Lucio Miele

Germline APC I1307K and MITF E318K variants in a patient with high-grade serous ovarian carcinoma: A case report

We report the case of a 76‑year‑old woman with high‑grade serous ovarian carcinoma (HGSOC) who was found to carry germline variants in APC I1307K and MITF E318K. Although neither variant is an established contributor to ovarian cancer risk, their co‑occurrence raises the possibility of polygenic or modifier effects on tumor susceptibility. The APC I1307K allele is a founder variant linked to increased colorectal cancer risk through the creation of a hypermutable region that predisposes to somatic mutations rather than classical tumor‑suppressor inactivation. In contrast, MITF E318K is a gain‑of‑function variant associated with melanoma and renal cell carcinoma, acting through altered transcriptional regulation that promotes cell proliferation and survival. While these genes do not interact directly, both converge on signaling pathways-WNT/β‑catenin, MAPK/ERK, and PI3K/AKT-that are widely implicated in ovarian carcinogenesis. There is a possibility that HGSOC in this patient is sporadic and unrelated to these two variants. Nevertheless, the case underscores the importance of comprehensive germline testing and highlights potential, yet underexplored, genetic interactions that may influence ovarian cancer risk. To our knowledge, this represents the first reported case of HGSOC in a patient harboring both variants, offering a hypothesis‑generating observation for future investigation.