Molecular landscape of gynecological malignancies in India as associated with distinct MSI and histotype-specific genomic features with therapeutic implications.

Abstract

e14567 Background: Gynaecological malignancies, including ovarian, endometrial, cervical, uterine sarcoma, and vulvar/vaginal cancers, are a major cause of morbidity and mortality among women in India. Limited genomic data from Indian patients restrict insights into population-specific tumor biology. This study aimed to characterize the genomic landscape of gynaecological cancers in an Indian cohort and identify clinically actionable alterations. Methods: A total of 615 histologically confirmed gynecological tumors underwent targeted sequencing to identify somatic variants, copy-number alterations, and gene fusions, with MSI and PD-L1 assessed where available. Co-occurrence and mutual exclusivity were evaluated using Fisher’s exact test with Benjamini-Hochberg correction (q < 0.05), and genomic profiles were compared with TCGA and other international cohorts. Results: Recurrent and co-occurring genomic alterations across 615 gynecological cancers (385 ovarian, 143 endometrial, 68 cervical, 11 uterine sarcoma, and 8 vulvar/vaginal) are summarized in Table 1. Ovarian cancers showed histotype-specific patterns, with TP53 alterations in serous tumors, PI3K/PTEN in endometrioid and clear-cell subtypes, and KRAS in mucinous tumors. MSI-H frequency was higher in ovarian cancers (7.8%), enriched in endometrioid tumors, while endometrial cancers showed a lower MSI-H rate (17.8%) than TCGA. Our analysis revealed population-specific mutation patterns. PD-L1 positivity was generally low, highest in cervical cancer (~40%), and tumor mutational burden was predominantly low to intermediate. Conclusions: This comprehensive genomic analysis of Indian gynecologic malignancies reveals both shared oncogenic drivers and distinct, population-specific molecular features. Uterine sarcomas exhibited distinct ATRX and FGF-axis alterations, highlighting actionable FGF-axis vulnerabilities rarely discussed in gynecologic precision oncology. MSI-H was enriched in ovarian endometrioid tumors but was less frequent in Indian endometrial cancers, underscoring histology- and population-specific MSI patterns. Low-intermediate TMB and limited PD-L1 expression suggest MSI may better predict immunotherapy response in this cohort. Recurrently altered genes and co-occurring genomic events. Cancer Type Recurrent Gene Alterations Co-occurring Alterations Ovarian Cancer TP53 ( 59% ) , PIK3CA ( 24% ) , PTEN (15%), and KRAS (13%) TP53-CCNE1 (p-value<0.05), PIK3CA-ARID1A ( p-value <0.01) Endometrial Cancer TP53 ( 57% ) , PTEN (39%), PIK3CA (37 % ) , and KRAS (19%) PIK3CA-MYC ( p-value <0.01), PIK3CA-BCL9 ( p-value <0.05) Cervical Cancer PIK3CA (43 % ), TP53 (29 % ) , KRAS (13%) and PTEN (13%) BRAF-RB1 (p-value <0.05 ), PIK3CA-ATR (p-value <0.05 ) Uterine Sarcoma TP53 (45%), ATRX (36%) FGF19/3 (27%) - Vulva/Vagina Cancer TP53 (38%), PTEN (25%) -