A Case of Polymerase Proofreading-Associated Polyposis: Challenges in Genetic Diagnosis

Polymerase proofreading-associated polyposis (PPAP) is a rare autosomal dominant hereditary syndrome caused by germline pathogenic variants in the POLE or POLD1 genes. It is clinically similar to familial adenomatous polyposis (FAP) and Lynch syndrome, making diagnosis difficult. Although the number of reported cases is increasing globally, PPAP remains underrecognized, particularly in Japan. Accurate diagnosis often requires comprehensive genetic testing, including multi-gene panel analysis and variant reinterpretation.

We report a rare case of PPAP in a 50-year-old woman with a complex clinical history involving multiple primary malignancies. The patient developed ovarian cancer in her 20s, followed by endometrial and contralateral ovarian cancers in her 30s. She was also diagnosed with early-stage colorectal cancer and polyposis, for which she underwent total colectomy with ileorectal anastomosis. Initially, she was suspected to have FAP or Lynch syndrome, but genetic testing revealed no pathogenic variants in APC, MUTYH, or mismatch repair genes. Subsequent multi-gene panel testing identified a POLE variant of uncertain significance (VUS), which was later reclassified as likely pathogenic. Based on this reinterpretation and her clinical phenotype, a diagnosis of PPAP was made. Her disease course included recurrent rectal polyps and carcinoma after colectomy, as well as breast cancer. No upper gastrointestinal polyposis was observed.

This case represents one of the few reported instances of PPAP in Japan and illustrates the diagnostic complexity of hereditary polyposis syndromes. It highlights the critical role of multi-gene panel testing and the importance of variant reinterpretation in establishing a definitive diagnosis. Continued surveillance and multidisciplinary care are essential for managing patients with PPAP.