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Peer-reviewedCC BY 4.0Molecular Oncology

Finding novel vulnerabilities of hypomorphic BRCA1 alleles

  • Anne Schreuder1,2,3
  • Klaas de Lint4
  • Hồ Mỹ Phúc Võ1,2
  • Mariana M. Góis1,5,6
  • Rosalie A. Kampen1,2
  • Marta San Martin Alonso1,2
  • Ilse Nootenboom1
  • Veronica Garzero1,2
  • Tiemen J. Wendel1,2
  • Rob M. F. Wolthuis4
  • Sylvie M. Noordermeer1,2
6 affiliations
  1. 1Department of Human Genetics Leiden University Medical Center The Netherlands
  2. 2Oncode Institute Utrecht The Netherlands
  3. 3Present address: Institute of Molecular Cancer Research University of Zurich Zurich Switzerland
  4. 4Department of Clinical Genetics, Section Oncogenetics Cancer Center Amsterdam, Amsterdam University Medical Center The Netherlands
  5. 5Laboratory of Applied Molecular Signalling State University of Campinas Brazil
  6. 6Laboratory of Applied Molecular Signalling Federal University of São Paulo Brazil
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Abstract

With the recent rise in CRISPR/Cas9‐mediated genome‐wide synthetic lethality screens, many new synthetic lethal targets have been identified for diseases with underlying genetic causes such as tumours with BRCA1 mutations. Such screens often use full deficiency of a protein to identify novel vulnerabilities. However, patient‐derived mutations not only result in full loss of the protein but often also concern missense mutations with hypomorphic phenotypes. Here, we study the genetic vulnerabilities of two previously described hypomorphic BRCA1 missense mutations and compare these to a BRCA1‐depleted setting to study whether this affects screening for synthetic lethal interactions. Our research showed that BRCA1I26A mutated cells have very similar vulnerabilities to BRCA1 wild‐type cells, confirming its low tumorigenic effect. In contrast, the BRCA1R1699Q mutation induced a more similar phenotype to BRCA1‐deficient cells. For this mutation, we also unveiled a unique vulnerability to the loss of NDE1. Specifically in BRCA1R1699Q mutated cells, and not BRCA1‐proficient or ‐deficient cells, NDE1 loss leads to increased genomic instability. Altogether, our findings highlight the importance to differentiate between patient‐derived mutations when assessing novel treatment targets.

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Cite

BibTeXRIS
BibTeX
@article{schreuder2026finding,
  title = {{Finding novel vulnerabilities of hypomorphic BRCA1 alleles}},
  author = {Anne Schreuder and Klaas de Lint and Hồ Mỹ Phúc Võ and Mariana M. Góis and Rosalie A. Kampen and Marta San Martin Alonso and Ilse Nootenboom and Veronica Garzero and Tiemen J. Wendel and Rob M. F. Wolthuis and Sylvie M. Noordermeer},
  journal = {Molecular Oncology},
  year = {2026},
  month = may,
  doi = {10.1002/1878-0261.70271},
  url = {https://doi.org/10.1002/1878-0261.70271},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Finding novel vulnerabilities of hypomorphic BRCA1 alleles
AU  - Anne Schreuder
AU  - Klaas de Lint
AU  - Hồ Mỹ Phúc Võ
AU  - Mariana M. Góis
AU  - Rosalie A. Kampen
AU  - Marta San Martin Alonso
AU  - Ilse Nootenboom
AU  - Veronica Garzero
AU  - Tiemen J. Wendel
AU  - Rob M. F. Wolthuis
AU  - Sylvie M. Noordermeer
PY  - 2026
DA  - 2026/05/29
JO  - Molecular Oncology
DO  - 10.1002/1878-0261.70271
UR  - https://doi.org/10.1002/1878-0261.70271
AB  - With the recent rise in CRISPR/Cas9‐mediated genome‐wide synthetic lethality screens, many new synthetic lethal targets have been identified for diseases with underlying genetic causes such as tumours with BRCA1 mutations. Such screens often use full deficiency of a protein to identify novel vulnerabilities. However, patient‐derived mutations not only result in full loss of the protein but often also concern missense mutations with hypomorphic phenotypes. Here, we study the genetic vulnerabilities of two previously described hypomorphic BRCA1 missense mutations and compare these to a BRCA1‐depleted setting to study whether this affects screening for synthetic lethal interactions. Our research showed that BRCA1I26A mutated cells have very similar vulnerabilities to BRCA1 wild‐type cells, confirming its low tumorigenic effect. In contrast, the BRCA1R1699Q mutation induced a more similar phenotype to BRCA1‐deficient cells. For this mutation, we also unveiled a unique vulnerability to the loss of NDE1. Specifically in BRCA1R1699Q mutated cells, and not BRCA1‐proficient or ‐deficient cells, NDE1 loss leads to increased genomic instability. Altogether, our findings highlight the importance to differentiate between patient‐derived mutations when assessing novel treatment targets.
SN  - 1574-7891
SN  - 1878-0261
ER  -