Germline mutations in Protection of Telomeres 1 in two families with Hodgkin lymphoma

Mary L McMaster; Chongkui Sun; Maria T Landi; Sharon A Savage; Melissa Rotunno; Xiaohong R Yang; Kristine Jones; Aurélie Vogt; Amy Hutchinson; Bin Zhu; Mingyi Wang; Belynda Hicks; Anand Thirunavukarason; Douglas R Stewart; Stella Koutros; Alisa M Goldstein; Stephen J Chanock; Neil E Caporaso; Margaret A Tucker; Lynn R Goldin; Yie Liu

doi:10.1111/bjh.15203

Germline mutations in Protection of Telomeres 1 in two families with Hodgkin lymphoma

Br J Haematol. 2018 May;181(3):372-377. doi: 10.1111/bjh.15203.

Authors

Mary L McMaster¹, Chongkui Sun², Maria T Landi³, Sharon A Savage¹, Melissa Rotunno⁴, Xiaohong R Yang³, Kristine Jones⁵, Aurélie Vogt⁵, Amy Hutchinson⁵, Bin Zhu⁵, Mingyi Wang⁵, Belynda Hicks⁵, Anand Thirunavukarason², Douglas R Stewart¹, Stella Koutros⁶, Alisa M Goldstein¹, Stephen J Chanock⁷, Neil E Caporaso⁶, Margaret A Tucker⁸, Lynn R Goldin³, Yie Liu²

Affiliations

¹ Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute; NIH, Bethesda, MD, USA.
² Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, Baltimore, MD, USA.
³ Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute; NIH, Bethesda, MD, USA.
⁴ Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, Bethesda, MD, USA.
⁵ Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute; NIH, Bethesda, MD, USA.
⁶ Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute; NIH, Bethesda, MD, USA.
⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute; NIH, Bethesda, MD, USA.
⁸ Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute; NIH, Bethesda, MD, USA.

Abstract

In a previous whole exome sequencing of patients from 41 families with Hodgkin lymphoma, we identified two families with distinct heterozygous rare coding variants in POT1 (D224N and Y36H), both in a highly conserved region of the gene. POT1 D224N mutant did not bind to a single-stranded telomere oligonucleotide in vitro suggesting the mutation perturbs POT1's ability to bind to the telomeric G-rich overhang. Human HT1080 cells expressing POT1 D224N and lymphoblastoid cells carrying Y36H both showed increased telomere length and fragility in comparison to wild type cells. This strongly suggests that mutant POT1 causes chromosome instability and may play a role in lymphomagenesis in these families.

Keywords: POT1; Hodgkin lymphoma; genetic analysis; genomic instability; telomere.

Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Amino Acid Substitution
Cell Line, Tumor
Chromosomal Instability*
Family*
Female
Germ-Line Mutation*
Hodgkin Disease* / genetics
Hodgkin Disease* / metabolism
Hodgkin Disease* / pathology
Humans
Male
Mutation, Missense*
Shelterin Complex
Telomere / genetics
Telomere / metabolism
Telomere-Binding Proteins* / genetics
Telomere-Binding Proteins* / metabolism

Substances

POT1 protein, human
Shelterin Complex
Telomere-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding