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

• Published in: HGG advances Vol. 4; no. 4; p. 100225
• Main Authors: Jensen, Marlene Richter, Jelsig, Anne Marie, Gerdes, Anne-Marie, Hölmich, Lisbet Rosenkrantz, Kainu, Kati Hannele, Lorentzen, Henrik Frank, Hansen, Mary Højgaard, Bak, Mads, Johansson, Peter A., Hayward, Nicholas K., Van Overeem Hansen, Thomas, Wadt, Karin A.W.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 12.10.2023; Elsevier
• Subjects: germline TINF2; long telomeres; multiple primary melanoma; multiple primary melanoma; germline TINF2; long telomeres
• ISSN: 2666-2477; 2666-2477
• DOI: 10.1016/j.xhgg.2023.100225

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. We report a germline TINF2 variant associated with long telomeres, which we identified in 10 individuals from six independent families, all with cancer history, predominantly melanomas, supportive of long-telomere-associated cancer predisposition. Our findings suggest a major role of TINF2 in Danish patients with multiple primary melanoma.