TINF2 is a haploinsufficient tumor suppressor that limits telomere length.

Isabelle Schmutz,Kaori K Takai,Liesbeth Spruijt,Seunga Sara Choo,Emma J Van Grinsven,Franziska K Lorbeer,Titia De Lange,Maaike Haadsma,Richarda M De Voer,Dirk Hockemeyer,Marjolijn Cj Jongmans,Arjen R Mensenkamp

doi:10.7554/elife.61235

Abstract

Telomere shortening is a presumed tumor suppressor pathway that imposes a proliferative barrier (the Hayflick limit) during tumorigenesis. This model predicts that excessively long somatic telomeres predispose to cancer. Here, we describe cancer-prone families with two unique TINF2 mutations that truncate TIN2, a shelterin subunit that controls telomere length. Patient lymphocyte telomeres were unusually long. We show that the truncated TIN2 proteins do not localize to telomeres, suggesting that the mutations create loss-of-function alleles. Heterozygous knock-in of the mutations or deletion of one copy of TINF2 resulted in excessive telomere elongation in clonal lines, indicating that TINF2 is haploinsufficient for telomere length control. In contrast, telomere protection and genome stability were maintained in all heterozygous clones. The data establish that the TINF2 truncations predispose to a tumor syndrome. We conclude that TINF2 acts as a haploinsufficient tumor suppressor that limits telomere length to ensure a timely Hayflick limit.

Highlights

The idea that telomere attrition could repress the outgrowth of early stage cancer originates from the observation that telomeres shorten in normal human cells (Harley et al, 1990; Hastie et al, 1990; de Lange et al, 1990; reviewed in Maciejowski and de Lange, 2017)
In agreement with this theory, telomere shortening leads to a proliferative barrier in vitro that can be overcome when telomerase is activated through expression of hTERT Bodnar et al, 1998; telomerase activity is required to create tumorigenic derivatives from normal human cells Hahn et al, 1999; and telomerase activation is a hallmark of human cancer (Shay and Bacchetti, 1997)
No loss of heterozygosity was detected in six tumors tested and second hits in TINF2 were excluded in four of the six tumors analyzed by whole-exome sequencing (F3:III-1; Astrocytoma, F2:II-1; Melanoma and breast cancer, F1:II-4; colorectal cancer (CRC), see Figure 1—figure supplement 2)

Summary

Introduction

The idea that telomere attrition could repress the outgrowth of early stage cancer originates from the observation that telomeres shorten in normal human cells (Harley et al, 1990; Hastie et al, 1990; de Lange et al, 1990; reviewed in Maciejowski and de Lange, 2017) In agreement with this theory, telomere shortening leads to a proliferative barrier in vitro (the Hayflick limit Shay and Wright, 2000) that can be overcome when telomerase is activated through expression of hTERT Bodnar et al, 1998; telomerase activity is required to create tumorigenic derivatives from normal human cells Hahn et al, 1999; and telomerase activation is a hallmark of human cancer (Shay and Bacchetti, 1997). After removal of telomerase, a cancer cell line with very long telomeres remained

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Conclusion