Unveiling a Genetic Link Between Adenomyosis and Carcinogenesis via Whole-Exome Sequencing: Could NTN1-Mediated Epithelial Mesenchymal Transition Be a Shared Mechanism?

Objective: Adenomyosis is a benign uterine condition characterized by the invasion of endometrial glands and stromal tissue into the myometrium. It exhibits cancer-like characteristics, such as epithelial-mesenchymal transition (EMT). We aimed to identify shared genetic variants between different cancers and adenomyosis, focusing on a family with women affected by both conditions.Materials and Methods: Among the four women with a family history of adenomyosis and carcinogenesis, two received pathologically confirmed diagnosis of ovarian adenocarcinoma and clear cell renal cell carcinoma (ccRCC). Genomic material was obtained from blood leukocytes, followed by whole exome sequencing to investigate novel and rare genetic variants related to both conditions.Results: Pathological evaluations excluded adenomyosis in the case diagnosed with ovarian mucinous adenocarcinoma, whereas it was confirmed in the case with ccRCC. A novel genetic variant, NTN1 p. (Ser271Ala), which triggers EMT and encourages tumor growth, was identified across all cases. The DynaMut prediction tool reported that this variant has a destabilizing impact on protein structure, which gained further support from four distinct prediction tools (ENCoM, mCSM, DUET, and MUpro). Additional rare variants in five genes were shared among the cases diagnosed with cancer.Conclusion: NTN1 may be involved in the pathobiology of carcinogenesis and adenomyosis, potentially linking these conditions through EMT. Functional studies are required to further investigate the impact of this novel variant.