Molecular contribution of BRCA1 and BRCA2 to genome instability in breast cancer patients: review of radiosensitivity assays

Fatemeh Sadeghi; Marzieh Asgari; Mojdeh Matloubi; Maral Ranjbar; Nahid Karkhaneh Yousefi; Tahereh Azari; Majid Zaki-Dizaji

doi:10.1186/s12575-020-00133-5

Molecular contribution of BRCA1 and BRCA2 to genome instability in breast cancer patients: review of radiosensitivity assays

Biol Proced Online. 2020 Oct 1:22:23. doi: 10.1186/s12575-020-00133-5. eCollection 2020.

Authors

Fatemeh Sadeghi^{1

2}, Marzieh Asgari³, Mojdeh Matloubi¹, Maral Ranjbar¹, Nahid Karkhaneh Yousefi⁴, Tahereh Azari¹, Majid Zaki-Dizaji^{5

6}

Affiliations

¹ Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
² Digestive Diseases Research Institute, Digestive Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
³ Rheumatology Research Center, Tehran University of Medical Sciences, Shariati Hospital, Kargar Ave, Tehran, Iran.
⁴ Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran.
⁵ Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran.
⁶ Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Abstract

Background: DNA repair pathways, cell cycle arrest checkpoints, and cell death induction are present in cells to process DNA damage and prevent genomic instability caused by various extrinsic and intrinsic ionizing factors. Mutations in the genes involved in these pathways enhances the ionizing radiation sensitivity, reduces the individual's capacity to repair DNA damages, and subsequently increases susceptibility to tumorigenesis.

Body: BRCA1 and BRCA2 are two highly penetrant genes involved in the inherited breast cancer and contribute to different DNA damage pathways and cell cycle and apoptosis cascades. Mutations in these genes have been associated with hypersensitivity and genetic instability as well as manifesting severe radiotherapy complications in breast cancer patients. The genomic instability and DNA repair capacity of breast cancer patients with BRCA1/2 mutations have been analyzed in different studies using a variety of assays, including micronucleus assay, comet assay, chromosomal assay, colony-forming assay, γ -H2AX and 53BP1 biomarkers, and fluorescence in situ hybridization. The majority of studies confirmed the enhanced spontaneous & radiation-induced radiosensitivity of breast cancer patients compared to healthy controls. Using G2 micronucleus assay and G2 chromosomal assay, most studies have reported the lymphocyte of healthy carriers with BRCA1 mutation are hypersensitive to invitro ionizing radiation compared to non-carriers without a history of breast cancer. However, it seems this approach is not likely to be useful to distinguish the BRCA carriers from non-carrier with familial history of breast cancer.

Conclusion: In overall, breast cancer patients are more radiosensitive compared to healthy control; however, inconsistent results exist about the ability of current radiosensitive techniques in screening BRCA1/2 carriers or those susceptible to radiotherapy complications. Therefore, developing further radiosensitivity assay is still warranted to evaluate the DNA repair capacity of individuals with BRCA1/2 mutations and serve as a predictive factor for increased risk of cancer mainly in the relatives of breast cancer patients. Moreover, it can provide more evidence about who is susceptible to manifest severe complication after radiotherapy.

Keywords: BRCA1; BRCA2; DNA repair pathway; apoptosis; breast cancer; cell cycle; genome stability; homologous recombination; non-homologous end joining; radiosensitivity.

Publication types

Review