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High-grade serous ovarian carcinoma, the “Achiles’ hill” for clinicians and molecular biologists: a molecular insight

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Abstract

High-grade serous ovarian carcinoma (HGSOC), the deadliest ovarian cancer, alone accounts for 90% of all its subtypes. Characterized by hallmark mutation of TP53, HGSOC show diverse molecular etiology. HGSOC can arise from both ovarian epithelium as well as the fimbrial epithelium of the fallopian tube. Ovulation induced reactive oxygen species, follicular fluid associated growth factor induced stemness, deregulation of hormone receptors like ER, FSHR, AR and hormones like FSH, LH, prolonged ovulation cycle, use of oral contraceptives are agonists of HGSOC while parity, breastfeeding provide protective effect from HGSOC development. Apart from a generic TP53 mutation, mutation of BRCA1/2, RAD51, BRIP1, PALB2, CHEK2, RAD50 etc., were reportedly associated with development of HGSOC. Epigenetic events like methylation of RASSF1A of RAS signaling pathway,OR51L1, OR51I1, OR51F1 etc. has been reported in HGSOC. Micro-RNAs like miR-1290, miR 27-a-3p miR23a, miR205 were reportedly upregulated in HGSOC. Amongst its cognate subtypes viz. differentiated, immunoreactive, mesenchymal, and proliferative, mesenchymal, and proliferative show worst prognosis. A system biology approach showed five major altered pathways in HGSOC, namely, RB, PI3K/RAS, NOTCH, HRR and FOXM1 signaling. For chemonaive patients, drugs that helps in efflux of reduced glutathione or prevent the redox coupling of GSH-GSSG, like Cisplatin, could be considered as the best therapeutic choice for HGSOC. For patients with BRCA1/2 mutations, PARP inhibitors alone or with Bevacizumab can be effective. Immune checkpoint inhibitors could be effective against immunoreactive subtypes. Identification of genes deregulated in chemoresistance could provide better insights in dealing with the disease.

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  1. Dept of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, 3081, Nayabad, Kolkata, 700094, India

    Rittwika Bhattacharya, Arijit Ghosh & Soma Mukhopadhyay

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  1. Rittwika Bhattacharya
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Bhattacharya, R., Ghosh, A. & Mukhopadhyay, S. High-grade serous ovarian carcinoma, the “Achiles’ hill” for clinicians and molecular biologists: a molecular insight. Mol Biol Rep 50, 9511–9519 (2023). https://doi.org/10.1007/s11033-023-08760-3

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