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

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