De novo familial adenomatous polyposis with germline double heterozygosity of APC/BRCA2: a case report and literature review.

Background: The widespread application of colonoscopy screening and genetic testing in colorectal cancer (CRC) treatment has led to the identification of a subset of familial adenomatous polyposis (FAP) patients who lack a family history of the disease but harbor germline gene mutations. Moreover, distinct genotypes may be associated with varied clinical presentations and therapeutic options. This case report describes a male patient with de novo FAP who harbored germline double heterozygosity (GDH) for APC and BRCA2 mutations. The patient underwent total colectomy, and genetic testing enabled personalized surveillance and management strategies for his family members.

Case Presentation: A 43-year-old male with no family history of cancer presented to the outpatient clinic of the Colorectal Surgery Department with complaints of constipation and hematochezia. Colonoscopy revealed hundreds of polyps throughout the colon and a rectal adenocarcinoma located 5 cm from the anal verge. Gastroduodenal endoscopy did not detect any upper gastrointestinal adenomas. The patient underwent laparoscopic total colectomy with abdominoperineal resection of the rectum and end ileostomy. With the consent of the patient and his family, genetic testing was performed. The index patient was found to carry an APC splicing site mutation (exon 15: c.1744-1G > A) and a BRCA2 missense mutation (exon 17: c.7976G > A: p.R2659K). His daughter was found to have inherited the same germline BRCA2 variant. Additionally, the rectal cancer exhibited proficient DNA mismatch repair (pMMR) status, ERBB2 copy number amplification, and a missense mutation, while the KRAS, NRAS, and BRAF genes were wild-type. Based on the genetic testing results and clinical manifestations, the index patient was diagnosed with familial adenomatous polyposis (FAP) and rectal cancer. Personalized surveillance and management strategies were implemented for the patient and his family, focusing on the risks of extra-colonic diseases and potential malignancies in the prostate, pancreas, breast, and ovaries.

Conclusion: De novo FAP with double germline mutations in APC and BRCA2, along with somatic ERBB2 mutations, is exceptionally rare among hereditary cancer cases. With the rapid advancements in genomics, the detection of multiple gene variants in individuals or families has become increasingly common. Additionally, the application of artificial intelligence (AI) in medical research may provide powerful tools for genetic analysis and clinical decision-making. Consequently, a comprehensive evaluation of family history, a deep understanding of hereditary cancer syndromes, and precise interpretation of genetic mutations are essential for personalized clinical management in the era of precision medicine. However, these tasks pose significant challenges for clinicians and genetic counselors alike.