A truncating germline mutation of TINF2 in individuals with thyroid cancer or melanoma results in longer telomeres.

Publication date: Jan 13, 2020

Our genome sequencing analysis revealed a frameshift mutation in the shelterin gene TINF2 gene in a large family with individuals affected with papillary thyroid carcinoma (PTC) and melanoma. Here we further characterized the mutation and screened for coding variants in the six shelterin genes in 24 families.

Sanger sequencing was performed to screen for the TINF2 mutation in the key family. Quantitative RT-PCR was used for TINF2 gene expression analysis. Exogenous expression and co-immunoprecipitation techniques were used for assessing TINF2 binding to TERF1. Relative telomere length (RTL) was quantified in DNAs from lymphocytes using quantitative real-time PCR. Whole exome sequencing (WES) was performed in 7 families with individuals affected with PTC and other cancer types. Screening for DNA variants in shelterin genes was performed using whole genome sequencing data from 17 families and WES data from 7 families.

The TINF2 mutation (TINF2 p.Trp198fs) showed complete co-segregation with PTC and melanoma in the key family. The mutation is not reported in databases and not identified in 23 other families we screened. The expression of TINF2 was borderline reduced in individuals with the mutation. The truncated TINF2 protein showed abolished binding to TERF1. The RTL in the individuals with the mutation was significantly longer when compared with those without the mutation from the same family as well as compared with 62 healthy controls. Among the 24 families we identified 3 missense and 1 synonymous variant(s) in two shelterin genes (TINF2 and ACD).

The rare frameshift mutation in the TINF2 gene and the associated longer telomere length suggest that dysregulated telomeres could be a mechanism predisposing to PTC and melanoma. DNA coding variants in shelterin genes are rare. Further studies are required to evaluate the roles of variants in shelterin genes in thyroid cancer and melanoma.

He, H., Li, W., Comiskey, D.F., Liyanarachchi, S., Nieminen, T.T., Wang, Y., DeLap, K.E., Brock, P., and de la Chapelle, A. A truncating germline mutation of TINF2 in individuals with thyroid cancer or melanoma results in longer telomeres. 25444. 2020 Thyroid.

Concepts Keywords
Exome Branches of biology
Frameshift Mutation Telomeres
Genome Molecular biology
Immunoprecipitation Chromosomes
Lymphocytes TINF2
Melanoma Shelterin
Missense ACD
Mutation Frameshift mutation
Papillary Thyroid Carcinoma Melanoma
Real Time PCR
Sanger Sequencing


Type Source Name
disease MESH thyroid cancer
pathway KEGG Thyroid cancer
disease MESH melanoma
pathway KEGG Melanoma
disease MESH frameshift mutation
disease MESH papillary thyroid carcinoma
disease MESH cancer


Original Article

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