Search Results (253)

In 2022, colorectal cancer (CRC) was the third most common type of cancer worldwide and the second most common in Europe. CRC ranked as the second leading cause of cancer-related deaths both worldwide and in Europe, with 904,019 and 247,966 deaths, respectively. The majority of CRC cases are sporadic (60–75%); however, 10–35% of CRC are estimated to result from the interaction of heritable and environmental factors. Among these, 5–6% are caused by inherited variants in genes that predispose to the development of CRC. Among the known inherited causes, Lynch Syndrome (LS), formerly known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is the most frequent and accounts for approximately 3% of all CRC. Here we review and update on multiple aspects of LS in the context of CRC, including its genetic and molecular basis, current guidelines for molecular screening and variant classification. Furthermore, we review functional assays that have been used to determine the biological impact of genetic variants of uncertain significance (VUS) and discuss future perspectives in the field. Full article

Understanding germline genetic variation is essential for improving human cancer care. Cancer predisposition genetic testing has become a part of the landscape of healthcare. Clinical guidelines have been established to identify individuals with monogenic risk, support variant classification, and guide enhanced cancer surveillance and prevention strategies. However, genetic mechanisms, cancer syndromes, genetic testing, patient education, and high-risk cancer management are often addressed in separate professional domains leading to limited cross-disciplinary understanding and confusion. A review tailored to a broad spectrum of clinicians is necessary to synthesize information, connect key concepts, and clearly define the principles and reasoning underlying recommended practice. Advanced genetic technology identified numerous genes and countless pathogenic variants contributing to a wide range of cancer predispositions. Rapid and accurate next-generation sequencing has enabled the routine use of multi-gene panel testing to stratify cancer risk. In precision cancer therapies, tumor genomic profiling frequently uncovers not only somatic alterations but also germline mutations, revealing additional cancer risk for the patients and their biological relatives. Beyond monogenic risks, the cumulative effect of numerous common polygenic factors can also significantly influence cancer susceptibility. Despite major advances in integrating germline genetic information into cancer care, substantial challenges remain in variant interpretation, precise risk stratification, and implementing personalized screening and prevention strategies. Using several cancer predisposition syndromes as examples, such as breast and ovarian cancer syndrome, Lynch syndrome, and Li-Fraumeni syndrome, the review provides a high-level overview of key concepts, the evolution of knowledge and technology, and the rationale underlying the current clinical management strategies. Full article

Background: Endometrial carcinoma (EC) is now classified primarily by molecular subtype—POLE-ultramutated, mismatch repair–deficient (dMMR), TP53-mutant/copy-number-high (CNH), and “no specific molecular profile” (NSMP)—a framework that has reshaped prognostic counseling and adjuvant therapy decisions. Yet several practically important questions remain insufficiently addressed in real-world cohorts: whether all four mismatch repair genes confer an equivalent favorable prognosis, whether all POLE alterations carry the same survival benefit or only specific pathogenic variants, and whether molecular subtypes retain prognostic value after adjustment for histology and tumor burden. Methods: We addressed these questions in 2901 patients pooled from the MSK-IMPACT 50K Clinical Sequencing Cohort (n = 2372; discovery) and the TCGA UCEC PanCancer Atlas (n = 529; validation)—the largest dual-cohort genomic analysis of EC reported to date. We performed individual MMR gene and combined dMMR survival stratification, multivariable Cox regression adjusted for age, histology, and sample type, and a pathogenicity-aware sensitivity analysis for POLE variants, with tumor mutational burden (TMB) compared across subgroups. Results: Across both cohorts, all four MMR gene–mutant subgroups (MLH1, MSH2, MSH6, PMS2) conferred equivalently favorable overall survival (OS) (six-group log-rank p = 7.66 × 10⁻¹² in discovery; p = 6.78 × 10⁻³ in validation), confirming dMMR as a class-level prognostic designation independent of which MMR gene is altered. Multivariable Cox regression demonstrated that POLE-ultramutated status retained an independent favorable effect (HR = 0.62, p = 0.038 in MSK; HR = 0.35, p = 0.028 in TCGA) after adjustment for age, histology, and sample type, while the favorable dMMR effect was largely accounted for by histologic context. Critically, a pathogenicity-aware sensitivity analysis revealed that the exceptional survival of the POLE subgroup is confined to canonical exonuclease-domain hotspot mutations (event rate 0.9% in MSK), whereas POLE variants of uncertain significance behave indistinguishably from NSMP-like tumors. Consistent with this finding, TMB was markedly elevated in canonical pathogenic POLE cases (median 138.7 mut/Mb in MSK; 247.4 in TCGA) but not in POLE-VUS-only cases (median 29.0 and 15.0, respectively; p < 0.001 between groups in both cohorts), confirming that the ultramutator phenotype is confined to canonical pathogenic POLE variants. We additionally characterize Uterine Clear Cell Carcinoma as a distinct histologic entity (n = 73; 3.0%) and report the POLE + TP53 co-mutant group (n = 90; 3.8%). Conclusions: These findings refine the molecular classification of EC in clinically meaningful ways: they support class-level immunotherapy eligibility based on dMMR status regardless of the specific MMR gene altered, demonstrate that POLE-ultramutated classification requires variant-level pathogenicity assessment, and identify TP53-mutant/CNH patients as the population with the most urgent unmet therapeutic need. Full article

Background: Microsatellite instability (MSI) is an important biomarker for the diagnosis of Lynch syndrome and for guiding immunotherapy in various solid tumors. Droplet digital PCR (ddPCR) has emerged as a highly sensitive method for detecting MSI, particularly in circulating tumor DNA (ctDNA). This study aimed to evaluate the analytical and clinical performance of a ddPCR assay using three MSI markers (BAT-26, ACVR2A, and DEFB105A/B) in colorectal, gastric, and endometrial cancers. Methods: Formalin-fixed paraffin-embedded (FFPE) samples from 190 patients (83 colorectal, 44 gastric, and 63 endometrial cancers) and 21 plasma samples from patients with metastatic solid tumors were analyzed. MSI status determined by ddPCR was compared with conventional PCR using a pentaplex panel and immunohistochemistry (IHC). Analytical performance, including limit of blank (LoB) and limit of detection (LoD), was evaluated using cell line DNA, and clinical cut-offs were established using receiver operating characteristic analysis. Results: The ddPCR assay demonstrated high analytical sensitivity, with LoD values of 0.075% for BAT-26, 0.1% for ACVR2A, and 0.025% for DEFB105A/B. Using optimized clinical cut-offs, the concordance rate between ddPCR and conventional PCR assays was 98.4% in tissue samples. Marker performance varied by cancer type, with reduced sensitivity observed in endometrial cancer. In plasma samples, MSI-H was detected in 1 of 21 cases (4.8%), and the overall concordance rate with tissue-based MSI status was 94.7%. Conclusions: The ddPCR assay demonstrated high concordance with conventional MSI testing methods and showed potential as a sensitive tool for MSI detection in both tissue and plasma samples. However, optimization of marker panels and establishment of sample-type-specific clinical cut-offs are required, particularly for ctDNA-based analysis. Further large-scale studies are needed to validate the clinical utility of ddPCR for MSI detection and monitoring. Full article

This paper aims to describe what is currently known about Lynch syndrome within Asian American populations. According to data collected by the US Census, as of 2022, 24.7 million people of Asian descent live in the United States. Cancer is the leading cause of death within this population, and as a result, it is crucial to identify ways that cancer can be identified at earlier and more treatable stages. Colorectal cancer is the third most common cancer diagnosis within the Asian American population, with an incidence of 37.1 per 100,000 Asian American men and 26.5 per 100,000 Asian American women. Lynch syndrome, the most common hereditary cause of colorectal cancer, has been incompletely described in this diverse population. This review addresses the available literature on the prevalence of Lynch syndrome in Asian American and Asian populations and differences in the manifestations of this syndrome between and within these populations, as well as in comparison to the non-Hispanic white population. Based on these differences, variances in screening rates, outcomes, and management strategies with respect to Asian ethnicity are also explored. Potential barriers to optimal management of Lynch syndrome in Asian American populations, with particular consideration of primary language and degree of cultural assimilation, are assessed. Future directions for research and recommendations to help address disparities or differences to optimize care for this group are also described. Full article

Background/Objectives: We aimed to test two different visual arrays for helping individuals accurately interpret colorectal cancer risk in Lynch syndrome. We also sought to examine factors associated with intention to share genetic test results with blood relatives. Methods: Participants were recruited through Amazon Mechanical Turk (July–August 2025). Participants completed an online REDCap survey evaluating genetic literacy/numeracy and risk perception (Tripartite Model of Risk Perception). Participants were randomized to a risk visualization—either a standard icon array or a sequential icon array intended to decrease cognitive load. Subsequently, participants were randomized to a communication choice scenario—a nondirective (choice) frame or an “enhanced choice” with a behavioral nudge based on the Theory of Planned Behavior. Results: Participants’ (n = 1041) estimation of colorectal cancer risk did not differ according to visualization type (icon array: 60.36 ± 15.86%, sequential array: 60.91 ± 15.73%, p = 0.58). Intention to share genetic testing outcomes with family members was not influenced by the behavioral nudge (p = 0.23). Neither risk estimation nor intent to communicate results to blood relatives were affected by individual perceived colorectal cancer risk, health literacy/numeracy, education, previous genetic testing, personal cancer history, or family cancer history (all p > 0.11 and p > 0.21, respectively). Conclusions: This study found that visual array type did not affect estimated cancer risk, and decision frame did not affect intention to share genetic testing results. Findings could inform the development of online approaches to expand decision support for hereditary cancer syndromes (Clinicaltrials.gov #NCT06994832). Full article

Microsatellite instability (MSI) testing is frequently used to screen patients for the early detection of Lynch syndrome, the most common hereditary colorectal cancer syndrome. MSI testing compares microsatellite repeat lengths in tumor DNA with those in matched normal tissue from the same patient. Therefore, precise sample identification is critical for obtaining reliable test results. The Penta-C and Penta-D pentanucleotide markers are widely used for sample identification in MSI testing. We investigated instability, defined as allelic mismatches or shifts, discordant fragment sizes, or the appearance of alleles in tumor DNA that were absent in the corresponding normal DNA, in the Penta-C and Penta-D loci across 2609 paired colorectal tumor and matched normal tissue or blood DNA samples. The allele sizes of both markers did not match in 0.3% of microsatellite-stable (MSS) and 12.3% of microsatellite instability-high (MSI-H) patients (p < 0.001, difference in proportions, 12.0% (95% CI, 8.9–15.1%)). Non-matching allele sizes in 12.3% of the MSI-H tumors suggest that other repeat markers may also be unstable and not suitable for sample identification in these tumors. Full article

Hereditary cancer syndromes (HCSs), including BRCA 1/2-associated hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS), confer substantial lifetime cancer risks, yet adherence to recommended risk-management strategies remains variable. This population-based retrospective cohort study examined cancer prevention practices, outcomes, and predictors of cancer occurrence among 476 BRCA and LS carriers identified through the Provincial Medical Genetics Program in Newfoundland and Labrador, Canada (2001–2022). Linked genetic, surgical, screening, and cancer registry data were evaluated, with adherence assessed during two intervals (2018–2020 and 2020–2022) based on NCCN guidelines. Participants were predominantly female (69%), with a mean age of 48.5 years at genetic testing; nearly 70% of primary cancers were already diagnosed at the time of testing. BRCA carriers demonstrated higher uptake of breast MRI (58–61%) and risk-reducing salpingo-oophorectomy (63–66%) compared with LS carriers’ colonoscopy uptake (42–44%). In univariate analyses, non-adherence during 2018–2020 was associated with increased odds of cancer after testing (OR ≈ 4.43, p < 0.001); this remained significant in the multivariate model (OR = 8.70; p = 0.0004). Individuals who did not follow recommended risk-management guidelines had nearly nine times greater odds of developing cancer after genetic testing than those who fully adhered to guidelines. Older age at referral (OR = 1.07/year, p < 0.001) also increased the odds of developing cancer. Study findings indicate that late referral and pre-existing cancers diminish the preventive impact of guideline-based risk management. System-level initiatives to promote earlier genetic testing, enhance cascade outreach, and strengthen surveillance pathways are needed to optimize cancer prevention and earlier cancer detection in high-risk populations. Full article

Background/Objectives: Lynch syndrome (LS), is traditionally managed uniformly despite being caused by pathogenic variants in four distinct mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2). This approach fails to leverage gene-specific characteristics for precision healthcare delivery. This review redefines LS as four distinct genetic syndromes and establishes a genotype-guided precision management framework to optimize risk stratification, surveillance, and therapeutic interventions. Methods: We synthesized molecular, clinical, and outcomes data from the Prospective Lynch Syndrome Database (8500+ carriers; 70,000 person-years), genomic studies characterizing gene-specific mutational patterns, and immunotherapy trials while referencing international guidelines [National Comprehensive Cancer Network (NCCN), European Hereditary Tumour Group (EHTG)/European Society of Coloproctology (ESCP), and European Society for Medical Oncology (ESMO)] to formulate genotype-stratified recommendations. Results: Fundamental molecular differences necessitate differentiated management strategies. MLH1 deficiency exhibits unique “two-in-one hit” mechanisms driving aggressive tumorigenesis with high interval cancer rates. MSH2 deficiency presents the highest tumor mutational burden (≈47 mutations per megabase; Mut/Mb) and broadest cancer spectrum. MSH6 deficiency displays distinctive high-single-nucleotide variant (SNV)/low-insertion–deletion (Indel) patterns often presenting as microsatellite instability-low (MSI-low) or microsatellite stable (MSS), complicating conventional detection. PMS2 deficiency demonstrates substantial attenuation due to redundancy. These translate into precision interventions: MLH1/MSH2 carriers require colonoscopy from age 25 at 1–2-year intervals with extended colectomy preferred, while MSH6/PMS2 carriers can defer surveillance to age 35–40 with longer intervals and undergo segmental resection. Immune checkpoint inhibitors (ICIs) are effective in deficient MMR (dMMR)/microsatellite instability-high (MSI-H) tumors across all four MMR genotypes. Conclusions: Genotype-specific precision management optimizes the benefit–burden balance, enhances early cancer detection, reduces overtreatment, and enables personalized genetic counseling, advancing precision healthcare for LS families and addressing critical gaps in hereditary cancer care. Full article

Background/Objectives: Colorectal cancer (CRC) is the third most common cancer worldwide. Accordingly, we aimed to investigate the frequency, types, and timelines of other cancers in patients diagnosed with CRC. Methods: Patients diagnosed with CRC between 1999 and 2023 were retrospectively included. We collected data on the demographics and diagnosis of any additional cancer, either prior to or following the CRC diagnosis. Data were retrieved from the Clalit database using the MDClone platform. Results: A total of 65,774 CRC patients were identified between 1999 and 2023. A second primary malignancy (SPM) was diagnosed in 13,679 patients (21%). Being female, smoking, and having chronic obstructive pulmonary disease were more frequent among patients with a SPM. Breast, prostate, and lung cancers were the most prevalent SPMs. The risk of developing SPM was highest during the first three years after CRC diagnosis, especially with respect to lung cancer, whereas the majority of breast and prostate cancers were diagnosed during the three years before CRC; the cumulative standardized incidence ratio was calculated to be 4.1 for any cancer. Conclusions: CRC patients have an increased second primary cancer. Patients diagnosed with CRC should be encouraged to undergo screening for other cancers, and those with Lynch-related cancers should be investigated for the syndrome. Patients with a diagnosis of breast or prostate cancer should be considered for colonoscopy screening. Full article

Endometrial cancer is the most common gynaecologic malignancy in high-income countries, with a rising incidence largely driven by reproductive factors, obesity, and prolonged exposure to unopposed oestrogens. Although most cases are sporadic, approximately 2–5% are associated with hereditary cancer syndromes, of which Lynch syndrome represents the most important contributor. Lynch syndrome results from germline mutations in DNA mismatch repair (MMR) genes and is associated with a substantially increased lifetime risk of endometrial cancer, reaching up to 71% in carriers of MutS homologue 6 (MSH6) mutations. Hereditary cancer predisposition typically follows an autosomal dominant inheritance pattern and may be suspected based on clinical warning signs such as early disease onset, multiple primary malignancies, a strong family history, or the presence of microsatellite instability in tumour tissue. In addition to Lynch syndrome, rarer genetic conditions—including Cowden syndrome (PTEN), Li–Fraumeni syndrome (TP53), polymerase proofreading–associated polyposis (POLE/POLD1), and hereditary breast and ovarian cancer syndromes (BRCA1/2)—also contribute to hereditary endometrial cancer risk. Recognition of these genetic backgrounds is essential for accurate diagnosis, personalised surveillance, and the implementation of targeted preventive and therapeutic strategies. Despite major advances in molecular diagnostics, hereditary endometrial cancer remains frequently underdiagnosed, leading to missed opportunities for cancer prevention among affected individuals and their families. This comprehensive review summarises current evidence on hereditary predispositions to endometrial cancer, with a particular emphasis on Lynch syndrome, and discusses underlying genetic mechanisms, inheritance patterns, diagnostic strategies, and clinical implications for screening, genetic counselling, and treatment optimisation. Full article

Background/Objectives: Individuals carrying pathogenic/likely pathogenic (P/LP) variants associated with hereditary breast and ovarian cancer (HBOC) and Lynch Syndrome (LS)- have increased risk for various types of cancer. The study compared health behaviors, i.e., smoking, alcohol consumption, level of physical activity, and body mass index (BMI) among affected and unaffected (never diagnosed) individuals with P/LP variants associated with HBOC or LS. Methods: We used baseline and 18-month follow-up data from individuals with HBOC- or LS-associated P/LP variants from the Swiss CASCADE study, an open-ended, prospective, family-based cohort. Generalized linear models with random effects were applied. Results: A total of 856 records from 518 participants (HBOC: 410; LS: 108) were analyzed. More than half (58%) of participants had at least one cancer diagnosis. After controlling for potential confounders, the proportion of current smokers was not significantly different between the two groups (ß = 3.5, p = 0.24). Alcohol intake was not associated with cancer diagnosis (adjusted: ß = −0.2, p = 0.57), although it was positively associated with time since genetic testing (ß = 0.11, p < 0.01). Levels of physical activity were lower among affected individuals compared to unaffected (adjusted: ß = −0.5, p = 0.03). There was no difference in BMI between the two groups. Conclusions: No significant differences in health behaviors, i.e., smoking, alcohol consumption, or BMI, were detected in individuals with P/LP variants associated with HBOC or LS unaffected by cancer and those with cancer diagnosis. Lower levels of physical activity in those with a cancer diagnosis could potentially be attributed to cancer treatment. Future studies should examine whether adjustments in health behavior are associated with the genetic diagnosis. Full article

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. Full article

Hereditary predisposition substantially shapes prevention and management across urologic oncology. This narrative review synthesizes contemporary, practice-oriented guidance on whom to test, what to test, how to act on results, and how to implement care equitably for hereditary forms of prostate cancer, renal cell carcinoma (RCC), urothelial carcinoma, pheochromocytoma/paraganglioma (PPGL), and adrenocortical carcinoma (ACC). We delineate between forms of indication-driven germline testing (e.g., universal testing in metastatic prostate cancer; early-onset, bilateral/multifocal, or syndromic RCC; reflex tumor mismatch repair (MMR)/microsatellite instability (MSI) screening in upper-tract urothelial carcinoma (UTUC); universal testing in PPGL; universal TP53 testing in ACC) and pair these strategies with minimum actionable gene sets and syndrome-specific surveillance frameworks. Key points include targeted prostate-specific antigen screening in BRCA2 carriers and the impact of BRCA/ATM variants on reclassification during active surveillance; major hereditary RCC syndromes with genotype-tailored surveillance and pathway-directed therapy (e.g., HIF-2α inhibition for von Hippel–Lindau disease); UTUC/bladder cancer in Lynch syndrome with tumor MMR/MSI screening, annual urinalysis (selective cytology), and immunotherapy opportunities in deficient MMR disease/MSI-H; PPGL management emphasizing universal germline testing, intensified surveillance for SDHB, cortical-sparing adrenalectomy, and emerging HIF-2α inhibition; and ACC care modified by Li–Fraumeni syndrome (minimization of radiation/genotoxic therapy with whole-body imaging surveillance). Testicular germ cell tumor remains largely polygenic, with no routine germline testing in typical presentations. Finally, we provide pre-/post-test genetic-counseling checklists and mainstreamed workflows with equity metrics to operationalize precision care and close real-world access gaps. Full article

Background: Endometrial hyperplasia (EH) represents a precursor lesion in the development of endometrial carcinoma, particularly the endometrioid subtype. Among the molecular pathways involved, microsatellite instability (MSI) resulting from DNA mismatch repair (MMR) deficiency has gained increasing attention as an early event in endometrial carcinogenesis. Objective: This study aimed to evaluate the expression of key MMR proteins (MLH1, PMS2, MSH2, and MSH6) in endometrial hyperplasia without atypia and endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia (EAH/EIN) to determine the prevalence and potential implications of MMR deficiency at the precancerous stage. Methods: Fifty-six cases of EH were analyzed, including 28 endometrial hyperplasia without atypia and 28 EAH/EIN. Immunohistochemical (IHC) analysis was performed to assess the nuclear expression of MMR proteins. Loss of expression was defined as complete absence of epithelial nuclear staining with retained stromal positivity. Results: MMR protein expression was retained in all cases of endometrial hyperplasia without atypia, while total loss of one or more MMR proteins was observed in 3 of 28 (10.7%) EAH/EIN. The most frequent pattern involved concurrent MLH1/PMS2 loss, consistent with sporadic MLH1 promoter hypermethylation. One case exhibited isolated MSH6 loss, suggesting a potential Lynch syndrome, and another showed combined MSH6/PMS2 loss. Conclusions: MMR deficiency appears confined to atypical EH, supporting its role as an early molecular alteration in the neoplastic sequence leading to endometrioid carcinoma. Identification of abnormal MMR expression in EH may facilitate risk stratification, guide reflex testing for MLH1 methylation, and prompt genetic counseling for hereditary cancer predisposition. Full article