Peer-reviewedCC BYCell
A telomere-to-telomere map of somatic mutation burden and functional impact in a cancer
13 affiliations
- 1Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA
- 2Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA
- 3Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
- 4Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
- 5Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA
- 6Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Northwest Genomics Center, University of Washington, Seattle, WA, USA
- 7Coriell Institute for Medical Research, Camden, NJ 08103, USA
- 8Pacific Northwest Research Institute, Seattle, WA, USA
- 9Broad Institute of MIT and Harvard, Cambridge, MA, USA
- 10Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Computational Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- 11Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA
- 12Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA; Biohub, San Francisco, San Francisco, CA, USA
- 13Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA. Electronic address: [email protected]
Abstract
Cancer genomes harbor extensive somatic genetic and epigenetic variation, yet large portions of the genome remain inaccessible to conventional reference-based analyses. Here, we demonstrate that pairing a near-telomere-to-telomere (near-T2T) diploid assembly of a donor with deep short- and long-read sequencing of their melanoma reveals that 16% of somatic variants localize to sequences absent from GRCh38, with satellite repeats acting as hotspots for UV-associated mutagenesis. Centromere kinetochore binding domains emerge as focal sites of chromosome arm aneuploidy breakpoints and somatic genetic variation, features we further demonstrate are also present in non-cancerous tissues. By contrast, extensive epigenetic remodeling of kinetochore binding domains appears specific to oncogenesis. Single-molecule telomere analyses reconstruct the cycle of telomere erosion and telomerase-mediated extension during tumor evolution, while haplotype-resolved chromatin maps reveal widespread somatic epimutations impacting regulatory elements. Together, these findings define previously inaccessible dimensions of somatic variation and establish a framework for telomere-to-telomere studies of human mosaicism.
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BibTeX
@article{sohn2026telomeretotelomere,
title = {{A telomere-to-telomere map of somatic mutation burden and functional impact in a cancer}},
author = {Min-Hwan Sohn and Danilo Dubocanin and Mitchell Robert Vollger and Youngjun Kwon and Anna Minkina and Katherine M. Munson and Samuel F. M. Hart and Jane Ranchalis and Nancy L. Parmalee and Adriana Estela Sedeño-Cortés and Jeffrey Ou and Shane J. Neph and Natalie Y.T. Au and Stephanie C. Bohaczuk and Brianne Carroll and Christian D. Frazar and William T. Harvey and Kendra Hoekzema and Huang Meng-fan and Caitlin N. Jacques and Dana M. Jensen and J. Thomas Kolar and Rosa Lee and Jiadong Lin and Kelsey A. Loy and Taralynn Mack and Yizi Mao and Matthew W. Mitchell and Meranda M Pham and Laura Scheinfeldt and Gretchen Smith and Erica Ryke and Joshua D. Smith and Lila Sutherlin and Elliott G. Swanson and Jeffrey M. Weiss and Claudia M.B. Carvalho and Tim H. H. Coorens and Kelley Harris and Chia‐Lin Wei and Evan E. Eichler and Nicolas Altemose and James T. Bennett and Andrew B. Stergachis},
journal = {Cell},
year = {2026},
month = oct,
doi = {10.1016/j.cell.2026.09.033},
url = {https://doi.org/10.1016/j.cell.2026.09.033},
note = {CC BY},
}
RIS
TY - JOUR
TI - A telomere-to-telomere map of somatic mutation burden and functional impact in a cancer
AU - Min-Hwan Sohn
AU - Danilo Dubocanin
AU - Mitchell Robert Vollger
AU - Youngjun Kwon
AU - Anna Minkina
AU - Katherine M. Munson
AU - Samuel F. M. Hart
AU - Jane Ranchalis
AU - Nancy L. Parmalee
AU - Adriana Estela Sedeño-Cortés
AU - Jeffrey Ou
AU - Shane J. Neph
AU - Natalie Y.T. Au
AU - Stephanie C. Bohaczuk
AU - Brianne Carroll
AU - Christian D. Frazar
AU - William T. Harvey
AU - Kendra Hoekzema
AU - Huang Meng-fan
AU - Caitlin N. Jacques
AU - Dana M. Jensen
AU - J. Thomas Kolar
AU - Rosa Lee
AU - Jiadong Lin
AU - Kelsey A. Loy
AU - Taralynn Mack
AU - Yizi Mao
AU - Matthew W. Mitchell
AU - Meranda M Pham
AU - Laura Scheinfeldt
AU - Gretchen Smith
AU - Erica Ryke
AU - Joshua D. Smith
AU - Lila Sutherlin
AU - Elliott G. Swanson
AU - Jeffrey M. Weiss
AU - Claudia M.B. Carvalho
AU - Tim H. H. Coorens
AU - Kelley Harris
AU - Chia‐Lin Wei
AU - Evan E. Eichler
AU - Nicolas Altemose
AU - James T. Bennett
AU - Andrew B. Stergachis
PY - 2026
DA - 2026/10/01
JO - Cell
DO - 10.1016/j.cell.2026.09.033
UR - https://doi.org/10.1016/j.cell.2026.09.033
AB - Cancer genomes harbor extensive somatic genetic and epigenetic variation, yet large portions of the genome remain inaccessible to conventional reference-based analyses. Here, we demonstrate that pairing a near-telomere-to-telomere (near-T2T) diploid assembly of a donor with deep short- and long-read sequencing of their melanoma reveals that 16% of somatic variants localize to sequences absent from GRCh38, with satellite repeats acting as hotspots for UV-associated mutagenesis. Centromere kinetochore binding domains emerge as focal sites of chromosome arm aneuploidy breakpoints and somatic genetic variation, features we further demonstrate are also present in non-cancerous tissues. By contrast, extensive epigenetic remodeling of kinetochore binding domains appears specific to oncogenesis. Single-molecule telomere analyses reconstruct the cycle of telomere erosion and telomerase-mediated extension during tumor evolution, while haplotype-resolved chromatin maps reveal widespread somatic epimutations impacting regulatory elements. Together, these findings define previously inaccessible dimensions of somatic variation and establish a framework for telomere-to-telomere studies of human mosaicism.
SN - 0092-8674
SN - 1097-4172
ER -