Loss-Of-Function Variants In Pot1 Predispose To Uveal Melanoma

JOURNAL OF MEDICAL GENETICS(2021)

Cited 4|Views48
No score
Abstract
Pathogenic germline variants in protection of telomeres 1 ( POT1 ) result in a tumour predisposition syndrome (POT1-TPDS), which includes cutaneous melanoma (CM), glioma, chronic lymphocytic leukaemia (CLL), colorectal cancer, thyroid cancer and sarcoma.1 Through whole-genome sequencing (WGS) of 20 Australian individuals affected with both CM and uveal melanoma (UM), our study identified two truncating variants in POT1 . Functional analyses assessing telomere length indicated longer telomeres in variant carriers, compared with healthy age-matched controls, similar to observations in CM patients with loss-of-function POT1 variants.2\n\nThe risk for development of cancers such as CM and UM is influenced by genetics. In UM, this has mainly been attributed to loss-of-function variants in BAP1 .3 Predisposition in CM is largely due to multiple low-penetrance susceptibility alleles; however, 5%–12% of cases report first-degree or second-degree relatives with CM and in a proportion of these families disease segregates with high-penetrance single gene variants in CDKN2A , CDK4 and the telomere maintenance genes POT1 , ACD , TERF2IP and TERT (reviewed in ref 4). Pathogenic germline variants in POT1 result in an increase in telomere length and susceptibility to many cancer types including CM, glioma, CLL, thyroid cancer, colorectal cancer, angiosarcoma1 and osteosarcoma,5 now termed the POT1-TPDS. There is also recent evidence to suggest histological differences in melanomas of POT1 variant carriers versus non-carriers, highlighting the importance of telomere dysfunction on tumour biology.6 POT1 binds to telomeric single-stranded DNA (ssDNA) overhangs, preventing telomerase accessibility. Highly conserved oligonucleotide/oligosaccharide-binding (OB) folds in POT1 are essential for specific binding to ssDNA, and loss of function of these OB domains leads to increased telomere elongation due to an inability to inhibit telomerase. Certain germline missense variants occurring in these OB domains, and other protein truncating variants, have been reported to disrupt POT1 function, leading to …
More
Translated text
Key words
genetics, eye diseases, genetic predisposition to disease, germ-line mutation, human genetics
AI Read Science
Must-Reading Tree
Example
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined