Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide. Hereditary forms, such as familial adenomatous polyposis (FAP) and Lynch syndrome, significantly impact disease onset, progression, and management. This study provides a structured overview of diagnostic approaches in CRC, specifically focusing on Lynch syndrome and FAP, including its attenuated variant. Methods: A 51-year-old male presented with altered bowel habits and rectal pain, with a family history of endometrial and oropharyngeal cancers. Colonoscopy revealed a rectosigmoid ulcer and multiple sessile polyps throughout the colon. Biopsy confirmed well-differentiated adenocarcinoma with high-grade dysplasia in rectal polyps. He underwent neoadjuvant chemoradiation followed by total proctocolectomy. Immunohistochemistry showed isolated loss of MSH6 protein. Genetic testing revealed a pathogenic APC gene mutation. Results: This case highlights the complex interaction between APC mutations and mismatch repair (MMR) protein deficiencies. Isolated MSH6 loss may raise suspicion for Lynch syndrome; however, since MSH6 functions with MSH2—an essential component of MMR—the intact expression of MSH2 reduces the likelihood of Lynch syndrome. The presence of ~30 polyps and APC mutation supports a diagnosis of attenuated FAP rather than Lynch syndrome. Conclusion: This case underscores the importance of integrating molecular diagnostics in CRC evaluation. Genetic testing is essential for differentiating between FAP, Lynch syndrome, and other hereditary syndromes, enabling precise clinical management and family risk assessment. Keywords: colorectal cancer; APC mutation; attenuated FAP; Lynch syndrome; MMR genes; MSI
Aishwarya et al. (Wed,) studied this question.