Prasanth Ariyannur

Integrated genomic and proteomic profiling reveals insights into chemoradiation resistance in cervical cancer

Cervical cancer is highly prevalent in India, with most cases being diagnosed at advanced stages. Despite the standard concurrent chemoradiotherapy (CCRT), 30–40% of patients' experience treatment failure, underscoring the need for improved therapeutic strategies. Understanding resistance mechanisms and identifying predictive biomarkers are crucial to improve treatment efficacy and enable personalized medicine. We conducted a comprehensive genomic and proteomic analysis to identify molecular signatures associated with CCRT. We identified recurrent mutations in phosphatidylinositol 4,5‐bisphosphate 3‐kinase catalytic subunit alpha isoform ( PIK3CA ) and histone‐lysine N‐methyltransferase 2D ( KMT2D ), with mutation signature analysis revealing a prevalent DNA dC‐ > dU‐editing enzyme, APOBEC mutagenesis signature. Distinct genomic alterations, including epidermal growth factor receptor ( EGFR ) amplification and serine/threonine kinase 11 ( STK11 ) deletion, were exclusively observed in the chemoradiation‐resistant cohort. Proteomic analysis identified 73 significantly dysregulated proteins, with syntaxin‐3 (STX3), SERPINB7, lipopolysaccharide‐binding protein (LBP), EMILIN2, and ribosyldihydronicotinamide dehydrogenase (quinone) (NQO2) being the top five upregulated proteins. Integrative pathway analysis highlighted an active DNA repair pathway in the resistant cohort. This study presents the first proteogenomic profiling of cervical cancer in the Indian population, linking molecular alterations to CCRT response. STK11 and STX3 emerged as predictive biomarkers for poor response, whereas EGFR presents as a promising therapeutic target in the resistant group.

Association of molecular subgroups with pathological parameters in endometrial carcinomas

Background: The integration of molecular features into the already existing pathological classification of endometrial carcinomas will offer significant prognostic information. As the literature search reveals, there are no studies from India that have classified these carcinomas based on molecular subtypes. The aim of the study was to classify endometrial carcinomas into four subtypes based on their molecular and immunohistochemical features and to find out the association of each of these molecular subtypes with the other pathological parameters. Methods: A prospective study was done on 37 consecutive cases of fresh hysterectomy specimens, biopsy-proven as endometrial carcinomas between November 2019 and August 2020. Three immunohistochemical markers (p53, mismatch repair proteins, MutS homolog6 and Postmeiotic seggregation 2 respectively[MSH6, and PMS2]), along with DNA (deoxyribonucleic acid) sequencing of selected regions of the POLE gene was performed in each of the 37 cases. Endometrial carcinomas were subclassified into four subtypes, and the association of each of these four subtypes with the other pathological parameters was also explored. Statistical analysis was done using the IBM Statistical Package for the Social Science (SPSS) Version 20.0 software (IBM SPSS, USA). Results: Among the 37 cases studied, eight (21.6%) cases were p53 abnormal, eight (21.6%) cases showed MMR-D (mismatch repair deficient), one case (2.7%) showed mutation of POLE, and 21 cases (56.8%) were assembled under p53 wild-type. Higher grade endometrial carcinomas showed more (80.0%) p53 abnormal (P < 0.001). All the p53 wild-type (100%) were of Type 1 endometrial carcinoma subtype (P = 0.001) and low-grade type (90.5%; P = 0.005). Conclusion: Our study confirms that the type of carcinoma and grade correlates with p53 expression, p53 abnormal being associated with higher grade and type 2 endometrial carcinomas, whereas p53 wild-type is associated with low-grade and type 1 endometrial carcinoma. There was only one case of the POLE subtype identifiable in our study.