Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.
Dale Garsed,
Tibor Zwimpfer,
Sian Fereday,
Ahwan Pandey,
Dinuka Ariyaratne,
Madawa Jayawardana,
Laura Twomey,
Céline Laumont,
Catherine Kennedy,
Adelyn Bolithon,
Nicola Meagher,
Katy Milne,
Phineas Hamilton,
Jennifer Alsop,
Antonis Antoniou,
George Au-Yeung,
Matthias Beckmann,
Amy Berrington de Gonzalez,
Christiani Bisinotto,
Freya Blome,
Clara Bodelon,
Jessica Boros,
Alison Brand,
Michael Carney,
Alicia Cazorla-Jimenez,
Derek Chiu,
Elizabeth Christie,
Anita Chudecka-Glaz,
Penny Coulson,
Kara Cushing-Haugen,
Cezary Cybulski,
Kathleen Darcy,
Cath David,
Trent Davidson,
Arif Ekici,
Esther Elishaev,
Julius Emons,
Tobias Engler,
Rhonda Farrell,
Anna Fischer,
Montserrat Garcia-Closas,
Aleksandra Gentry-Maharaj,
Prafull Ghatage,
Rosalind Glasspool,
Philipp Harter,
Andreas Hartkopf,
Arndt Hartmann,
Sebastian Heikaus,
Brenda Hernandez,
Anusha Hettiaratchi,
Sabine Heublein,
David Huntsman,
Mercedes Jimenez-Linan,
Michael Jones,
Eunjoung Kang,
Ewa Kaznowska,
Tomasz Kluz,
Felix Kommoss,
Gottfried E Konecny,
Rutgerus Kruitwagen,
Jessica Kwon,
Diether Lambrechts,
Cheng-Han Lee,
Jenny Lester,
Samuel Leung,
Yee Leung,
Anna Linder,
Jolanta Lissowska,
Liselore Loverix,
Jan Lubiński,
Constantina Mateoiu,
Lain McNeish,
Malak Moubarak,
Gregg Nelson,
Nikilyn Nevins,
Alexander Olawaiye,
Siel Olbrecht,
Sandra Orsulic,
Ana Osorio,
Carmel Quinn,
Ganendra Raj Mohan,
Isabelle Ray-Coquard,
Cristina Rodriguez-Antona,
Patricia Roxburgh,
Matthias Rübner,
Stuart Salfinger,
Spinder Samra,
Minouk Schoemaker,
Hans-Peter Sinn,
Gabe Sonke,
Linda Steele,
Colin Stewart,
Aline Talhouk,
Adeline Tan,
Christopher Tarney,
Sarah Taylor,
Koen Van de Vijver,
Maaike Avan der Aa,
Toon Van Gorp,
Els Van Nieuwenhuysen,
Lilian van Wagensveld,
Andrea Wahner-Hendrickson,
Christina Walter,
Chen Wang,
Julia Welz,
Nicolas Wentzensen,
Lynne Wilkens,
Stacey Winham,
Boris Winterhoff,
Michael Anglesio,
Andrew Berchuck,
Francisco Candido do Reis,
Paul Cohen,
Thomas Conrads,
Philip Crowe,
Jennifer Doherty,
Peter Fasching,
Renée Fortner,
Maria Garcia,
Simon Gayther,
Marc Goodman,
Jacek Gronwald,
Holly Harris,
Florian Heitz,
Hugo Horlings,
Beth Karlan,
Linda Kelemen,
George Maxwell,
Usha Menon,
Francesmary Modugno,
Susan Neuhausen,
Joellen Schildkraut,
Annette Staebler,
Karin Sundfeldt,
Anthony Swedlow,
Ignace Vergote,
Anna Wu,
James Brenton,
Paul Pharoah,
Celeste Pearce,
Malcolm Pike,
Ellen Goode,
Susan Ramus,
Martin Köbel,
Brad Nelson,
Anna DeFazio,
Michael Friedlander,
David Bowtell
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 unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.