Nageswara Rao Dunna

Integrated case–control and in silico analysis of DNA double-strand break repair gene variants (RAD51, XRCC2, XRCC3, XRCC4, and LIG4) for ovarian cancer susceptibility

The contribution of low-penetrance DNA repair genes (DRGs) to ovarian cancer (OC) risk remains poorly understood. Variants in homologous recombination repair (HRR) and non-homologous end joining (NHEJ) pathway genes may influence genomic stability and modulate OC susceptibility. This population-based case-control study (474 subjects; 237 OC patients and 237 controls) evaluated polymorphisms in RAD51, XRCC2, XRCC3 (HRR), and XRCC4, LIG4 (NHEJ) to assess their role in OC predisposition. Genotyping was performed using PCR-RFLP, and logistic regression estimated risk associations. Multifactor Dimensionality Reduction (MDR) analysis examined SNP-SNP interactions, while in silico tools and electrostatic surface mapping predicted structural and functional effects. Significant associations were observed for RAD51 (rs1801320), where individuals with the mutant CC genotype showed a 2.8-fold higher OC risk (OR = 2.85; 95 % CI = 1.15-7.06; p = 0.049), and the CT genotype of LIG4 (rs1805388) conferred a 1.85-fold increased risk (OR = 1.85; 95 % CI = 1.11-3.07; p = 0.0097). Conversely, CT genotype carriers of XRCC3 (rs861539) exhibited reduced OC risk (OR = 0.49; 95 % CI = 0.32-0.75; p = 0.003). XRCC2 and XRCC4 showed no significant associations. However, XRCC2 variants correlated with tumor grade and menopausal status, and XRCC3 with tumor histology. MDR analysis revealed strong interactions between XRCC3 and RAD51, followed by combinations involving XRCC2, suggesting synergistic HRR gene effects. In silico predictions indicated XRCC2 R188H is destabilizing, XRCC3 T241M has mixed effects, and LIG4 T9I is stabilizing. Overall, RAD51 and LIG4 polymorphisms may contribute to OC susceptibility in South Indian women. Larger, multi-center studies are warranted to validate these findings and explore their potential as predictive biomarkers for OC.

Decoding the Impact of Genetic Polymorphisms in Xenobiotic Metabolizing Enzymes and Ovarian Cancer: A Comprehensive Review

ABSTRACT Ovarian cancer (OC), the third most common and fatal gynecological malignancy, is a heterogeneous disease characterized by genomic instability. The interaction between genetic and environmental factors, including xenobiotics, plays a crucial role in OC initiation, progression, and treatment resistance. Xenobiotic metabolism (XM) is a key process for metabolizing and detoxifying environmental carcinogens, drugs, and other xenobiotics. Variations in XM genes (XMGs), such as those encoding cytochrome P450s (CYPs), UDP‐glucuronosyltransferases (UGTs), sulfotransferases (SULTs), N‐acetyltransferases, and glutathione S‐transferases (GSTs), can alter enzyme activity, thereby affecting detoxification, hormone metabolism, and clinical outcomes. Previous research has shown the effects of genetic variants on XM in OC, underscoring the importance of pharmacogenomics in tailoring personalized treatments. However, challenges persist, including individual variability, study inconsistencies, and insufficient ovarian‐specific data on XM. This review provides a comprehensive overview of XM in OC. It emphasizes the importance of phase I and II enzymes in detoxification and biotransformation, and ABC transporters in drug metabolism and chemoresistance. This review provides insights into the emerging roles of CYPs, GSTs, glutathione peroxidases, myeloperoxidase, catalase, superoxide dismutase, SULTs, and UGTs, and addresses the need for further research to understand their influence on OC risk and prognosis. By addressing the gaps in ovarian‐specific XM research, including their role in susceptibility and treatment response, these insights have the potential to advance targeted therapeutic strategies and overcome the challenges of chemoresistance in OC.

Analysis of pathogenic variants in BRCA1 and BRCA2 genes using next-generation sequencing in women with triple negative breast cancer from South India

The frequency of triple-negative breast cancer (TNBC) incidence varies among different populations suggesting the involvement of genetic components towards TNBC development. Previous studies have reported that BRCA1/2 germline mutations confer a lifetime risk of developing TNBC. However, there is hardly any information regarding the common pathogenic variants (PVs) in BRCA1/2 genes that contribute to TNBC in the Indian population. Hence, we screened for PVs in BRCA1/2 and their association with clinico-pathological features in TNBC patients. The study recruited 59 TNBC patients without hereditary breast and ovarian cancer (HBOC) from South India. The entire BRCA1 and BRCA2 genes were sequenced for the 59 patients using the Illumina HiSeq X Ten sequencer. Among the 59 TNBC genomic DNA samples sequenced, BRCA mutations were identified in 8 patients (13.6%), BRCA1 mutations in 6 patients, and BRCA2 mutations in 2 patients. Among the 6 BRCA1 mutations, three were c.68_69delAG (185delAG) mutation. Remarkably, all the TNBC patients with BRCA mutations exhibited higher-grade tumors (grade 2 or 3). However, among all the BRCA mutation carriers, only one patient with a BRCA2 mutation (p.Glu1879Lys) developed metastasis. Our data advocates that South Indian women with higher grade TNBC tumors and without HBOC could be considered for BRCA mutation screening, thereby enabling enhanced decision-making and preventive therapy.