Search Results (20)

Lynch syndrome (LS)—also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC)—is caused by pathogenic germline mutations in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. Although it accounts for only 1–5% of all colorectal cancers (CRCs), LS presents with a particularly high lifetime cancer risk and often occurs at younger ages. Identifying LS in patients under 60 years old is crucial for targeted surveillance and early interventions. Variations in clinical presentation and prognosis may exist based on the specific gene mutated, yet these patterns are not fully elucidated. This review aims to synthesize data on clinical outcomes among LS patients under 60, with an emphasis on how different MMR gene mutation patterns might influence prognosis, survival, and treatment decisions. Five population-based studies examining CRC patients younger than 60 years were included according to predefined eligibility criteria. Two independent reviewers screened and extracted data focusing on MMR deficiency detection methods (microsatellite instability [MSI] and/or immunohistochemistry [IHC]), rates of confirmed germline mutations, frequency of BRAF testing, and clinical endpoints such as stage distribution, survival outcomes, and recurrence. Risk of bias was assessed using standardized tools appropriate to each study design. The synthesis focused on comparing outcomes among individuals with MLH1, MSH2, MSH6, and PMS2 mutations, as well as delineating the proportion of patients with sporadic MSI under 60 years of age. Across the five studies, MSI positivity in CRC patients under 60 years ranged from 7.5% to 13%. The frequency of confirmed germline MMR mutations varied between 0.8% and 5.2% in specific cohorts, aligning with LS prevalence estimates of 1–5%. Different mutation patterns correlated with some variation in clinical presentation. Cases with MSH2 and MLH1 mutations more frequently exhibited synchronous or metachronous tumors, while MSH6 and PMS2 mutations displayed more heterogeneous IHC patterns. Where survival data were provided, LS patients under 60 years had better overall survival compared to MMR-proficient individuals, though some studies also noted a potential lack of benefit from standard 5-fluorouracil adjuvant therapy in MMR-deficient tumors. Screening by MSI or by IHC—supplemented with BRAF mutation testing to exclude sporadic MSI—facilitates early detection of LS in CRC patients under 60 and highlights notable differences between mutation types. Although overall outcomes for LS patients can be favorable, especially for stage II disease, the precise impact of each specific mutated gene on clinical course remains heterogeneous. Future large-scale prospective studies are needed to clarify optimal screening protocols and individualized treatment strategies for LS patients under 60. Full article

Colorectal cancer (CRC) ranks third in terms of cancer incidence worldwide and is responsible for 8% of all deaths globally. Approximately 10% of CRC cases are caused by inherited pathogenic mutations in driver genes involved in pathways that are crucial for CRC tumorigenesis and progression. These hereditary mutations significantly increase the risk of initial benign polyps or adenomas developing into cancer. In recent years, the rapid and accurate sequencing of CRC-specific multigene panels by next-generation sequencing (NGS) technologies has enabled the identification of several recurrent pathogenic variants with established functional consequences. In parallel, rare genetic variants that are not characterized and are, therefore, called variants of uncertain significance (VUSs) have also been detected. The classification of VUSs is a challenging task because each amino acid has specific biochemical properties and uniquely contributes to the structural stability and functional activity of proteins. In this scenario, the ability to computationally predict the effect of a VUS is crucial. In particular, in silico prediction methods can provide useful insights to assess the potential impact of a VUS and support additional clinical evaluation. This approach can further benefit from recent advances in artificial intelligence-based technologies. In this review, we describe the main in silico prediction tools that can be used to evaluate the structural and functional impact of VUSs and provide examples of their application in the analysis of gene variants involved in hereditary CRC syndromes. Full article

Cascade genetic testing and surveillance reduce morbidity and mortality in Lynch syndrome. However, barriers to conveying information about genetic disorders within families result in low uptake of genetic testing. Provider-mediated interventions may increase uptake but raise legal and ethical concerns. We describe 30 years of national experience with cascade genetic testing combining family- and provider-mediated contact in Lynch syndrome families in the Danish Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Register. We aimed to estimate the added value of information letters to family members in Lynch syndrome families (provider-mediated contact) compared to family members not receiving such letters and thus relying on family-mediated contact. National clinical practice for cascade genetic testing, encompassing infrastructure, legislation, acceptance, and management of the information letters, is also discussed. Cascade genetic testing resulted in 7.3 additional tests per family. Uptake of genetic testing was 54.4% after family-mediated and 64.9% after provider-mediated contact, corresponding to an odds ratio of 1.8 (p < 0.001). The uptake of genetic testing was highest in the first year after diagnosis of Lynch syndrome in the family, with 72.5% tested after provider-mediated contact. In conclusion, the Danish model combining family- and provider-mediated contact can increase the effect of cascade genetic testing. Full article

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), accounts for 2–3% of all colorectal cancers. This autosomal dominant disorder is associated with a predisposition to endometrial, stomach, small bowel, pancreatic, biliary tract, ovary, urinary tract, brain, and skin tumors. Lynch syndrome is caused by the mutation of the MLH1, MSH2 (EPCAM), MSH6, and PMS2 genes. In this article, a case study of a 70-year-old female patient with Lynch syndrome is presented. Over a span of 30 years, the patient underwent multiple surgical procedures for a total of thirteen different malignancies. She was found to have a deleterious pathogenic gene MSH2 (NM_000251.2) variant (mutation) c.1774_1775insT in the 12th exon. This variant, c.1774_1775insT, represents a novel finding, as it has not been previously reported in existing databases or literature. No other case of 13 metachronous tumors in a patient with Lynch syndrome was found in the literature. Full article

Lynch syndrome (LS), also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is an autosomal dominant cancer syndrome which causes about 2–3% of cases of colorectal carcinoma. The development of LS is due to the genetic and epigenetic inactivation of genes involved in the DNA mismatch repair (MMR) system, causing an epiphenomenon known as microsatellite instability (MSI). Despite the fact that the genetics of the vast majority of MSI-positive (MSI⁺) cancers can be explained, the etiology of this specific subset is still poorly understood. As a possible new mechanism, it has been recently demonstrated that the overexpression of certain microRNAs (miRNAs, miRs), such as miR-155, miR-21, miR-137, can induce MSI or modulate the expression of the genes involved in LS pathogenesis. MiRNAs are small RNA molecules that regulate gene expression at the post-transcriptional level by playing a critical role in the modulation of key oncogenic pathways. Increasing evidence of the link between MSI and miRNAs in LS prompted a deeper investigation into the miRNome involved in these diseases. In this regard, in this study, we discuss the emerging role of miRNAs as crucial players in the onset and progression of LS as well as their potential use as disease biomarkers and therapeutic targets in the current view of precision medicine. Full article

Lynch syndrome, formerly known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), characterized by a defective DNA mismatch repair, is the most common autosomal dominant hereditary predisposition to several malignancies. LS patients typically exhibit an elevated risk of developing multiple primary malignancies with early onset. The most commonly involved organs are those with an accelerated cellular turnover. The colon and endometrium are the most commonly affected sites, however, the spectrum of neoplastic involvement extends beyond these organs and can involve the entire digestive tract, ovarium, urothelium, skin, and breast with varying incidences depending on the specific pathogenic variants affecting the MMR genes (MLH1, MSH2, MSH6, PMS2 and EPCAM). A conservative estimate suggests that the prevalence of mutations associated with Lynch syndrome in the general populations is 1 in 279 individuals. Over the last 25 years, significant advancements have been achieved comprehending the biology of cancers related to Lynch syndrome, alongside developing strategies for cancer prevention, risk mitigation, and targeted therapies. In Western countries, advancement in medical research and practice have led to the establishment of national programs that offer comprehensive approaches to diagnosis, screening, and targeted treatment options for Lynch syndrome patients.Romania lacks an oncogenetic program, which means that this disease, despite its personal and familial impact, remains opportunistically diagnosed. It is the most prevalent hereditary autosomal disease with oncological manifestations and yet no screening programs or targeted treatment protocols are available for Romanian patients with Lynch Syndrome.The Romanian healthcare system needs to align with the oncogenetics models of the Western world, which provide tailored screening and treatment programs for patients and their families. This article underlines the international position regarding prophylactic measures, diagnostic and treatment programs for Lynch syndrome and aims to motivate Romanian healthcare professionals to take action. Full article

Background: The association between Lynch syndrome (LS) and a higher risk of upper tract urothelial carcinoma is well established, but its effect on the risk of bladder and kidney cancers remains controversial. This review aimed to compare the relative risk (RR) of bladder and kidney cancer in confirmed LS germline mutation carriers compared to the general population. Methods: Medline, Embase, Cochrane Central, and Google Scholar were searched on 14 July 2022 for studies published in English that reported on the rates of urological cancer in adults with confirmed LS germline mutation. The quality of included studies was assessed using Cochrane’s tool to evaluate risk of bias in cohort studies. Random effects meta-analysis estimated the pooled relative risk of bladder and kidney cancer in LS carriers compared to the general population. The quality of the overall evidence was evaluated using GRADE. Results: Of the 1839 records identified, 5 studies involving 7120 participants from 3 continents were included. Overall, LS carriers had a statistically significantly higher RR of developing bladder cancer (RR: 7.48, 95% CI: 3.70, 15.13) and kidney cancer (RR: 3.97, 95% CI: 1.23, 12.81) compared to unaffected participants (p < 0.01). The quality of the evidence was assessed as “low” due to the inclusion of cohort studies, the substantial heterogeneity, and moderate-to-high risk of bias. Conclusion: Lynch syndrome is associated with a significant increase in the relative risk of kidney and bladder cancer. Clinicians should adopt a lower threshold for germline mutation genetic testing in individuals who present with bladder cancer. Further studies evaluating the role and cost-effectiveness of novel urine-based laboratory tests are needed. High-quality studies in histologically proven renal cell carcinoma and their underlying germline mutations are necessary to strengthen the association with LS. Full article

Hereditary non-polyposis colorectal cancer is also known as Lynch syndrome. Lynch syndrome is associated with pathogenetic variants in one of the mismatch repair (MMR) genes. In addition to colorectal cancer, the inefficiency of the MMR system leads to a greater predisposition to cancer of the endometrium and other cancers of the abdominal sphere. Molecular diagnosis is performed to identify pathogenetic variants in MMR genes. However, for many patients with clinically suspected Lynch syndrome, it is not possible to identify a pathogenic variant in MMR genes. Molecular diagnosis is essential for referring patients to specific surveillance to prevent the development of tumors related to Lynch syndrome. This review summarizes the main aspects of Lynch syndrome and recent advances in the field and, in particular, emphasizes the factors that can lead to the loss of expression of MMR genes. Full article

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Hereditary CRC syndromes account for approximately 5–10% of all CRC, with a lifetime risk of CRC that approaches 50–80% in the absence of endoscopic or surgical treatment. Hereditary CRC syndromes can be phenotypically divided into polyposis and non-polyposis syndrome, mainly according to the conditions of polyps. The typical representatives are familial adenomatous polyposis (FAP) and Lynch syndromes (LS), respectively. Over the past few decades, molecular genetics enhanced the discovery of cancer-predisposing genes and revolutionized the field of clinical oncology. Hereditary CRC syndromes have been a key part of this effort, with data showing that pathogenic variants are present in up to 10% of cases. Molecular phenotypes of tumors can not only help identify individuals with genetic susceptibility to CRC but also guide the precision prevention and treatment for the development of CRC. This review emphasizes the molecular basis and prevention strategies for hereditary CRC syndromes. Full article

A number of mutations in the RPS20 gene encoding the ribosomal protein uS10 have been found to be associated with a predisposition to hereditary non-polyposis colorectal carcinoma (CRC). We transfected HEK293T cells with constructs carrying the uS10 minigene with mutations identical to those mentioned above and examined the effects of the produced proteins on the cellular transcriptome. We showed that uS10 with mutations p.V50SfsX23 or p.L61EfsX11 cannot be incorporated into 40S ribosomal subunits, while the protein with the missense mutation p.V54L functionally replaces the respective endogenous protein in the 40S subunit assembly and the translation process. The comparison of RNA-seq data obtained from cells producing aberrant forms of uS10 with data for those producing the wild-type protein revealed overlapping sets of upregulated and downregulated differently expressed genes (DEGs) related to several pathways. Among the limited number of upregulated DEGs, there were genes directly associated with the progression of CRC, e.g., PPM1D and PIGN. Our findings indicate that the accumulation of the mutant forms of uS10 triggers a cascade of cellular events, similar to that which is triggered when the cell responds to a large number of erroneous proteins, suggesting that this may increase the risk of cancer. Full article

Even though colorectal cancer (CRC) is one of the most preventable cancers, it is currently one of the deadliest. Worryingly, incidence in people <50 years has increased unexpectedly, and for unknown causes, despite the successful implementation of screening programs in the population aged >50 years. Thus, there is a need to improve early diagnosis detection strategies by identifying more precise biomarkers. In this scenario, the analysis of exosomes is given considerable attention. Previously, we demonstrated the exosome lipidome was able to classify CRC cell lines according to their malignancy. Herein, we investigated the use of the lipidome of plasma extracellular vesicles as a potential source of non-invasive biomarkers for CRC. A plasma exosome-enriched fraction was analyzed from patients undergoing colonoscopic procedure. Patients were divided into a healthy group and four pathological groups (patients with hyperplastic polyps; adenomatous polyps; invasive neoplasia (CRC patients); or hereditary non-polyposis CRC. The results showed a shift from 34:1- to 38:4-containing species in the pathological groups. We demonstrate that the ratio Σ34:1-containing species/Σ38:4-containing species has the potential to discriminate between healthy and pathological patients. Altogether, the results reinforce the utility of plasma exosome lipid fingerprint to provide new non-invasive biomarkers in a clinical context. Full article

Lynch syndrome (LS) increases cancer risk. There is considerable individual variation in LS cancer occurrence, which may be moderated by lifestyle factors, such as body weight and physical activity (PA). The potential associations of lifestyle and cancer risk in LS are understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, PA, and cancer risk among Finnish LS carriers. The participants (n = 465, 54% women) self-reported their adulthood body weight and PA at 10-year intervals. Overall cancer risk and colorectal cancer (CRC) risk was analyzed separately for men and women with respect to longitudinal and near-term changes in body weight and PA using extended Cox regression models. The longitudinal weight change was associated with an increased risk of all cancers (HR 1.02, 95% CI 1.00–1.04) and CRC (HR 1.03, 1.01–1.05) in men. The near-term weight change was associated with a lower CRC risk in women (HR 0.96, 0.92–0.99). Furthermore, 77.6% of the participants retained their PA category over time. Men in the high-activity group had a reduced longitudinal cancer risk of 63% (HR 0.37, 0.15–0.98) compared to men in the low-activity group. PA in adulthood was not associated with cancer risk among women. These results emphasize the role of weight maintenance and high-intensity PA throughout the lifespan in cancer prevention, particularly in men with LS. Full article

Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1, MSH2, MSH6, and PMS2, and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years. Full article

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a disorder caused by an autosomal dominant heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes. Individuals with LS are at an increased risk of developing colorectal and extracolonic cancers, such as endometrial, small bowel, or ovarian. In this review, the mutations involved with LS and their diagnostic methods are described and compared, as are their current uses in clinical decision making. Nowadays, LS diagnosis is based on a review of family medical history, and when necessary, microsatellite instability (MSI) or/and immunohistochemistry (IHC) analyses should be performed. In the case of a lack of MMR protein expression (dMMR) or MSI-H (MSI-High) detection in tumor tissue, molecular genetic testing can be undertaken. More and more genetic testing for LS is based mainly on next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA), which provide better and quicker information about the molecular profile of patients as well as individuals at risk. Testing based on these two methods should be the standard and commonly used. The identification of individuals with mutations provides opportunities for the detection of cancer at an early stage as well as the introduction of proper, more effective treatment, which will result in increased patient survival and reduced costs of medical care. Full article

Of all the neoplastic sites, colorectal cancer (CRC) is one of the most common cancers in the family. Studies estimate that approximately 30% of all the CRC cases are a hereditary form of the disease with a potentially high impact on the quality of life (QoL), with a high risk of recurrence, and with bio–psycho–social functioning. The aim of the study was to assess the QoL of colorectal cancer patients with genetic risk by using the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire version QLQ-CR29. Materials and methods: The cross-sectional, single-center study was performed on a group of 32 patients with genetic risk of colorectal cancer, who underwent preoperative chemoradiation and surgery. Results: The series of values for the scores on the symptom scale varied between 15 and 30, and the average level of symptom scores did not differ significantly between gender (22.0 vs. 22.75; p = 0.636), highlighting a moderate impairment of QoL. Scores for the emotional functioning scale were significantly lower in men (10.33 vs. 13.25; p = 0.049), as were the scores for the physical functions (15.67 vs. 19.15; p = 0.039), showing a decrease in QoL. Conclusions: The overall score showed an average QoL in patients with colorectal cancer with genetic risk, highlighting significant differences in psycho-emotional functioning between women and men. Full article