Homologous recombination DNA repair defects in PALB2-associated breast cancers Academic Article uri icon

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 SK
  • 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

publication date

  • 2019