QIMR Berghofer

Homologous recombination DNA repair defects in PALB2-associated breast cancers

Abstract

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.

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-Merida, Rodrigo; Cavallone, Luca; Rezoug, Zoulikha; Nguyen-Dumont, Tu; Peterlongo, Paolo; Tondini, Carlo; Terkelsen, Thorkild; Ronlund, 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.; 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; Mane, 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
Journal NPJ BREAST CANCER
Pages
Volume 5
Date 1/08/2019
Grant ID
Funding Body NHMRC
URL http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/s41523-019-0115-9