High-depth whole genome sequencing of premalignant breast lesions reveals rearrangement hotspots and personalized management opportunities

Lucia Chmelova; Helen R. Davies; Andrea Degasperi; Giuseppe Rinaldi; Leon Wils; Daniella Black; Yasin Memari; Gene C. C. Koh; Scott Shooter; Lennart Mulder; Petra Kristel; Karoly Szuhai; Gino Prasad; Ivy Tsz-Lo Wong; Jens Luebeck; Yogesh Kumar; Jan Czarnecki; Shadi Basyuni; Zoya Kingsbury; Mark T. Ross; Øystein Garred; Margit Riis; Karin T. Lande; Johan Vallon-Christersson; Anna Ehinger; Amit Agrawal; Stuart A. McIntosh; Vineet Bafna; Paul S. Mischel; Fariba Behbod; Proteeti Bhattacharjee; Deborah Collyar; Helen Davies; Andrew Futreal; E. Shelley Hwang; Jos Jonkers; Nicholas Navin; Donna Pinto; Daniel Rea; Elinor J. Sawyer; Marjanka Schmidt; Hilary Stobart; Alastair Thompson; Marja van Oirsouw; Jacco van Rheenen; Ellen Verschuur; Lodewyk F. A. Wessels; Jelle Wesseling; Johan Staaf; Therese Sørlie; Esther H. Lips; Serena Nik-Zainal

doi:10.1038/s41467-026-72952-1

High-depth whole genome sequencing of premalignant breast lesions reveals rearrangement hotspots and personalized management opportunities

L Lucia Chmelova H Helen R. Davies A Andrea Degasperi G Giuseppe Rinaldi L Leon Wils D Daniella Black Y Yasin Memari G Gene C. C. Koh S Scott Shooter L Lennart Mulder P Petra Kristel K Karoly Szuhai G Gino Prasad I Ivy Tsz-Lo Wong J Jens Luebeck Y Yogesh Kumar J Jan Czarnecki S Shadi Basyuni Z Zoya Kingsbury M Mark T. Ross � Øystein Garred M Margit Riis K Karin T. Lande J Johan Vallon-Christersson A Anna Ehinger A Amit Agrawal S Stuart A. McIntosh V Vineet Bafna P Paul S. Mischel F Fariba Behbod P Proteeti Bhattacharjee D Deborah Collyar H Helen Davies A Andrew Futreal E E. Shelley Hwang J Jos Jonkers N Nicholas Navin D Donna Pinto D Daniel Rea E Elinor J. Sawyer M Marjanka Schmidt H Hilary Stobart A Alastair Thompson M Marja van Oirsouw J Jacco van Rheenen E Ellen Verschuur L Lodewyk F. A. Wessels J Jelle Wesseling J Johan Staaf T Therese Sørlie E Esther H. Lips S Serena Nik-Zainal

Abstract

Abstract Ductal carcinoma in situ is a non-obligate precursor lesion of breast cancer. Often detected by mammography, most cases are managed through surgical and/or radiotherapy approaches. Today, it is not possible to predict which patients will progress to invasive disease. Here, we evaluate high-depth whole-genome sequenced ductal carcinoma in situ, enriched for high-grade clinical lesions, to understand whether deep WGS could reveal biological insights and/or personalized therapeutic vulnerabilities that may be targetable. We find genomic locations that are likely susceptible to producing the initiating lesion for structural variations prone to subsequent evolution, termed SHOREs. We additionally highlight individualized therapeutic potential that would otherwise not be appreciable without whole genome sequencing. We posit that holistic whole genome sequencing profiling could offer a more precise stratification approach, discerning higher-risk cases for prospective clinical studies on personalized therapies, from truly low-risk cases suitable for active monitoring.

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Article Details

Journal Nature Communications

Volume / Issue Vol. 17, Issue 1

Published May 19, 2026

DOI 10.1038/s41467-026-72952-1

ISSN 2041-1723

Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio

ISSN: 2041-1723 Open Access Life Sciences

Authors (52)

L

Lucia Chmelova

H

Helen R. Davies

A

Andrea Degasperi

G

Giuseppe Rinaldi

L

Leon Wils

D

Daniella Black

Y

Yasin Memari

G

Gene C. C. Koh

S

Scott Shooter

L

Lennart Mulder

P

Petra Kristel

K

Karoly Szuhai

G

Gino Prasad

I

Ivy Tsz-Lo Wong

J

Jens Luebeck

Y

Yogesh Kumar

J

Jan Czarnecki

S

Shadi Basyuni

Z

Zoya Kingsbury

M

Mark T. Ross

�

Øystein Garred

M

Margit Riis

K

Karin T. Lande

J

Johan Vallon-Christersson

A

Anna Ehinger

A

Amit Agrawal

S

Stuart A. McIntosh

V

Vineet Bafna

P

Paul S. Mischel

F

Fariba Behbod

P

Proteeti Bhattacharjee

D

Deborah Collyar

H

Helen Davies

A

Andrew Futreal

E

E. Shelley Hwang

J

Jos Jonkers

N

Nicholas Navin

D

Donna Pinto

D

Daniel Rea

E

Elinor J. Sawyer

M

Marjanka Schmidt

H

Hilary Stobart

A

Alastair Thompson

M

Marja van Oirsouw

J

Jacco van Rheenen

E

Ellen Verschuur

L

Lodewyk F. A. Wessels

J

Jelle Wesseling

J

Johan Staaf

T

Therese Sørlie

E

Esther H. Lips

S

Serena Nik-Zainal

High-depth whole genome sequencing of premalignant breast lesions reveals rearrangement hotspots and personalized management opportunities

Abstract

Article Details

Journal Info

Authors (52)

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