Myeloid neoplasms in individuals with breast and ovarian cancer and the association with deleterious germline variants

Gynecol Oncol. 2024 Aug:187:235-240. doi: 10.1016/j.ygyno.2024.05.026. Epub 2024 May 31.

Abstract

Historically, the increased incidence of myeloid neoplasms observed in individuals with breast and ovarian cancer has been attributed exclusively to prior exposure to cancer-directed therapies. However, as the association between deleterious germline variants and the development of hematopoietic malignancies (HMs) becomes better established, we propose the increased incidence of myeloid neoplasms in those with breast and ovarian cancer may be at least partially related to underlying germline cancer predisposition alleles. Deleterious germline variants in BRCA1/2, ATM, CHEK2, PALB2, and other related genes prevent normal homologous recombination DNA repair of double-strand breaks, leading to reliance on less effective repair mechanisms. This results in a high lifetime risk of breast and ovarian cancer, and likely also increases the risk of subsequent therapy-related myeloid neoplasms (t-MNs). These deleterious germline variants likely increase the risk for de novo HMs as well, as evidenced by the increased incidence of HMs observed in those with deleterious germline BRCA1/2 variants even in the absence of prior cancer-directed therapy. Thus, the association between poly(ADP-ribose) polymerase (PARP) inhibitors and other solid tumor directed therapies and the development of t-MNs may be confounded by the presence of deleterious germline variants which inherently increase the risk of both de novo and t-MNs, and additional data regarding the direct toxic effects of these drugs on bone marrow function are needed.

Publication types

  • Review

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Breast Neoplasms* / genetics
  • Checkpoint Kinase 2 / genetics
  • Fanconi Anemia Complementation Group N Protein
  • Female
  • Genes, BRCA2
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation*
  • Hematologic Neoplasms / genetics
  • Humans
  • Neoplasms, Second Primary / epidemiology
  • Neoplasms, Second Primary / genetics
  • Ovarian Neoplasms* / genetics
  • Poly(ADP-ribose) Polymerase Inhibitors / adverse effects
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use

Substances

  • CHEK2 protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Checkpoint Kinase 2
  • ATM protein, human
  • Poly(ADP-ribose) Polymerase Inhibitors
  • PALB2 protein, human
  • Fanconi Anemia Complementation Group N Protein