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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;
[...]
Homologous recombination DNA repair defects in PALB2-associated breast cancers
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- Medientyp: E-Artikel
- Titel: Homologous recombination DNA repair defects in PALB2-associated breast cancers
- Beteiligte: 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; [...]
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Erschienen:
Springer Science and Business Media LLC, 2019
- Erschienen in: npj Breast Cancer, 5 (2019) 1
- Sprache: Englisch
- DOI: 10.1038/s41523-019-0115-9
- ISSN: 2374-4677
- Entstehung:
- Anmerkungen:
- Beschreibung: <jats:title>Abstract</jats:title><jats:p>Mono-allelic germline pathogenic variants in the <jats:italic>Partner And Localizer of BRCA2</jats:italic> (<jats:italic>PALB2</jats:italic>) 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 <jats:italic>PALB2</jats:italic>-associated breast cancers (BCs), and whether <jats:italic>PALB2</jats:italic>-associated BCs display bi-allelic inactivation of <jats:italic>PALB2</jats:italic> and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic <jats:italic>PALB2</jats:italic> germline mutations were analyzed by whole-exome sequencing (WES, <jats:italic>n</jats:italic> = 16) or targeted capture massively parallel sequencing (410 cancer genes, <jats:italic>n</jats:italic> = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the <jats:italic>PALB2</jats:italic> wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. <jats:italic>PALB2</jats:italic>-associated BCs were found to be heterogeneous at the genetic level, with <jats:italic>PIK3CA</jats:italic> (29%), <jats:italic>PALB2</jats:italic> (21%), <jats:italic>TP53</jats:italic> (21%), and <jats:italic>NOTCH3</jats:italic> (17%) being the genes most frequently affected by somatic mutations. Bi-allelic <jats:italic>PALB2</jats:italic> inactivation was found in 16 of the 24 cases (67%), either through LOH (<jats:italic>n</jats:italic> = 11) or second somatic mutations (<jats:italic>n</jats:italic> = 5) of the wild-type allele. High LST scores were found in all 12 <jats:italic>PALB2</jats:italic>-associated BCs with bi-allelic <jats:italic>PALB2</jats:italic> inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of <jats:italic>PALB2</jats:italic> was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic <jats:italic>PALB2</jats:italic> inactivation in <jats:italic>PALB2</jats:italic>-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of <jats:italic>PALB2</jats:italic>-associated BCs without <jats:italic>PALB2</jats:italic> bi-allelic inactivation lack genomic features of HRD.</jats:p>
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