WRN deficiency generates oncogenic rearrangements at TA-rich tandem repeats
Abstract
Werner syndrome, a premature-aging disorder caused by inherited loss of the WRN helicase, predisposes to a narrow set of cancers, including melanoma and sarcoma, through mechanisms that have been unclear. WRN resolves the secondary structures that TA-dinucleotide repeats form, a role established for the expanded repeats of mismatch-repair-deficient cancers. We show that WRN loss also destabilizes native, unexpanded TA-rich tandem repeats, which become fragile sites where chromosomes break and rearrange. In melanoma these rearrangements recurrently produce an identical 15.7Mb-long deletion that transcriptionally activates TERT, the earliest driver of these tumors, and separately disrupt tumor suppressors such as CDKN2A/B and NF1. The same class of rearrangement occurs in WRN-deficient cancers of other types. WRN deficiency is thus a source of instability at TA-rich tandem repeats that generates oncogenic rearrangements.
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BibTeX
@misc{wang2026deficiency,
title = {{WRN deficiency generates oncogenic rearrangements at TA-rich tandem repeats}},
author = {Meng Wang and Hui Pan and Anastasia Samarkina and Austin John Escobar and Noel Cruz Pacheco and Satoru Mizuhashi and Jamie D. Aquino and Katy K. Tsai and Adil I. Daud and Ivan EI-Sayed and Haruto Nishida and Sakuhei Fujiwara and Takashi Hirano and Sine Phelan and Allan O’Keefe and Sean Dinneen and A. Hunter Shain and Makoto Goto and Iwei Yeh and Boris C. Bastian},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.16.758976},
url = {https://www.biorxiv.org/content/10.64898/2026.10.16.758976v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - WRN deficiency generates oncogenic rearrangements at TA-rich tandem repeats
AU - Meng Wang
AU - Hui Pan
AU - Anastasia Samarkina
AU - Austin John Escobar
AU - Noel Cruz Pacheco
AU - Satoru Mizuhashi
AU - Jamie D. Aquino
AU - Katy K. Tsai
AU - Adil I. Daud
AU - Ivan EI-Sayed
AU - Haruto Nishida
AU - Sakuhei Fujiwara
AU - Takashi Hirano
AU - Sine Phelan
AU - Allan O’Keefe
AU - Sean Dinneen
AU - A. Hunter Shain
AU - Makoto Goto
AU - Iwei Yeh
AU - Boris C. Bastian
PY - 2026
DA - 2026/10/16
PB - bioRxiv
DO - 10.64898/2026.10.16.758976
UR - https://www.biorxiv.org/content/10.64898/2026.10.16.758976v1
AB - Werner syndrome, a premature-aging disorder caused by inherited loss of the WRN helicase, predisposes to a narrow set of cancers, including melanoma and sarcoma, through mechanisms that have been unclear. WRN resolves the secondary structures that TA-dinucleotide repeats form, a role established for the expanded repeats of mismatch-repair-deficient cancers. We show that WRN loss also destabilizes native, unexpanded TA-rich tandem repeats, which become fragile sites where chromosomes break and rearrange. In melanoma these rearrangements recurrently produce an identical 15.7Mb-long deletion that transcriptionally activates TERT, the earliest driver of these tumors, and separately disrupt tumor suppressors such as CDKN2A/B and NF1. The same class of rearrangement occurs in WRN-deficient cancers of other types. WRN deficiency is thus a source of instability at TA-rich tandem repeats that generates oncogenic rearrangements.
SN - 2692-8205
ER -