Nature Communications

Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma

T Tibor A. Zwimpfer S Sian Fereday A Ahwan Pandey D Dinuka Ariyaratne M Madawa W. Jayawardana L Laura Twomey C Céline M. Laumont C Catherine J. Kennedy A Adelyn Bolithon N Nicola S. Meagher K Katy Milne P Phineas Hamilton J Jennifer Alsop A Antonis C. Antoniou G George Au-Yeung M Matthias W. Beckmann (Department of Gynecology and Obstetrics, University Hospital Erlangen) A Amy Berrington de Gonzalez C Christiani Bisinotto F Freya Blome C Clara Bodelon J Jessica Boros A Alison H. Brand M Michael E. Carney A Alicia Cazorla-Jiménez D Derek S. Chiu E Elizabeth L. Christie A Anita Chudecka-Głaz P Penny Coulson K Kara L. Cushing-Haugen C Cezary Cybulski K Kathleen M. Darcy C Cath David T Trent Davidson A Arif B. Ekici E Esther Elishaev J Julius Emons T Tobias Engler R Rhonda Farrell A Anna Fischer M Montserrat García-Closas A Aleksandra Gentry-Maharaj P Prafull Ghatage R Rosalind Glasspool P Philipp Harter A Andreas D. Hartkopf A Arndt Hartmann (Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen) S Sebastian Heikaus B Brenda Y. Hernandez A Anusha Hettiaratchi S Sabine Heublein D David G. Huntsman M Mercedes Jimenez-Linan M Michael E. Jones E Eunyoung Kang E Ewa Kaznowska T Tomasz Kluz F Felix K. F. Kommoss G Gottfried Konecny R Roy F. P. M. Kruitwagen J Jessica Kwon D Diether Lambrechts C Cheng-Han Lee J Jenny Lester S Samuel C. Y. Leung Y Yee Leung A Anna Linder J Jolanta Lissowska L Liselore Loverix J Jan Lubiński C Constantina Mateoiu I Iain A. McNeish M Malak Moubarak G Gregg S. Nelson N Nikilyn Nevins A Alexander B. Olawaiye S Siel Olbrecht S Sandra Orsulic A Ana Osorio C Carmel M. Quinn G Ganendra Raj Mohan I Isabelle Ray-Coquard C Cristina Rodríguez-Antona P Patricia Roxburgh M Matthias Ruebner S Stuart G. Salfinger S Spinder Samra M Minouk J. Schoemaker H Hans-Peter Sinn G Gabe S. Sonke L Linda Steele C Colin J. R. Stewart A Aline Talhouk A Adeline Tan C Christopher M. Tarney S Sarah E. Taylor K Koen K. Van de Vijver M Maaike A. van der Aa T Toon Van Gorp E Els Van Nieuwenhuysen L Lilian Van-Wagensveld A Andrea E. Wahner-Hendrickson C Christina Walter C Chen Wang J Julia Welz N Nicolas Wentzensen (Division of Cancer Epidemiology and Genetics National Cancer Institute, National Institutes of Health Rockville Maryland USA) L Lynne R. Wilkens S Stacey J. Winham B Boris Winterhoff M Michael S. Anglesio A Andrew Berchuck F Francisco J. Candido dos Reis P Paul A. Cohen T Thomas P. Conrads P Philip Crowe J Jennifer A. Doherty P Peter A. Fasching R Renée T. Fortner M María J. García S Simon A. Gayther M Marc T. Goodman J Jacek Gronwald H Holly R. Harris F Florian Heitz H Hugo M. Horlings B Beth Y. Karlan L Linda E. Kelemen G G. Larry Maxwell U Usha Menon F Francesmary Modugno S Susan L. Neuhausen J Joellen M. Schildkraut A Annette Staebler K Karin Sundfeldt A Anthony J. Swerdlow I Ignace Vergote A Anna H. Wu J James D. Brenton P Paul D. P. Pharoah C Celeste Leigh Pearce M Malcolm C. Pike E Ellen L. Goode S Susan J. Ramus M Martin Köbel B Brad H. Nelson A Anna deFazio M Michael L. Friedlander D David D. L. Bowtell D Dale W. Garsed

Abstract

Abstract BRCA -associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA -deficient tumors experience poor outcomes. In a large HGSC cohort (n = 1389) including 282 individuals with pathogenic germline BRCA variants (g BRCA pv), residual disease after primary surgery has limited prognostic effect in g BRCA pv-carriers compared to non-carriers, and prognostic outcomes differ based on the mutation location within functional domains of the BRCA genes. Multi-omic profiling is performed on 154 tumors, enriched for patients with BRCA -deficient tumors that experienced short overall survival ( ≤ 3 years, n = 42). Patients with BRCA2 -deficient HGSC and loss of NF1 survive twice as long as those without NF1 loss, whereas PIK3CA , RAD21 and MYC amplification define BRCA2 -deficient HGSC with exceptionally short survival. Patients with BRCA1 -deficient HGSC and a more elevated HRD score survive significantly longer. BRCA1 -deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.

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Article Details

Volume / Issue Vol. 17, Issue 1
Published April 01, 2026
ISSN 2041-1723
Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio
ISSN: 2041-1723 Open Access Life Sciences

Authors (148)

T

Tibor A. Zwimpfer

S

Sian Fereday

A

Ahwan Pandey

D

Dinuka Ariyaratne

M

Madawa W. Jayawardana

L

Laura Twomey

C

Céline M. Laumont

C

Catherine J. Kennedy

A

Adelyn Bolithon

N

Nicola S. Meagher

K

Katy Milne

P

Phineas Hamilton

J

Jennifer Alsop

A

Antonis C. Antoniou

G

George Au-Yeung

M

Matthias W. Beckmann

Department of Gynecology and Obstetrics, University Hospital Erlangen

A

Amy Berrington de Gonzalez

C

Christiani Bisinotto

F

Freya Blome

C

Clara Bodelon

J

Jessica Boros

A

Alison H. Brand

M

Michael E. Carney

A

Alicia Cazorla-Jiménez

D

Derek S. Chiu

E

Elizabeth L. Christie

A

Anita Chudecka-Głaz

P

Penny Coulson

K

Kara L. Cushing-Haugen

C

Cezary Cybulski

K

Kathleen M. Darcy

C

Cath David

T

Trent Davidson

A

Arif B. Ekici

E

Esther Elishaev

J

Julius Emons

T

Tobias Engler

R

Rhonda Farrell

A

Anna Fischer

M

Montserrat García-Closas

A

Aleksandra Gentry-Maharaj

P

Prafull Ghatage

R

Rosalind Glasspool

P

Philipp Harter

A

Andreas D. Hartkopf

A

Arndt Hartmann

Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen

S

Sebastian Heikaus

B

Brenda Y. Hernandez

A

Anusha Hettiaratchi

S

Sabine Heublein

D

David G. Huntsman

M

Mercedes Jimenez-Linan

M

Michael E. Jones

E

Eunyoung Kang

E

Ewa Kaznowska

T

Tomasz Kluz

F

Felix K. F. Kommoss

G

Gottfried Konecny

R

Roy F. P. M. Kruitwagen

J

Jessica Kwon

D

Diether Lambrechts

C

Cheng-Han Lee

J

Jenny Lester

S

Samuel C. Y. Leung

Y

Yee Leung

A

Anna Linder

J

Jolanta Lissowska

L

Liselore Loverix

J

Jan Lubiński

C

Constantina Mateoiu

I

Iain A. McNeish

M

Malak Moubarak

G

Gregg S. Nelson

N

Nikilyn Nevins

A

Alexander B. Olawaiye

S

Siel Olbrecht

S

Sandra Orsulic

A

Ana Osorio

C

Carmel M. Quinn

G

Ganendra Raj Mohan

I

Isabelle Ray-Coquard

C

Cristina Rodríguez-Antona

P

Patricia Roxburgh

M

Matthias Ruebner

S

Stuart G. Salfinger

S

Spinder Samra

M

Minouk J. Schoemaker

H

Hans-Peter Sinn

G

Gabe S. Sonke

L

Linda Steele

C

Colin J. R. Stewart

A

Aline Talhouk

A

Adeline Tan

C

Christopher M. Tarney

S

Sarah E. Taylor

K

Koen K. Van de Vijver

M

Maaike A. van der Aa

T

Toon Van Gorp

E

Els Van Nieuwenhuysen

L

Lilian Van-Wagensveld

A

Andrea E. Wahner-Hendrickson

C

Christina Walter

C

Chen Wang

J

Julia Welz

N

Nicolas Wentzensen

Division of Cancer Epidemiology and Genetics National Cancer Institute, National Institutes of Health Rockville Maryland USA

L

Lynne R. Wilkens

S

Stacey J. Winham

B

Boris Winterhoff

M

Michael S. Anglesio

A

Andrew Berchuck

F

Francisco J. Candido dos Reis

P

Paul A. Cohen

T

Thomas P. Conrads

P

Philip Crowe

J

Jennifer A. Doherty

P

Peter A. Fasching

R

Renée T. Fortner

M

María J. García

S

Simon A. Gayther

M

Marc T. Goodman

J

Jacek Gronwald

H

Holly R. Harris

F

Florian Heitz

H

Hugo M. Horlings

B

Beth Y. Karlan

L

Linda E. Kelemen

G

G. Larry Maxwell

U

Usha Menon

F

Francesmary Modugno

S

Susan L. Neuhausen

J

Joellen M. Schildkraut

A

Annette Staebler

K

Karin Sundfeldt

A

Anthony J. Swerdlow

I

Ignace Vergote

A

Anna H. Wu

J

James D. Brenton

P

Paul D. P. Pharoah

C

Celeste Leigh Pearce

M

Malcolm C. Pike

E

Ellen L. Goode

S

Susan J. Ramus

M

Martin Köbel

B

Brad H. Nelson

A

Anna deFazio

M

Michael L. Friedlander

D

David D. L. Bowtell

D

Dale W. Garsed

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