TINF2 is a major susceptibility gene in Danish patients with multiple primary melanoma

Marlene Richter Jensen; Anne Marie Jelsig; Anne-Marie Gerdes; Lisbet Rosenkrantz Hölmich; Kati Hannele Kainu; Henrik Frank Lorentzen; Mary Højgaard Hansen; Mads Bak; Peter A Johansson; Nicholas K Hayward; Thomas Van Overeem Hansen; Karin A W Wadt

doi:10.1016/j.xhgg.2023.100225

TINF2 is a major susceptibility gene in Danish patients with multiple primary melanoma

HGG Adv. 2023 Jul 23;4(4):100225. doi: 10.1016/j.xhgg.2023.100225. eCollection 2023 Oct 12.

Authors

Affiliations

¹ Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark.
² Department of Plastic and Reconstructive Surgery, Herlev and Gentofte Hospital, 2730 Herlev, Denmark.
³ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁴ Department of Dermatology and Allergology, Herlev and Gentofte Hospital, 2900 Gentofte, Denmark.
⁵ Department of Dermatology, Aarhus University Hospital, 8200 Aarhus, Denmark.
⁶ QIMR Berghofer, Brisbane, QLD 4006, Australia.

Abstract

TINF2 encodes the TINF2 protein, which is a subunit in the shelterin complex critical for telomere regulation. Three recent studies have associated six truncating germline variants in TINF2 that have previously been associated with a cancer predisposition syndrome (CPS) caused by elongation of the telomeres. This has added TINF2 to the long telomere syndrome genes, together with other telomere maintenance genes such as ACD, POT1, TERF2IP, and TERT. We report a clinical study of 102 Danish patients with multiple primary melanoma (MPM) in which a germline truncating variant in TINF2 (p.(Arg265Ter)) was identified in four unrelated participants. The telomere lengths of three variant carriers were >90% percentile. In a routine diagnostic setting, the variant was identified in two more families, including an additional MPM patient and monozygotic twins with thyroid cancer and other cancer types. A total of 10 individuals from six independent families were confirmed carriers, all with cancer history, predominantly melanoma. Our findings suggest a major role of TINF2 in Danish patients with MPM. In addition to melanoma, other cancers in the six families include thyroid, renal, breast, and sarcoma, supporting a CPS in which melanoma, thyroid cancer, and sarcoma predominate. Further studies are needed to establish the full spectrum of associated cancer types and characterize lifetime cancer risk in carriers.

Keywords: germline TINF2; long telomeres; multiple primary melanoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Denmark / epidemiology
Humans
Melanoma* / genetics
Neoplasms, Multiple Primary*
Sarcoma*
Syndrome
Telomere-Binding Proteins / genetics
Thyroid Neoplasms*

Substances

TINF2 protein, human
Telomere-Binding Proteins