Homologous recombination DNA repair defects in PALB2-associated breast cancers

• DOI: 10.1038/s41523-019-0115-9
• Publication Date: 2019-08-08T10:20:54Z
• Authors: Anqi Li; Felipe C. Geyer; Pedro Blecua; Ju Youn Lee; Pier Selenica; David N. Brown; Fresia Pareja; Simon S. K. Lee; Rahul Kumar; Barbara Rivera; Rui Bi; Salvatore Piscuoglio; Hannah Y. Wen; John R. Lozada; Rodrigo Gularte-M...; Luca Cavallone; Zoulikha Rezoug; Tu Nguyen-Dumont; Paolo Peterlongo; Carlo Tondini; Thorkild Terkelsen; Karina Rønlund; Susanne E. Boonen; Arto Mannerma; Robert Winqvist; Marketa Janatova; Pathmanathan Raja...; Bing Xia; Larry Norton; Mark E. Robson; Pei-Sze Ng; Lai-Meng Looi; Melissa C. Southey; Britta Weigelt; Teo Soo-Hwang; Marc Tischkowitz; William D. Foulkes; Jorge S. Reis-Filho; ; Morteza Aghmesheh; David Amor; Leslie Andrews; Yoland Antill; Rosemary Balleine; Jonathan Beesley; Anneke Blackburn; Michael Bogwitz; Melissa Brown; Matthew Burgess; Jo Burke; Phyllis Butow; Liz Caldon; Ian Campbell; Alice Christian; Christine Clarke; Paul Cohen; Ashley Crook; James Cui; Margaret Cummings; Sarah-Jane Dawson; Anna De Fazio; Martin Delatycki; Alex Dobrovic; Tracy Dudding; Pascal Duijf; Edward Edkins; Stacey Edwards; Gelareh Farshid; Andrew Fellows; Michael Field; James Flanagan; Peter Fong; John Forbes; Laura Forrest; Stephen Fox; Juliet French; Michael Friedlander; David Gallego Ortega; Michael Gattas; Graham Giles; Grantley Gill; Margaret Gleeson; Sian Greening; Eric Haan; Marion Harris; Nick Hayward; Ian Hickie; John Hopper; Clare Hunt; Paul James; Mark Jenkins; Rick Kefford; Maira Kentwell; Judy Kirk; James Kollias; Sunil Lakhani; Geoff Lindeman; Lara Lipton; Lizz Lobb; Sheau Lok; Finlay Macrea; Graham Mann; Deb Marsh; Sue-Anne McLachlan; Bettina Meiser; Roger Milne; Sophie Nightingale; Shona O’Connell; Nick Pachter; Briony Patterson; Kelly Phillips; Mona Saleh; Elizabeth Salisbury; Christobel Saunders; Jodi Saunus; Clare Scott; Rodney Scott; Adrienne Sexton; Andrew Shelling; Peter Simpson; Allan Spigelman; Mandy Spurdle; Jennifer Stone; Jessica Taylor; Heather Thorne; Alison Trainer; Georgia Trench; Kathy Tucker; Jane Visvader; Logan Walker; Mathew Wallis; Rachael Williams; Ingrid Winship; Kathy Wu; Mary Anne Young
• Keywords: PALB2

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk breast cancer development, consistent with role PALB2 homologous recombination (HR) DNA repair. Here, we sought define repertoire somatic genetic alterations PALB2-associated cancers (BCs), and whether BCs display bi-allelic inactivation and/or genomic features HR-deficiency (HRD). Twenty-four patients mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel (410 genes, 8). Somatic alterations, loss heterozygosity (LOH) wild-type allele, large-scale state transitions (LSTs) mutational signatures defined. found be heterogeneous at level, PIK3CA (29%), (21%), TP53 NOTCH3 (17%) being genes most frequently affected mutations. Bi-allelic was 16 24 cases (67%), either through LOH (n 11) second 5) allele. High LST scores all 12 sequenced WES, which eight displayed HRD-related signature 3. In addition, significantly associated high scores. Our findings suggest that identification is required for personalization HR-directed therapies, such as platinum salts PARP inhibitors, vast majority without lack HRD.