Gynecological cancers comprise a heterogeneous group of malignancies arising from the female reproductive tract, most commonly involving the uterus, ovaries, and cervix. Together, they accounted for more than 1.47 million new cases and 680,000 deaths worldwide in 2022, with substantial global disparities in incidence and mortality. Their development reflects a multifactorial interplay of genetic susceptibility, hormonal and metabolic dysregulation, and lifestyle influences. Gynecologic malignancies are biologically heterogeneous diseases, and despite advances in molecular profiling, reliable biomarkers for prognostic evaluation and therapeutic stratification remain limited.
Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is a transmembrane protein that functions as a tumor suppressor by regulating receptor tyrosine kinases and promoting bone morphogenetic protein (BMP) signaling. Elevated LRIG1 expression has been linked to favorable prognosis in various human cancers, though its prognostic role in gynecologic malignancies remains under investigation.
Ovarian carcinoma represents the eighth leading cause of cancer-related death among women worldwide, largely due to late-stage diagnosis, high recurrence rates, and treatment resistance. To investigate the role of LRIG1 in biologic fluids, a quantitative LRIG1-specific single-molecule array assay was developed. LRIG1 plasma levels were measured in 486 patients with suspected ovarian masses. Elevated LRIG1 levels correlated with poor prognosis and independently predicted outcomes in stage III ovarian carcinoma, indicating its potential as a biomarker. To further validate its role, a novel monoclonal anti-LRIG1 antibody, named 10C8, was developed. Immunohistochemical analyses across three independent ovarian carcinoma cohorts revealed an inverse correlation between tumor immunoreactivity and plasma levels, and higher LRIG1 expression in malignant versus benign or borderline tumors. However, prognostic significance varied by histological subtype and disease stage, suggesting a context-dependent clinical utility.
Cervical cancer is a major global health concern, with early-stage disease (FIGO IA2–IB1) carrying a risk of lymph node metastasis (LNM) in approximately 15% of patients. The presence of LNM often necessitates combined surgical and radiotherapeutic treatment, which substantially increases morbidity and adverse effects. Current preoperative diagnostic tools lack sufficient sensitivity to accurately predict nodal involvement prior to surgery. In this context, the ability of LRIG1 immunoreactivity to predict LNM was evaluated among 67 early-stage cervical carcinoma cases. This analysis revealed that high LRIG1 expression correlated with risk of LNM (odds ratio 9.5), suggesting a potential role as a predictive and prognostic biomarker in cervical cancer.
In endometrioid endometrial carcinoma, a subset of early-stage patients experience relapse, underscoring the need for improved prognostic indicators. Transcriptomic analysis of TCGA cases showed that elevated expression of several BMP signal-promoting genes correlated with poorer survival, whereas one BMP signal-suppressing gene was linked to improved outcome. Based on these findings, a tissue microarray of 241 stage I tumors was constructed to evaluate the prognostic relevance of LRIG1 tumor immunoreactivity. No significant association was observed between LRIG1 tumor immunoreactivity and relapse-free survival, though higher LRIG1 staining correlated with increased estrogen receptor, progesterone receptor, and Ki-67 expression.
To identify genes mediating resistance to platinum-taxane based chemotherapy in ovarian carcinoma, a series of human-mouse xenograft models were investigated. Genetic barcode experiments revealed that approximately 500-5,000 tumor-initiating cells contributed to tumor formation in the OVCAR3, OVCAR4, OVCAR8, and OVSAHO xenograft models. These results will guide future efforts to genetically screen for potential treatment targets in chemotherapy-resistant ovarian carcinoma.
Together, these studies provide new insights into the biological and prognostic roles of LRIG1 across major gynecologic cancers.