Simple Summary
Lynch syndrome (LS) is the most common autosomal dominant hereditary colorectal cancer syndrome, resulting from germline pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, MSH6, PMS2, and deletions in EPCAM. The spectrum of tumors associated with LS is broad, and disease phenotype is quite variable, with risk of cancer development largely dependent on the involved gene. Accurate diagnosis through genetic testing and comprehensive family history assessments to identify at-risk individuals is critical to the facilitation of personalized cancer surveillance and prevention strategies. This narrative review aims to provide a comprehensive understanding of LS, from its molecular basis to current guidelines informing clinical and therapeutic practices.
Abstract
Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a hereditary cancer syndrome significantly increasing the risk of colorectal cancer (CRC) and various extracolonic cancers, including endometrial, ovarian, and gastric cancers. LS results from germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes, such as MLH1, MSH2, MSH6, and PMS2, leading to microsatellite instability (MSI). This review explores the multifaceted aspects of LS, covering clinical presentation, genetic underpinnings, and emerging therapeutic strategies. The discussion explores the importance of identifying at-risk individuals, facilitating personalized cancer surveillance and prevention strategies. Molecular insights into distinguishing between sporadic and LS-associated cancers are also examined, with a focus on somatic testing methods, including MSI and immunohistochemistry (IHC). The gynecological cancer risks, particularly those related to endometrial and ovarian malignancies, are addressed, underscoring the need for early detection and risk-reducing interventions. Recent advancements in the management of colorectal and other LS-related cancers are highlighted, with particular attention to the growing role of immunotherapy, including immune checkpoint inhibitors, and immunoprevention strategies. With ongoing advances in our understanding of LS, opportunities for earlier detection, more effective prevention, and innovative treatments continue to expand. This narrative review adopts a multidisciplinary approach to provide a comprehensive understanding of LS, from its genetic basis to current clinical and therapeutic practices, with the ultimate goal of improving patient outcomes and enhancing the quality of care.