Srabani Roy Chowdhury (MAKAUT, WB)
HGSC or High-Grade Serous Ovarian Carcinoma is considered to be an aggressive type of ovarian cancer. Deleterious mutations present in the DNA repair gene RAD51C are drivers of defective homologous recombination in High-Grade Serous Ovarian Carcinoma (HGSC). These are emerging biomarkers of PARP inhibitor sensitivity. A PARP inhibitor is targeted cancer therapy. It is effective in cancers that have faulty DNA repair. This makes them sensitive to drugs that are DNA-damaging. DNA repair genes like BRCA1 and BRCA2 make cancer cells more susceptible to PARP inhibitors when they are found faulty.
PARP inhibition
A unique characteristic has been observed in the cancerous cells susceptible to PARP inhibitors. The susceptible cells contained epigenetic marks. These marks can express or silence any genes. In this case, they are associated with the silencing of the RAD51C gene. Patient-Derived Xenografts were used to study the epigenetic marks pattern of the cancer cells involved in PARP inhibition. RAD51C gene is involved in DNA repair. That is why complete silencing of the RAD51C gene is necessary. Because if there are any DNA repair capabilities present, epigenetic marks will be lost. This will make it resistant to the treatment. Previous studies have shown that incomplete silencing of the BRCA1 gene renders ineffective PARP inhibition. BRCA1/2 mutated ovarian cancers have shown positive results for PARP inhibitors.
Women are generally diagnosed with ovarian cancer after it has advanced to a late stage. Most women cannot make it after vigorous and strong treatments. PARP inhibition treatments have shown little success and improvement in the survival of the patients. In women with BRCA1/2 mutated cancers, PARP inhibitors have extended the survival period for women with late diagnosis or advanced cancer. It has also delayed the first cancer recurrence by at least three and a half years. Studies show that women with genetic mutations to inactivate the RAD51C are more in need of PARP inhibitors. In the Patient-Derived Xenografts, the silencing of the RAD51C gene was associated with methylation patterns that were complete and heterogeneous. These patterns were involved in genomic scarring. However, treatment with PARP inhibitors removed the methylated RAD51C.
Conclusion
Researchers suggest that women with high-Grade Serous Ovarian Carcinoma should keep monitoring its progression regularly. PARP inhibition will not be effective if the gene silencing capability is lost. Silencing patterns play a vital role in PARP inhibition. Studies show many complex silencing patterns of the RAD51C. However, PARP inhibition treatment is highly beneficial for women and can be a game-changer in the field of ovarian cancer treatments.
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References:
- Nesic, K., Kondrashova, O., Hurley, R. M., McGehee, C. D., Vandenberg, C. J., Ho, G.-Y., Lieschke, E., Dall, G., Bound, N., Shield-Artin, K., Radke, M., Musafer, A., Chai, Z. Q., Eftekhariyan Ghamsari, M. R., Harrell, M. I., Kee, D., Olesen, I., McNally, O., Traficante, N., … Scott, C. L. (2021). Acquired RAD51C promoter methylation loss causes PARP inhibitor resistance in high grade serous ovarian carcinoma. Cancer Research, canres.0774.2021. https://doi.org/10.1158/0008-5472.CAN-21-0774
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