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Genomic instability in non-breast/ovarian malignancies of individuals with germline pathogenic variants in BRCA1/2.
Elze, Lisa; van der Post, Rachel S; Vos, Janet R; Mensenkamp, Arjen R; Pamidimarri Naga, Samhita; Hampstead, Juliet E; Vermeulen, Emma; Oorsprong, Michiel; Hofste, Tom; Simons, Michiel; Nagtegaal, Iris D; Hoogerbrugge, Nicoline; de Voer, Richarda M; Ligtenberg, Marjolijn J L.
Afiliação
  • Elze L; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
  • van der Post RS; Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
  • Vos JR; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
  • Mensenkamp AR; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
  • Pamidimarri Naga S; Department of Medical Oncology, Radboud university medical center, Nijmegen, The Netherlands.
  • Hampstead JE; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
  • Vermeulen E; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
  • Oorsprong M; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
  • Hofste T; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
  • Simons M; Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
  • Nagtegaal ID; Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
  • Hoogerbrugge N; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
  • de Voer RM; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
  • Ligtenberg MJL; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
J Natl Cancer Inst ; 2024 Jul 03.
Article em En | MEDLINE | ID: mdl-38960732
ABSTRACT

BACKGROUND:

Individuals with germline pathogenic variants (gPVs) in BRCA1 or BRCA2 (BRCA1/2) are at a high risk of breast- and ovarian carcinomas (BOCs) with BRCA1/2-deficiency and homologous recombination deficiency (HRD) that can be detected by analysis of genome-wide genomic instability features such as large-scale state transitions, telomeric allelic imbalances and genomic loss-of-heterozygosity. Malignancies with HRD are more sensitive to platinum-based therapies and PARP inhibitors. Here, we aim to investigate the fraction of non-BOC malignancies that have BRCA1/2-deficiency and genomic instability features.

METHODS:

The full tumor history of a large historical clinic-based consecutive cohort of 2,965 individuals with gPVs in BRCA1/2 was retrieved via the Dutch nationwide pathology databank (Palga). In total, 169 non-BOC malignancies were collected and analyzed with targeted next-generation sequencing and shallow whole-genome sequencing to determine somatic second hit alterations and genomic instabilities indicative of HRD, respectively.

RESULTS:

BRCA1/2-deficiency was detected in 27% (21/79) and 23% (21/90) of 20 different types of non-BOC malignancies of individuals with gPVs in BRCA1 and BRCA2, respectively. These malignancies had a higher genomic instability score than BRCA1- or BRCA2-proficient malignancies (P < .001 and P < .001, respectively).

CONCLUSIONS:

BRCA1/2-deficiency and genomic instability features were found in 27% and 23% of a broad spectrum of non-BOC malignancies in individuals with gPVs in BRCA1 and BRCA2, respectively. Evaluation of the effectivity of PARP-inhibitors in these individuals should be focused on tumors with confirmed absence of a wild type allele.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: J Natl Cancer Inst Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: J Natl Cancer Inst Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Holanda