Homologous recombination DNA repair defects in PALB2- associated breast cancers
Creators: name: Li, Anqi
name: Geyer, Felipe C.
name: Blecua, Pedro
name: Lee, Ju Youn
name: Selenica, Pier
name: Brown, David N.
name: Pareja, Fresia
name: Lee, Simon S. K.
name: Kumar, Rahul
name: Rivera, Barbara
name: Bi, Rui
name: Piscuoglio, Salvatore
name: Wen, Hannah Y.
name: Lozada, John R.
name: Gularte-Mérida, Rodrigo
name: Cavallone, Luca
name: Rezoug, Zoulikha
name: Nguyen-Dumont, Tu
name: Peterlongo, Paolo
name: Tondini, Carlo
name: Terkelsen, Thorkild
name: Rønlund, Karina
name: Boonen, Susanne E.
name: Mannerma, Arto
name: Winqvist, Robert
name: Janatova, Marketa
name: Rajadurai, Pathmanathan
name: Xia, Bing
name: Norton, Larry
name: Robson, Mark E.
name: Ng, Pei-Sze
name: Looi, Lai-Meng
name: Southey, Melissa C.
name: Weigelt, Britta
name: Soo-Hwang, Teo
name: Tischkowitz, Marc
name: Foulkes, William D.
name: Reis-Filho, Jorge S.
name: Aghmesheh, Morteza
name: Amor, David
name: Andrews, Leslie
name: Antill, Yoland
name: Balleine, Rosemary
name: Beesley, Jonathan
name: Blackburn, Anneke
name: Bogwitz, Michael
name: Brown, Melissa
name: Burgess, Matthew
name: Burke, Jo
name: Butow, Phyllis
name: Caldon, Liz
name: Campbell, Ian
name: Christian, Alice
name: Clarke, Christine
name: Cohen, Paul
name: Crook, Ashley
name: Cui, James
name: Cummings, Margaret
name: Dawson, Sarah-Jane
name: De Fazio, Anna
name: Delatycki, Martin
name: Dobrovic, Alex
name: Dudding, Tracy
name: Duijf, Pascal
name: Edkins, Edward
name: Edwards, Stacey
name: Farshid, Gelareh
name: Fellows, Andrew
name: Field, Michael
name: Flanagan, James
name: Fong, Peter
name: Forbes, John
name: Forrest, Laura
name: Fox, Stephen
name: French, Juliet
name: Friedlander, Michael
name: Ortega, David Gallego
name: Gattas, Michael
name: Giles, Graham
name: Gill, Grantley
name: Gleeson, Margaret
name: Greening, Sian
name: Haan, Eric
name: Harris, Marion
name: Hayward, Nick
name: Hickie, Ian
name: Hopper, John
name: Hunt, Clare
name: James, Paul
name: Jenkins, Mark
name: Kefford, Rick
name: Kentwell, Maira
name: Kirk, Judy
name: Kollias, James
name: Lakhani, Sunil
name: Lindeman, Geoff
name: Lipton, Lara
name: Lobb, Lizz
name: Lok, Sheau
name: Macrea, Finlay
name: Mann, Graham
name: Marsh, Deb
name: McLachlan, Sue-Anne
name: Meiser, Bettina
name: Milne, Roger
name: Nightingale, Sophie
name: O’Connell, Shona
name: Pachter, Nick
name: Patterson, Briony
name: Phillips, Kelly
name: Saleh, Mona
name: Salisbury, Elizabeth
name: Saunders, Christobel
name: Saunus, Jodi
name: Scott, Clare
name: Scott, Rodney
name: Sexton, Adrienne
name: Shelling, Andrew
name: Simpson, Peter
name: Spigelman, Allan
name: Spurdle, Mandy
name: Stone, Jennifer
name: Taylor, Jessica
name: Thorne, Heather
name: Trainer, Alison
name: Trench, Georgia
name: Tucker, Kathy
name: Visvader, Jane
name: Walker, Logan
name: Wallis, Mathew
name: Williams, Rachael
name: Winship, Ingrid
name: Wu, Kathy
name: Young, Mary Anne
Publisher: name: Apollo - University of Cambridge Repository
Year: 2019
Subjects: Article
/631/67/1347
/631/67/68
/692/699/67/69
article

description: 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.