PCDHGC3 hypermethylation as a diagnostic and prognostic biomarker in adrenocortical carcinomas

Gallego Nuria Valdes; Victorero Tamara Cubiella; Villar Diana Rodriguez; Raul Rodriguez-Aguilar; Cubero Jorge Hernando; Marta Araujo-Castro; Felicia Hanzu; Paula Jimenez-Fonseca; Romero Maria Dolores Chiara

doi:10.1530/endoabs.107.012

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Endocrine Abstracts (2024) 107 012 | DOI: 10.1530/endoabs.107.012

IACS9 9th International Adrenal Cancer Symposium 2024 Abstracts (18 abstracts)

PCDHGC3 hypermethylation as a diagnostic and prognostic biomarker in adrenocortical carcinomas

Nuria Valdés Gallego ¹ , Tamara Cubiella Victorero ² , Diana Rodríguez Villar ³ , Raúl Rodríguez-Aguilar ³ , Jorge Hernando Cubero ⁴ , Marta Araujo-Castro ⁵ , Felicia Hanzu ⁶ , Paula Jiménez-Fonseca ⁷ & María Dolores Chiara Romero ²

Author affiliations

¹Endocrinology & Nutrition Department, Hospital Universitario Cruces, Bizkaia, & Biobizkaia Health Research Institute, University of the Basque Country (UPV/EHU), CIBERDEM, CIBERER, Endo-ERN, Spain ²Institute of Sanitary Research of the Principality of Asturias (ISPA), Oviedo, Spain &Institute of Oncology of the Principality of Asturias, University of Oviedo, Oviedo, Spain ³Department of Pathology, Hospital Universitario de Cabueñes, Gijón, Spain ⁴Medical Oncology Department, Hospital Universitario de Vall d´Hebron, Barcelona, Spain ⁵Endocrinology & Nutrition Department, Hospital Universitario Ramón y Cajal, Madrid, Spain & Instituto de Investigación Biomédica Ramón y Cajal (IRYCIS), Spain ⁶Endocrinology & Nutrition Department, Hospital Universitario Clínic Barcelona, Barcelona, Spain ⁷Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain

Background: Our previous research highlighted the role of protocadherin (PCDHC) gene clusters in neuroendocrine tumors. We discovered a link between de novo methylation of the PCDHGC3 gene and the development of metastases in pheochromocytomas/paragangliomas. Moreover, we identified PCDHGC3 hypermethylation as a key factor in distinguishing gastrointestinal (GI) neuroendocrine carcinomas (GI-NECs) from GI-neuroendocrine tumors. Adrenocortical carcinomas (ACCs) are rare, aggressive tumors, and differentiating them from adrenocortical adenomas (ADs) can be challenging.

Objective: This study aims to assess whether epigenetic alterations of PCDHGC3 could serve as clinically relevant biomarkers of malignancy in adrenocortical tumors.

Materials and Methods: The hypermethylation of the PCDHGC3 gene promoter was analyzed in 50 ACCs and 12 ADs. Statistical analysis was performed using SPSS Statistics v29, and the ROC curve was employed to determine the predictive value for the diagnosis of ACC.

Results: The percentage of PCDGH3 methylation in the 50 ACCs was statistically higher than in the 12 ADs: 2.7±2.5% vs. 0.92±0.13%, P = 0.014, with an area under the curve (AUC) of 0.912±0.038 (95% CI: 0.837–0.986). For a Youden index of 0.88, a methylation percentage >1.10% showed an AUC of 0.94±0.29 (95% CI: 0.883–0.997), with a sensitivity of 88%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 66.7% for differentiating ACCs from ADs. A positive correlation was found with ACC size (r = 0.40, P = 0.005), but not with the Weiss score, Ki-67, or age. The percentage of PCDGH3 methylation in ACCs with ENSAT stage IV was higher compared to other stages (4.1±4.1% vs. 2.1±1.3%, P = 0.021). Kaplan-Meier analysis showed that time to metastasis development in ENSAT stages I-III was shorter in patients with methylation >1.10% (31±10.4 vs. 13±2.2 months, P = 0.034).

Conclusions: Our study suggests that PCDGH3 hypermethylation could be a useful diagnostic biomarker for differentiating ACCs from ADs, and a prognostic biomarker for identifying patients at higher risk of disease progression.