Germline pathogenic variants (PVs) of the APC gene cause familial adenomatous polyposis (FAP), whereas PVs in DNA mismatch repair (MMR) genes underlie Lynch Syndrome (LS), formerly known as hereditary non polyposis colorectal cancer (HNPCC). The coexistence of both hereditary syndromes in a single individual has been reported extremely rarely and only in a few patients, and the scant literature on this topic suggests an earlier onset and a more rapidly worsening form of colorectal cancer, compared with subjects who carry a single mutation. Here we describe a 16-year-old female who presented with multiple colonic polyps as well as an invasive colorectal carcinoma, and was found to harbor heterozygous pathogenic variants (PV) both in APC and MSH2 genes. Our patient also represents the unique reported case harboring both a MSH2-EPCAM large rearrangement in association with a frameshift APC PV. This case illustrates the unique clinical phenotype that can arise from simultaneous FAP and LS pathogenic mutations, highlights the importance of comprehensive genetic testing in young patients with aggressive disease and ultimately suggests a personalized follow-up and surveillance program in this case.
Lynch syndrome is the most common hereditary cancer predisposition syndrome, yet remains substantially underdiagnosed despite effective risk reduction strategies. Identification of affected individuals is critical to enable cancer prevention, early detection, and cascade testing of at-risk relatives. Multiple complementary approaches to Lynch syndrome detection exist, each with distinct strengths and limitations across clinical settings. In this review, we summarize established and emerging strategies for Lynch syndrome identification in those with a personal and family history of colorectal neoplasia. Tumor-based mismatch repair deficiency testing remains an effective and cost-efficient screening strategy but is limited by incomplete implementation and imperfect sensitivity. Direct germline testing can overcome some of these limitations and identify additional hereditary cancer syndromes, though considerations regarding yield, cost, and interpretation remain. Family history-based approaches and risk prediction models offer additional tools but are constrained by challenges in data collection and clinical uptake. Optimizing Lynch syndrome identification will require integration of these strategies alongside system-level interventions to improve access, uptake, and equity in genetic evaluation.
The 21st Century Cures Act Final Rule is a federal law recently implemented in the United States of America which prompted a practice shift among genetic counselors who historically disclosed genetic testing results by directly speaking with patients. Herein, we report participant experiences following a single-center’s approach of patients selecting provider-facilitated versus immediate release of hereditary cancer genetic testing results in the electronic health record preceding provider review. A voluntary survey was sent to patients who completed pre-test genetic counseling and hereditary cancer genetic testing within the University of Pennsylvania Health System. Responses were analyzed using descriptive statistics. Participants (n = 153) were predominately White (77
Lynch syndrome is the most common hereditary colorectal cancer syndrome, and colonoscopy remains the cornerstone of prevention. However, surveillance is limited by missed lesions, variable procedural quality, accelerated neoplastic progression, and the continued occurrence of post-colonoscopy colorectal cancers. This review examines gene-specific differences in colorectal cancer and adenoma risk, quality standards for surveillance colonoscopy, emerging artificial intelligence technologies, and complementary non-endoscopic strategies. Contemporary studies conducted in expert settings have reported higher adenoma detection rates, reflecting improvements in colonoscopy quality. At the same time, randomized trials have shown no clear additional benefit from computer-aided detection when added to high-quality colonoscopy. Among complementary strategies, fecal immunochemical testing may support prioritization and risk stratification, although its optimal threshold, testing interval, and safety for postponing colonoscopy remain uncertain. In parallel, blood-based biomarkers for cancer prediction remain exploratory. Future progress will depend on wider implementation of quality-assured surveillance and prospective validation of adjunctive tools that can safely guide colonoscopy timing and reduce the occurrence of post-colonoscopy colorectal cancers.
Lynch syndrome, one of the most common hereditary cancer predisposition syndromes, is caused by pathogenic variants in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and the EPCAM gene. Individuals who inherit pathogenic variants in Lynch-associated genes experience increased lifetime risk of colorectal, endometrial, and several other cancer types. Risks of Lynch-associated cancers vary by the affected gene and within each gene, especially for lower penetrance genes. This poses challenges for clinicians to provide patients and families with accurate cancer risk estimates and determine individualized surveillance protocols. Compounding this challenge is that study designs and potential biases could yield different risk estimates. In this review, we present up-to-date Lynch syndrome cancer risk estimates and discuss how study design could impact these risk estimates.
