bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023–10–15
two papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes.
  2. A BRCA2 germline mutation and high expression of immune checkpoints in a TNBC patient.
  1. Int J Mol Sci. 2023 Oct 06. pii: 14940. [Epub ahead of print]24(19):
    p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes.
    Jeanne Rakotopare, Franck Toledo.
      Mice with a constitutive increase in p53 activity exhibited features of dyskeratosis congenita (DC), a bone marrow failure syndrome (BMFS) caused by defective telomere maintenance. Further studies confirmed, in humans and mice, that germline mutations affecting TP53 or its regulator MDM4 may cause short telomeres and alter hematopoiesis, but also revealed features of Diamond-Blackfan anemia (DBA) or Fanconi anemia (FA), two BMFSs, respectively, caused by defects in ribosomal function or DNA repair. p53 downregulates several genes mutated in DC, either by binding to promoter sequences (DKC1) or indirectly via the DREAM repressor complex (RTEL1, DCLRE1B), and the p53-DREAM pathway represses 22 additional telomere-related genes. Interestingly, mutations in any DC-causal gene will cause telomere dysfunction and subsequent p53 activation to further promote the repression of p53-DREAM targets. Similarly, ribosomal dysfunction and DNA lesions cause p53 activation, and p53-DREAM targets include the DBA-causal gene TSR2, at least 9 FA-causal genes, and 38 other genes affecting ribosomes or the FA pathway. Furthermore, patients with BMFSs may exhibit brain abnormalities, and p53-DREAM represses 16 genes mutated in microcephaly or cerebellar hypoplasia. In sum, positive feedback loops and the repertoire of p53-DREAM targets likely contribute to partial phenotypic overlaps between BMFSs of distinct molecular origins.
    Keywords:  DREAM repressor complex; Diamond–Blackfan anemia; Fanconi anemia; cerebellar hypoplasia; dyskeratosis congenita; microcephaly; p53
    DOI:  https://doi.org/10.3390/ijms241914940
  2. Cell Death Discov. 2023 Oct 09. 9(1): 370
    A BRCA2 germline mutation and high expression of immune checkpoints in a TNBC patient.
    TOR CENTRE
      Triple-negative breast cancer (TNBC) is the most aggressive subtype of mammary carcinoma. Here, we describe a case of an 81-year-old female diagnosed with ductal triple negative breast cancer with a germline pathogenic variant in BReast CAncer gene2 (BRCA2). Genetic testing also revealed the presence of four somatic mutations in the ephrin type-A receptor 3 (EphA3), TP53, BRCA1-associated protein (BAP1), and MYB genes. The BRCA2, TP53, and BAP1 gene mutations are highly predictive of a defective homologous recombination repair system and subsequent chromosomal instability in this patient. Coherently, the patient displayed a strong homologous recombination deficiency signature and high tumor mutational burden status, which are generally associated with increased probability of immune neoantigens formation and presentation, and with tumor immunogenicity. Analysis of immune checkpoint revealed high expression of programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), programmed death 1 (PD1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA 4), suggesting that the patient might likely benefit from immunotherapies. Altogether, these findings support an unveiled link between BRCA2 inactivation, HR deficiency and increased expression of immune checkpoints in TNBC. This clinical case highlights the importance of screening TNBC patients for genetic mutations and TMB biomarkers in order to predict the potential efficacy of immunotherapy.
    DOI:  https://doi.org/10.1038/s41420-023-01651-3
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