Supplementary Table 3.
Figure 3:
Figure 3:
Box plots of average TMB for different categories of POT1 mutation status.
See this image and copyright information in PMC

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