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Castells-Roca L, Gutiérrez-Enríquez S, Bonache S, et al. Clinical consequences of BRCA2 hypomorphism. NPJ Breast Cancer. 2021;7(1):117doi: 10.1038/s41523-021-00322-9.
Castells-Roca, L., Gutiérrez-Enríquez, S., Bonache, S., Bogliolo, M., Carrasco, E., Aza-Carmona, M., Montalban, G., Muñoz-Subirana, N., Pujol, R., Cruz, C., Llop-Guevara, A., Ramírez, M. J., Saura, C., Lasa, A., Serra, V., Diez, O., Balmaña, J., & Surrallés, J. (2021). Clinical consequences of BRCA2 hypomorphism. NPJ breast cancer, 7(1), 117. https://doi.org/10.1038/s41523-021-00322-9
Castells-Roca, Laia, et al. "Clinical consequences of BRCA2 hypomorphism." NPJ breast cancer vol. 7,1 (2021): 117. doi: https://doi.org/10.1038/s41523-021-00322-9
Castells-Roca L, Gutiérrez-Enríquez S, Bonache S, Bogliolo M, Carrasco E, Aza-Carmona M, Montalban G, Muñoz-Subirana N, Pujol R, Cruz C, Llop-Guevara A, Ramírez MJ, Saura C, Lasa A, Serra V, Diez O, Balmaña J, Surrallés J. Clinical consequences of BRCA2 hypomorphism. NPJ Breast Cancer. 2021 Sep 09;7(1):117. doi: 10.1038/s41523-021-00322-9. PMID: 34504103; PMCID: PMC8429460.
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NPJ Breast Cancer. 2021 Sep 09;7(1):117. doi: 10.1038/s41523-021-00322-9.

Clinical consequences of BRCA2 hypomorphism.

NPJ breast cancer

Laia Castells-Roca, Sara Gutiérrez-Enríquez, Sandra Bonache, Massimo Bogliolo, Estela Carrasco, Miriam Aza-Carmona, Gemma Montalban, Núria Muñoz-Subirana, Roser Pujol, Cristina Cruz, Alba Llop-Guevara, María J Ramírez, Cristina Saura, Adriana Lasa, Violeta Serra, Orland Diez, Judith Balmaña, Jordi Surrallés

Affiliations

  1. Genome Instability and DNA repair Syndromes Group and Join Unit UAB-IR Sant Pau on Genomic Medicine, Biomedical Research Institute IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
  2. Genetics Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
  3. Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  4. Center for Biomedical Network Research on Rare Diseases (CIBERER) U-745, Barcelona, Spain.
  5. Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  6. CHU de Québec - Université Laval Research Center, Oncology division, 9 Rue McMahon, Québec city, G1R 3S3, Québec, Canada.
  7. Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  8. Breast Cancer and Melanoma Group, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  9. Center for Biomedical Network Research on Rare Diseases (CIBERER) U-705, Barcelona, Spain.
  10. Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. [email protected].
  11. Genome Instability and DNA repair Syndromes Group and Join Unit UAB-IR Sant Pau on Genomic Medicine, Biomedical Research Institute IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. [email protected].
  12. Genetics Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. [email protected].
  13. Center for Biomedical Network Research on Rare Diseases (CIBERER) U-745, Barcelona, Spain. [email protected].

PMID: 34504103 PMCID: PMC8429460 DOI: 10.1038/s41523-021-00322-9

Abstract

The tumor suppressor FANCD1/BRCA2 is crucial for DNA homologous recombination repair (HRR). BRCA2 biallelic pathogenic variants result in a severe form of Fanconi anemia (FA) syndrome, whereas monoallelic pathogenic variants cause mainly hereditary breast and ovarian cancer predisposition. For decades, the co-occurrence in trans with a clearly pathogenic variant led to assume that the other allele was benign. However, here we show a patient with biallelic BRCA2 (c.1813dup and c.7796 A > G) diagnosed at age 33 with FA after a hypertoxic reaction to chemotherapy during breast cancer treatment. After DNA damage, patient cells displayed intermediate chromosome fragility, reduced survival, cell cycle defects, and significantly decreased RAD51 foci formation. With a newly developed cell-based flow cytometric assay, we measured single BRCA2 allele contributions to HRR, and found that expression of the missense allele in a BRCA2 KO cellular background partially recovered HRR activity. Our data suggest that a hypomorphic BRCA2 allele retaining 37-54% of normal HRR function can prevent FA clinical phenotype, but not the early onset of breast cancer and severe hypersensitivity to chemotherapy.

© 2021. The Author(s).

References

  1. Am J Hum Genet. 2013 May 2;92(5):800-6 - PubMed
  2. Anemia. 2012;2012:238731 - PubMed
  3. Hum Mutat. 2019 Sep;40(9):1593-1611 - PubMed
  4. Blood. 2011 Sep 1;118(9):2430-42 - PubMed
  5. Am J Hum Genet. 2007 Nov;81(5):873-83 - PubMed
  6. J Med Genet. 2020 Apr;57(4):258-268 - PubMed
  7. Cancer Res. 2017 Jun 1;77(11):2789-2799 - PubMed
  8. Blood. 2004 Apr 15;103(8):3226-9 - PubMed
  9. Genet Med. 2015 May;17(5):405-24 - PubMed
  10. Annu Rev Genet. 1998;32:95-121 - PubMed
  11. Pediatr Blood Cancer. 2012 Mar;58(3):462-5 - PubMed
  12. Haematologica. 2009 Apr;94(4):487-95 - PubMed
  13. Clin Genet. 2020 Apr;97(4):668-669 - PubMed
  14. Science. 2002 Jul 26;297(5581):606-9 - PubMed
  15. Science. 2013 Feb 15;339(6121):819-23 - PubMed
  16. Ann Hematol. 2020 May;99(5):913-924 - PubMed
  17. Ann Oncol. 2018 May 1;29(5):1203-1210 - PubMed
  18. Am J Hum Genet. 2021 Mar 4;108(3):458-468 - PubMed
  19. Genome Biol. 2002 Jun 18;3(7):RESEARCH0034 - PubMed
  20. Blood. 2005 Feb 1;105(3):1329-36 - PubMed
  21. Mol Cell. 2015 Jul 16;59(2):176-87 - PubMed
  22. Nature. 2014 Jul 17;511(7509):362-5 - PubMed
  23. J Med Genet. 2007 Jan;44(1):1-9 - PubMed
  24. J Med Genet. 2014 Feb;51(2):71-5 - PubMed
  25. Cold Spring Harb Perspect Biol. 2015 Apr 01;7(4):a016600 - PubMed
  26. Nature. 1997 Apr 24;386(6627):804-10 - PubMed
  27. Genes Dev. 1999 Oct 15;13(20):2633-8 - PubMed
  28. Methods Enzymol. 2008;449:177-201 - PubMed
  29. Nat Rev Cancer. 2018 Mar;18(3):168-185 - PubMed
  30. Curr Opin Genet Dev. 2015 Aug;33:32-40 - PubMed
  31. Nat Commun. 2018 Mar 6;9(1):967 - PubMed
  32. Genet Med. 2019 Feb;21(2):293-302 - PubMed
  33. Annu Rev Cancer Biol. 2018 Mar;2:313-336 - PubMed
  34. Mol Cell. 2015 Nov 5;60(3):351-61 - PubMed
  35. Science. 2002 Sep 13;297(5588):1837-48 - PubMed
  36. J Med Genet. 2011 Apr;48(4):242-50 - PubMed
  37. Eur J Hum Genet. 2014 Aug;22(8):979-87 - PubMed
  38. EMBO Mol Med. 2018 Dec;10(12): - PubMed

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