Hereditary colorectal cancer (CRC) syndromes account for up to 5% of CRC. Patients have an increased risk of CRC and extracolonic cancers, both of which develop at an early age. The main polyposis syndromes include familial adenomatous polyposis, MYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and PTEN hamartoma syndrome. The non-polyposis syndromes include Lynch syndrome and familial colorectal cancer type X. Each of the syndromes have distinct but sometimes overlapping phenotypes. Clinical evaluation and ultimately the underlying germline genetic pathogenic variants define the syndromes. Each syndrome has polyp, CRC, and extracolonic risks and management is based on early and timely surveillance with therapeutic and often extended prophylactic surgery. Surgical intervention strategies are individualized, considering not only the earlier onset of malignancies and heightened risks for metachronous cancers but also the patient's needs and quality of life. This article reviews the different diagnostic approaches to hereditary CRC and highlights subsequent disease-specific management and surgical decision-making strategies.

Immune checkpoint inhibitors (ICIs) have significantly advanced cancer therapy, yet their efficacy in tumors with low tumor mutational burden (TMB) remains suboptimal. In this study, we aimed to elucidate the impact of somatic mutations on overall survival (OS) in TMB-low patients treated with ICIs and to explore the potential for personalized treatment selection through machine learning.

We conducted a comprehensive analysis of 1172 TMB-low (TMB < 10 mutations per megabase) patients with cancer receiving ICIs, examining the association between specific gene mutations and OS. Additionally, we developed a decision tree model (DTM) to predict OS based on clinical features and tumor mutational profiles.

Our findings reveal that mutations in DAXX, HLA-A, H3C2, IGF1R, CTNNB1, SMARCA4, KMT2D, and TP53 are significantly associated with poorer survival outcomes in the multivariate analysis. Remarkably, for renal cell carcinoma (RCC) patients, VHL mutations predicted improved OS following ICI even when adjusted for age, sex, and microsatellite instability (MSI) status in both multivariate analysis and the DTM model.

These results reinforce the prevailing notion that TMB alone does not predict ICI response, highlighting the critical role of individual gene mutations in TMB-low tumors under ICI therapy. Furthermore, our study demonstrates the promise of machine learning models in optimizing ICI treatment decisions, paving the way for more precise and effective therapeutic strategies in this patient population.

This study was aimed at characterizing whether the autosomal short tandem repeats (STRs) used in forensic identification might differ between leukemic blood samples and saliva samples.

Blood and saliva samples were collected from 27 patients diagnosed with acute leukemia in Riyadh City, KSA. DNA was extracted, and 15 STR loci were amplified.

Approximately 59.3% of patients with leukemia exhibited mutations at the STR loci. Loss of heterozygosity (LOH) occurred in 40.7% of the patients at D19S433, D16S539, vWA, D13S317, TH01, FGA, and D2S1338. Microsatellite instability (MSI) was detected in 22.2% of patients at TPOX, vWA, D19S433, D16S539, and D18S51. D19S433 and D16S539 were the most affected loci, exhibiting an alteration percentage of 18.52%, followed by vWA (11.11%); in contrast, D2S1338, D18S51, and TPOX were the least affected loci, showing a mutation percentage of 3.7%. D13S317, TH01, and FGA showed moderate genetic mutation (7.41%). CSF1PO, D21S11, D3S1358, D5S818, D7S820, D8S1179, and amelogenin did not show genetic changes in all samples. The overall genetic variability between saliva and blood samples significantly differed (P < 0.001).

Our results demonstrate the potential application of forensically used STR loci in diagnosis and monitoring of patients with leukemia. Further study applying next generation sequencing technology is necessary to validate these findings and explore the clinical applications of forensically used STRs as diagnostic tools for leukemia.

Gastric cancer (GC) is a malignant tumor with one of the lowest five-year survival rates. Traditional first-line treatment regimens, such as platinum drugs, have limited therapeutic efficacy in treating advanced GC and significant side effects, greatly reducing patient quality of life. In contrast, trastuzumab and other immune checkpoint inhibitors, such as nivolumab and pembrolizumab, have demonstrated consistent and reliable efficacy in treating GC. Here, we discuss the intrinsic characteristics of GC from a molecular perspective and provide a comprehensive review of classification and treatment advances in the disease. Finally, we suggest several strategies based on the intrinsic molecular characteristics of GC to aid in overcoming clinical challenges in the development of precision medicine and improve patient prognosis.

In the United States, Black individuals have higher rates of cancer mortality than any other racial group. Here, we examine chromosome copy number changes in cancers from more than 1800 self-reported Black patients. We find that tumors from self-reported Black patients are significantly more likely to exhibit whole-genome duplications (WGDs), a genomic event that enhances metastasis and aggressive disease, compared to tumors from self-reported white patients. This increase in WGD frequency is observed across multiple cancer types, including breast, endometrial, and lung cancer, and is associated with shorter patient survival. We further demonstrate that combustion byproducts are capable of inducing WGDs in cell culture, and cancers from self-reported Black patients exhibit mutational signatures consistent with exposure to these carcinogens. In total, these findings identify a type of genomic alteration that is associated with environmental exposures and that may influence racial disparities in cancer outcomes.

Microsatellite instability (MSI) is an indispensable biomarker in cancer immunotherapy. Currently, MSI scoring methods by high-throughput omics methods have gained popularity and demonstrated better performance than the gold standard method for MSI detection. However, the MSI detection method on expression data, especially single-cell expression data, is still lacking, limiting the scope of clinical application and prohibiting the investigation of MSI at a single-cell level. Herein, we developed MSIsensor-RNA, an accurate, robust, adaptable, and standalone software to detect MSI status based on expression values of MSI-associated genes. We demonstrated the favorable performance and promise of MSIsensor-RNA in both bulk and single-cell gene expression data in multiplatform technologies including RNA sequencing (RNA-seq), microarray, and single-cell RNA-seq. MSIsensor-RNA is a versatile, efficient, and robust method for MSI status detection from both bulk and single-cell gene expression data in clinical studies and applications. MSIsensor-RNA is available at https://github.com/xjtu-omics/msisensor-rna.

 Endometrial carcinoma, the most prevalent gynecologic malignancy in developed countries, represents a significant public health issue worldwide. DNA mismatch repair (dMMR) deficiency is an important molecular mechanism in endometrial carcinoma development, clinical course, and prognosis.

 This study aimed to determine the incidence and histological subtypes of endometrial carcinoma among Bahraini women, evaluate the prevalence of MMR deficiency using immunohistochemistry in these patients and analyze the association between MMR deficiency and clinicopathological features, including potential links to Lynch syndrome.

 This single-center retrospective study included 115 endometrial carcinoma patients diagnosed between January 2020 to June 2023. Immunohistochemistry was used to assess the expression of the four main MMR proteins (MLH1, MSH2, MSH6, PMS2). Clinicopathological features and survival outcomes were compared between MMR-deficient and MMR-proficient tumors. Medical records of patients were retrieved from I-SEHA system. Statistical analysis was done using SPSS.

 The study included a wide age range of patients, with a mean age of 59.5 years. The majority were Bahraini nationals. Endometrioid carcinoma was the most common histologic subtype (73%), followed by serous carcinoma (8.7%). Most patients presented with early-stage disease (76.8% stage I), and 39.8% had low-grade tumors. Significant proportions of cases showed loss of expression of mismatch repair (MMR) proteins MLH1 (24.2%), PMS2 (25%), MSH6 (14.5%), and MSH2 (12.7%), without significant associations with age.  Conclusion: This study found endometrial cancer to be a significant health concern in Bahrain, with a relatively high prevalence and younger age of onset compared to global averages. The data shows a predominance of endometrioid subtype and higher-grade tumors. Notably, a substantial proportion exhibited MMR deficiency, an important biomarker. These findings suggest the need for enhanced screening, early detection, and tailored treatment approaches in Bahrain. Further research and robust national cancer registries are warranted to fully understand the underlying risk factors and guide evidence-based interventions to mitigate the burden of this disease.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and been extensively used for patients with metastastic colorectal cancer (mCRC), especially those harboring deficient mismatch repair/ microsatellite instability (dMMR/MSI). However, the majority of mCRC are classified as proficient mismatch repair/microsatellite stability(pMMR/MSS) type characterized by a cold immune microenvironment, rendering them generally unresponsive to ICIs. How to improve the efficacy of ICIs for these patients is an important issue to be solved. On the one hand, it is urgent to discover the predictive biomarkers and clinical characteristics associated with effectiveness and expand the subset of pMMR/MSS mCRC patients who benefit from ICIs. Additionally, combined strategies are being explored to modulate the immune microenvironment of pMMR/MSS CRC and facilitate the conversion of cold tumors into hot tumors. In this review, we have focused on the recent advancements in the predictive biomarkers and combination therapeutic strategies with ICIs for pMMR/MSS mCRC.

Prognostic assessment for colorectal cancer (CRC) displays substantial heterogeneity, as reliance solely on traditional TNM staging falls short of achieving precise individualized predictions. The integration of diverse biological information sources holds the potential to enhance prognostic accuracy.

To establish a comprehensive multi-tiered precision prognostic evaluation system for CRC by amalgamating gene expression profiles, clinical characteristics, and tumor microsatellite instability (MSI) status in CRC patients.

We integrated genomic data, clinical information, and survival follow-up data from 483 CRC patients obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. MSI-related gene modules were identified using differential expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA). Three prognostic models were constructed: MSI-Related Gene Prognostic Model (Model I), Clinical Prognostic Model (Model II), and Integrated Multi-Layered Prognostic Model (Model III) by combining clinical features. Model performance was assessed and compared using Receiver Operating Characteristic (ROC) curves, Kaplan-Meier analysis, and other methods.

Six MSI-related genes were selected for constructing Model I (AUC = 0.724); Model II used two clinical features (AUC = 0.684). Compared to individual models, the integrated Model III exhibited superior performance (AUC = 0.825) and demonstrated good stability in an independent dataset (AUC = 0.767).

This study successfully developed and validated a comprehensive multi-tiered precision prognostic assessment model for CRC, providing an effective tool for personalized medical management of CRC.

Microsatellite instability (MSI) is a genetic marker that is useful in the detection and treatment of Lynch syndrome (Sd). Although conventional techniques such as immunohistochemistry (IHC) and polymerase chain reaction (PCR) are the standards for MSI detection, the advent of next-generation sequencing (NGS) has offered new possibilities, especially with circulating DNA.

We present the case of a 26-year-old patient with Lynch Sd and a BRAF-mutated metastatic colon cancer. The discordant MSI results between the conventional methods and NGS posed challenges in making treatment decisions. Subsequent NGS analysis revealed a high MSI status, leading to participation in an immunotherapy trial, with remarkable clinical response.

This case emphasizes the importance of comprehensive molecular profiling and strong interdisciplinary collaborations, especially in cases with ambiguous MSI results.

Deficient mismatch repair (dMMR) results in microsatellite instability (MSI), a pronounced mutator phenotype. High-frequency MSI (MSI-H)/dMMR is gaining increasing interest as a biomarker for advanced cancer patients to determine their eligibility for immune checkpoint inhibitors (ICIs). Various methods based on next-generation sequencing (NGS) have been developed to assess the MSI status. Comprehensive genomic profiling (CGP) testing can precisely ascertain the MSI status as well as genomic alterations in a single NGS test. The MSI status can be also ascertained through the liquid biopsy-based CGP assays. MSI-H has thus been identified in various classes of tumors, resulting in a greater adoption of immunotherapy, which is hypothesized to be effective against malignancies that possess a substantial number of mutations and/or neoantigens. NGS-based studies have also characterized MSI-driven carcinogenesis, including significant rates of fusion kinases in colorectal cancers (CRCs) with MSI-H that are targets for therapeutic kinase inhibitors, particularly in MLH1-methylated CRCs with wild-type KRAS/BRAF. NTRK fusion is linked to the colorectal serrated neoplasia pathway. Recent advances in investigations of MSI-H malignancies have resulted in the development of novel diagnostic or therapeutic techniques, such as a synthetic lethal therapy that targets the Werner gene. DNA sensing in cancer cells is required for antitumor immunity induced by dMMR, opening up novel avenues and biomarkers for immunotherapy. Therefore, clinical relevance exists for analyses of MSI and MSI-H-associated genomic alterations in malignancy. In this article, we provide an update on MSI-driven carcinogenesis, with an emphasis on unique landscapes of diagnostic and immunotherapeutic strategies.

Immune checkpoint inhibitors (ICIs) revolutionized the management of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) gastrointestinal (GI) cancers. Based on notable results observed in the metastatic setting, several clinical trials investigated ICIs as neoadjuvant treatment (NAT) for localized dMMR/MSI-H GI cancers, achieving striking results in terms of clinical and pathological responses and creating the opportunity to spare patients from neoadjuvant chemotherapy and/or radiotherapy and even surgical resection. Nevertheless, these impressive findings are mainly derived from small proof of concept phase II studies and there are still several open questions to address. Moreover, dMMR/MSI-H represents a limited subgroup accounting for less than 10% of GI cancers. Consequently, many efforts have been produced to investigate neoadjuvant ICIs also in mismatch repair-proficient/microsatellite stable (MSS) cancers, considering the potential synergistic effect in combining immune-targeted agents with standard therapies such as chemo and/or radiotherapy. However, results for combining ICIs to the standard of care in the unselected population are still unsatisfactory, without improvements in event-free survival in esophago-gastric adenocarcinoma for the addition of pembrolizumab to chemotherapy, and sometimes limited benefit in patients with locally advanced rectal cancer. Therefore, a major challenge will be to identify among the heterogenous spectrum of this disease, those patients that could take advantage of neoadjuvant immunotherapy and deliver the most effective treatment. In this review we discuss the rationale of NAT in GI malignancies, summarize the available evidence regarding the completed trials that evaluated this treatment strategy in both MSI-H and MSS tumors. Finally, we discuss ongoing studies and future perspectives to render neoadjuvant immunotherapy another arrow in the quiver for the treatment of locally advanced GI tumors.

Monkeypox (MPOX), a zoonotic disease originating in Western and Central Africa in 1970, has seen a recent surge in outbreaks across 100+ countries. A comparative analysis of 404 Monkeypox virus (MPXV) genomes revealed notable changes in microsatellite abundance and density, especially within Clades I, IIa, and IIb. Each clade exhibited unique microsatellite motifs, with twenty-six conserved loci specific to MPXV, suggesting their potential as molecular markers in diagnostics. Additionally, nine genes in the MPXV genome featured ten variable hotspot microsatellite regions associated with surface protein synthesis and host control. Notably, gene OPG153, especially at the SSR locus '(ATC)n', exhibited the most pronounced variations among lineages over time and plays a role in virus pathogenesis within the host cell. These findings not only enhance our understanding of MPXV unique molecular profile but also offer valuable insights into potential pathogenic and evolutionary implications.

Despite significant advancements in prevention and treatment, colorectal cancer (CRC) remains the third leading cause of cancer-related deaths. Animal models, including xenografts, syngeneic, and genetically engineered, have emerged as indispensable tools in cancer research. These models offer a valuable platform to address critical questions regarding molecular pathogenesis and test therapeutic interventions before moving on to clinical trials. Advancements in CRC animal models have also facilitated the advent of personalized and precision medicine. Patient-derived xenografts and genetically engineered mice that mirror features of human tumors allow for tailoring treatments to specific CRC subtypes, improving treatment outcomes and quality of life. To overcome the limitations of individual model systems, recent studies have employed a multi-modal approach, combining different animal models, 3D organoids, and in vitro studies. This integrative approach provides a comprehensive understanding of CRC biology, including the tumor microenvironment and therapeutic responses, driving the development of more effective and personalized therapeutic interventions. This review discusses the animal models used for CRC research, including recent advancements and limitations of these animal models.

CCDC58, a member of the CCDC protein family, has been primarily associated with the malignant progression of hepatocellular carcinoma (HCC) and breast cancer, with limited research conducted on its involvement in other tumor types. We aimed to assess the significance of CCDC58 in pan-cancer. We utilized the TCGA, GTEx, and UALCAN databases to perform the differential expression of CCDC58 at both mRNA and protein levels. Prognostic value was evaluated through univariate Cox regression and Kaplan-Meier methods. Mutation and methylation analyses were conducted using the cBioPortal and SMART databases. We identified genes interacting with and correlated to CCDC58 through STRING and GEPIA2, respectively. Subsequently, we performed GO and KEGG enrichment analyses. To gain insights into the functional status of CCDC58 at the single-cell level, we utilized CancerSEA. We explored the correlation between CCDC58 and immune infiltration as well as immunotherapy using the ESTIMATE package, TIMER2.0, TISIDB, TIDE, TIMSO, and TCIA. We examined the relationship between CCDC58 and tumor heterogeneity, stemness, DNA methyltransferases, and MMR genes. Lastly, we constructed a nomogram based on CCDC58 in HCC and investigated its association with drug sensitivity. CCDC58 expression was significantly upregulated and correlated with poor prognosis across various tumor types. The mutation frequency of CCDC58 was found to be increased in 25 tumors. We observed a negative correlation between CCDC58 expression and the methylation sites in the majority of tumors. CCDC58 showed negative correlations with immune and stromal scores, as well as with NK T cells, Tregs, CAFs, endothelial cells, and immunomodulators. Its value in immunotherapy was comparable to that of tumor mutational burden. CCDC58 exhibited positive correlations with tumor heterogeneity, stemness, DNA methyltransferase genes, and MMR genes. In HCC, CCDC58 was identified as an independent risk factor and demonstrated potential associations with multiple drugs. CCDC58 demonstrates significant clinical value as a prognostic marker and indicator of immune response across various tumor types. Its comprehensive analysis provides insights into its potential implications in pan-cancer research.

The application of immune checkpoint inhibitor (ICI) using monoclonal antibodies has brought about a profound transformation in the clinical outcomes for patients grappling with advanced gastric cancer (GC). Nonetheless, despite these achievements, the quest for effective functional biomarkers for ICI therapy remains constrained. Recent research endeavours have shed light on the critical involvement of modified epigenetic regulators in the pathogenesis of gastric tumorigenesis, thus providing a glimpse into potential biomarkers. Among these regulatory factors, AT-rich interaction domain 1A (ARID1A), a pivotal constituent of the switch/sucrose non-fermentable (SWI/SNF) complex, has emerged as a promising candidate. Investigations have unveiled the pivotal role of ARID1A in bridging the gap between genome instability and the reconfiguration of the tumour immune microenvironment, culminating in an enhanced response to ICI within the landscape of gastric cancer treatment. This all-encompassing review aims to dissect the potential of ARID1A as a valuable biomarker for immunotherapeutic approaches in gastric cancer, drawing from insights garnered from both preclinical experimentation and clinical observations.

Epigenetic alterations, including aberrant DNA methylation, are now recognized as bone fide hallmarks of cancer, which can contribute to cancer initiation, progression, therapy responses and therapy resistance. Methylation of gene promoters can have a range of impacts on cancer risk, clinical stratification and therapeutic outcomes. We provide several important examples of genes, which can be silenced or activated by promoter methylation and highlight their clinical implications. These include the mismatch DNA repair genes MLH1 and MSH2, homologous recombination DNA repair genes BRCA1 and RAD51C, the TERT oncogene and genes within the P15/P16/RB1/E2F tumour suppressor axis. We also discuss how these methylation changes might occur in the first place - whether in the context of the CpG island methylator phenotype or constitutional DNA methylation. The choice of assay used to measure methylation can have a significant impact on interpretation of methylation states, and some examples where this can influence clinical decision-making are presented. Aberrant DNA methylation patterns in circulating tumour DNA (ctDNA) are also showing great promise in the context of non-invasive cancer detection and monitoring using liquid biopsies; however, caution must be taken in interpreting these results in cases where constitutional methylation may be present. Thus, this review aims to provide researchers and clinicians with a comprehensive summary of this broad, but important subject, illustrating the potentials and pitfalls of assessing aberrant DNA methylation in cancer.

Lynch syndrome (LS) is a hereditary cancer predisposition syndrome with a significantly increased risk of colorectal and endometrial cancers. Current standard practice involves universal screening for LS in patients with newly diagnosed colorectal or endometrial cancer using a multi-step screening protocol (MSP). However, MSP may not always accurately identify LS cases. To address this limitation, we compared the diagnostic performance of immediate germline sequencing (IGS) with MSP in a high-risk group.

A total of 31 Taiwanese women with synchronous or metachronous endometrial and colorectal malignancies underwent MSP which included immunohistochemical staining of DNA mismatch repair (MMR) proteins, MLH1 promoter hypermethylation analysis, and germline sequencing to identify pathogenic variants. All patients who were excluded during MSP received germline sequencing for MMR genes to simulate IGS for the detection of LS.

Our findings indicate that IGS surpassed MSP in terms of diagnostic yield (29.0% vs. 19.4%, respectively) and sensitivity (90% vs. 60%, respectively). Specifically, IGS successfully identified nine LS cases, which is 50% more than the number detected through MSP. Additionally, germline methylation analysis revealed one more LS case with constitutional MLH1 promoter hypermethylation, bringing the total LS cases to ten (32.3%). Intriguingly, we observed no significant differences in clinical characteristics or overall survival between patients with and without LS in our cohort.

Our study suggests that IGS may potentially offer a more effective approach compared to MSP in identifying LS among high-risk patients. This advantage is evident when patients have been pre-selected utilizing specific clinical criteria.

Colorectal cancer (CRC) is one of the most frequent types of cancer, with high incidence rates and mortality globally. The extended timeframe for developing CRC allows for the potential screening and early identification of the disease. Furthermore, studies have shown that survival rates for patients with cancer are increased when diagnoses are made at earlier stages. Recent research suggests that the development of CRC, including its precancerous lesion, is influenced not only by genetic factors but also by epigenetic variables. Studies suggest epigenetics plays a significant role in cancer development, particularly CRC. While this approach is still in its early stages and faces challenges due to the variability of CRC, it shows promise as a potential method for understanding and addressing the disease. This review examined the current evidence supporting genetic and epigenetic biomarkers for screening and diagnosis. In addition, we also discussed the feasibility of translating these methodologies into clinical settings. Several markers show promising potential, including the methylation of vimentin (VIM), syndecan-2 (SDC2), and septin 9 (SEPT9). However, their application as screening and diagnostic tools, particularly for early-stage CRC, has not been fully optimized, and their effectiveness needs validation in large, multi-center patient populations. Extensive trials and further investigation are required to translate genetic and epigenetic biomarkers into practical clinical use. biomarkers, diagnostic biomarkers.

Several studies have shown that microsatellite changes can be profiled in urine for the detection of bladder cancer. The use of microsatellite analysis (MSA) for bladder cancer detection requires a comprehensive analysis of as many as 15 to 20 markers, based on the amplification and interpretations of many individual MSA markers, and it can be technically challenging. Here, to develop fast, more efficient, standardized, and less costly MSA for the detection of bladder cancer, we developed three multiplex-polymerase-chain-reaction-(PCR)-based MSA assays, all of which were analyzed via a genetic analyzer. First, we selected 16 MSA markers based on 9 selected publications. Based on samples from Johns Hopkins University (the JHU sample, the first set sample), we developed an MSA based on triplet, three-tube-based multiplex PCR (a Triplet MSA assay). The discovery, validation, and translation of biomarkers for the early detection of cancer are the primary focuses of the Early Detection Research Network (EDRN), an initiative of the National Cancer Institute (NCI). A prospective study sponsored by the EDRN was undertaken to determine the efficacy of a novel set of MSA markers for the early detection of bladder cancer. This work and data analysis were performed through a collaboration between academics and industry partners. In the current study, we undertook a re-analysis of the primary data from the Compass study to enhance the predictive power of the dataset in bladder cancer diagnosis. Using a four-stage pipeline of modern machine learning techniques, including outlier removal with a nonlinear model, correcting for majority/minority class imbalance, feature engineering, and the use of a model-derived variable importance measure to select predictors, we were able to increase the utility of the original dataset to predict the occurrence of bladder cancer. The results of this analysis showed an increase in accuracy (85%), sensitivity (82%), and specificity (83%) compared to the original analysis. The re-analysis of the EDRN study results using machine learning statistical analysis proved to achieve an appropriate level of accuracy, sensitivity, and specificity to support the use of the MSA for bladder cancer detection and monitoring. This assay can be a significant addition to the tools urologists use to both detect primary bladder cancers and monitor recurrent bladder cancer.

Bladder cancer (here we refer to transitional carcinoma of bladder) is a major cause of morbidity and mortality in the Western world, and recent understanding of its etiology, the molecular characteristics associated with its progression, renders bladder cancer an ideal candidate for screening. Cystoscopy is invasive and sometimes carries unwanted complications, but it is the gold standard for the detection of bladder cancer. Urine cytology, while the most commonly used test as an initial screening tool, is of limited value due to its low sensitivity, particularly for low-grade tumors. Several new "molecular assays" for the diagnosis of urothelial cancer have been developed over the last two decades. Here, we have established our new bladder cancer test based on an assay established for the Early Detection Research Network (EDRN) study. As a part of the study, a quality control CLIA/College of American Pathology (CAP) accredited laboratory, (QA Lab), University of Maryland Baltimore Biomarker Reference Laboratory (UMB-BRL), performed quality assurance analysis. Quality assurance measures included a concordance study between the testing laboratory (AIBioTech), also CLIA/CAP accredited, and the QA lab to ensure that the assay was performed and the results were analyzed in a consistent manner. Therefore, following the technical transfer and training of the microsatellite analysis assay to the UMB-BRL and prior to the initiation of analysis of the clinical samples by the testing lab, a series of qualification studies were performed. This report details the steps taken to ensure qualification of the assay and illustrates the technical challenges facing biomarker validation of this kind.

Neoadjuvant chemotherapy (NAC) significantly improved the prognosis of patients with locally advanced gastric cancer (LAGC). Several biomarkers, including HER2 and MMR/MSI are crucial for treatment decisions in the advanced stage but, currently, no biomarkers can guide the choice of NAC in clinical practice. Our aim was to evaluate the role of MSI and HER2 status on clinical outcomes.

We retrospectively collected LAGC patients treated with NAC and surgery +/- adjuvant chemotherapy from 2006 to 2018. HER2 and MSI were assessed on endoscopic and surgical samples. Pathologic complete response (pCR) rate, overall survival (OS), and event-free survival (EFS) were estimated and evaluated for association with downstaging and MSI.

We included 76 patients, 8% were classified as MSI-H, entirely consistent between endoscopic and surgical samples. Six percent of patients were HER2 positive on endoscopic and 4% on surgical samples. Tumor downstaging was observed in 52.5% of cases, with three pCR (5.1%), none in MSI-H cancers. According to MSI status, event-free survival (EFS) and overall survival (OS) were higher for MSI-H patients to MSS [EFS not reached vs 30.0 months, p = 0.08; OS not reached vs 39.6 months, p = 0.10].

Our work confirms the positive prognostic effect of MSI-H in the curative setting of LAGC, not correlated with pathologic tumor downstaging. Prospective ad-hoc trial and tumor molecular profiling are eagerly needed.

Colorectal cancer (CRC) signifies a significant healthcare challenge in Southeast Asia. Despite advancements in screening approaches and treatment modalities, significant medical gaps remain, ranging from prevention and early diagnosis to determining targeted therapy and establishing personalized approaches to managing CRC. There is a need to expand more validated biomarkers in clinical practice. An advanced technique incorporating high-throughput mass spectrometry as a liquid biopsy to unravel a repertoire of glycoproteins and glycans would potentially drive the development of clinical tools for CRC screening, diagnosis and monitoring, and it can be further adapted to the existing standard-of-care procedure. Therefore this review offers a perspective on glycoproteomics-driven liquid biopsy and its potential integration into the clinical care of CRC in the southeast Asia region.

Gastrointestinal cancers account for 11.6 % of all cancers, and are the second most frequently diagnosed type of cancer worldwide. Traditional Chinese medicine (TCM), together with Western medicine or alone, has unique advantages for the prevention and treatment of cancers, including gastrointestinal cancers. Syndrome differentiation and treatment are basic characteristics of the theoretical system of TCM. TCM syndromes are the result of the differentiation of the syndrome and the basis of treatment. Genomics, transcriptomics, proteomics, metabolomics, intestinal microbiota, and serology, generated around the central law, are used to study the biological basis of TCM syndromes in gastrointestinal cancers. This review summarizes current research on the biological basis of TCM syndrome in gastrointestinal cancers and provides useful references for future research on TCM syndrome in gastrointestinal cancers.

Lynch Syndrome (LS) is an autosomal dominant inheritance disorder characterized by genetic predisposition to develop cancer, caused by pathogenic variants in the genes of the mismatch repair system. Cases are detected by implementing the Amsterdam II and the revised Bethesda criteria, which are based on family history.

Patients who meet the criteria undergo posterior tests, such as germline DNA sequencing, to confirm the diagnosis. However, these criteria have poor sensitivity, as more than one-quarter of patients with LS do not meet the criteria. It is very likely that the lack of sensitivity of the criteria is due to the incomplete penetrance of this syndrome. The penetrance and risk of developing a particular type of cancer are highly dependent on the affected gene and probably of the variant. Patients with variants in low-penetrance genes have a lower risk of developing a cancer associated with LS, leading to families with unaffected generations and showing fewer clear patterns. This study focuses on describing genetic aspects of LS cases that underlie the lack of sensitivity of the clinical criteria used for its diagnosis.

Universal screening could be an option to address the problem of underdiagnosis.

Several studies have shown that microsatellite changes can be profiled in the urine to detect bladder cancer. Microsatellite analysis (MSA) of bladder cancer detection requires a comprehensive analysis of up to 15-20 markers based on amplifying and interpreting many individual MSA markers, which can be technically challenging. To develop fast, efficient, standardized, and less costly MSA to detect bladder cancer, we developed three multiplex polymerase chain reaction (PCR) based MSA assays, all of which were analyzed by a genetic analyzer. First, we selected 16 MSA markers based on nine publications. We developed MSA assays based on triplet or three-tube-based multiplex PCR (Triplet MSA assay) using samples from Johns Hopkins University (JHU Sample, first set of samples). In the second set of samples (samples from six cancer patients and fourteen healthy individuals), our Triplet Assay with 15 MSA markers correctly predicted all 6/6 cancer samples to be cancerous and 14/14 healthy samples to be healthy. Although we could improve our report with more clinical information from patient samples and an increased number of cancer patients, our overall results suggest that our Triplet MSA Assay combined with a genetic analyzer is a potentially time- and cost-effective genetic assay for bladder cancer detection and has potential use as a dependable assay in patient care.

To investigate the expression of EBV products and frequency of gallstone disease (GD) among different microsatellite status in colorectal cancer (CRC) with BRAFV600E mutation.

We collected 30 CRC patients with BRAFV600E mutation and 10 BRAF ( -) CRC patients as well as 54 healthy subjects. Tumor tissue samples were collected to detect the mutation of BRAF, KRAS, and TP53. Microsatellite status was determined by immunohistochemistry and PCR. EBER in situ hybridization was performed to detect EBV. In addition, we also collected clinical information about the patients.

We found that although EBV products were detected in CRC, there were no significant differences in the EBV distribution between the different BRAF groups. Our study demonstrated that BRAFV600E mutation and BRAFV600E with MSI were significantly more frequent in the right CRC. Furthermore, the KRAS mutation rate in the BRAF-wild-type group was proved to be significantly higher than that in the BRAF mutation group. In addition, we revealed that BRAF mutation and MSI were independent risk factors of TNM stage. The frequency of GD was higher in CRC patients than in general population, and although there was no significant difference between CRC with or without BRAFV600E mutation, the highest frequency of GD was found in MSS CRC with BRAFV600E mutation.

EBV plays a role in CRC, but is not a determinant of different microsatellite status in CRC with BRAFV600E mutation. The frequency of GD in MSS CRC with BRAFV600E mutation is significantly higher than that in the general population.

Microsatellite instability (MSI) occurs in several cancer types and is commonly used for prognosis and as a predictive biomarker for immune checkpoint therapy.

We analyzed n = 263 formalin-fixed paraffin-embedded (FFPE) tumor specimens (127 colorectal cancer (CRC), 55 endometrial cancer (EC), 33 stomach adenocarcinoma (STAD), and 48 solid tumor specimens of other tumor types) with a capillary electrophoresis based multiplex monomorphic marker MSI-PCR panel and an amplicon-based NGS assay for microsatellite instability (MSI+). In total, n = 103 (39.2%) cases with a known defect of the DNA mismatch repair system (dMMR), determined by a loss in protein expression of MSH2/MSH6 (n = 48, 46.6%) or MLH1/PMS2 (n = 55, 53.4%), were selected. Cases with an isolated loss of MSH6 or PMS2 were excluded.

The overall sensitivity and specificity of the NGS assay in comparison with the MSI-PCR were 92.2% and 98.8%. With CRC cases a nearly optimal concordance was reached (sensitivity 98.1% and specificity 100.0%). Whereas EC cases only show a sensitivity of 88.6% and a specificity of 95.2%, caused by several cases with instability in less than five monomorphic markers, which could be difficult to analyze by NGS (subtle MSI+ phenotype).

MSI analysis of FFPE DNA by NGS is feasible and the results show a high concordance in comparison with the monomorphic marker MSI-PCR. However, cases with a subtle MSI+ phenotype, most frequently manifest in EC, have a risk of a false-negative result by NGS and should be preferentially analyzed by capillary electrophoresis.

There is an urgent need for markers to predict the efficacy of different chemotherapy drugs. Herein, we examined whether microsatellite instability (MSI) status can predict tumor multidrug sensitivity and explored the underlying mechanisms. We downloaded data from several public databases. Drug sensitivity was compared between the high microsatellite instability (MSI-H) and microsatellite-stable/low microsatellite instability (MSS/MSI-L) groups. In addition, we performed pathway enrichment analysis and cellular chemosensitivity assays to explore the mechanisms by which MSI status may affect drug sensitivity and assessed the differences between drug-treated and control cell lines. We found that multiple MSI-H tumors were more sensitive to a variety of chemotherapy drugs than MSS/MSI-L tumors, and especially for CRC, chemosensitivity is enhanced through the downregulation of DDR pathways such as NHEJ. Additional DNA damage caused by chemotherapeutic drugs results in further downregulation of DDR pathways and enhances drug sensitivity, forming a cycle of increasing drug sensitivity.

Endometrial cancer is one of the most common cancers in developing and developed countries. Although the detection of this cancer is high at the early stages, there is still a lack of markers to monitor the disease, its recurrence, and metastasis. MiRNAs are in charge of the post-transcriptional regulation of genes responsible for the most important biological processes, which is why they are increasingly used as biomarkers in many types of cancer. Many studies have demonstrated the influence of miRNAs on the processes related to carcinogenesis. The characteristics of miRNA expression profiles in endometrial cancer will allow their use as diagnostic and prognostic biomarkers. This paper focuses on the discussion of selected miRNAs based on the literature and their role in the development of endometrial cancer.

Prostate cancer (PCa) has a distinct molecular signature, including characteristic chromosomal translocations, gene deletions and defective DNA damage repair mechanisms. One crucial pathway involved is homologous recombination deficiency (HRD) and it is found in almost 20% of metastatic castrate-resistant PCa (mCRPC). Inherited/germline mutations are associated with a hereditary predisposition to early PCa development and aggressive behavior. BRCA2, ATM and CHECK2 are the most frequently HRD-mutated genes. BRCA2-mutated tumors have unfavorable clinical and pathological characteristics, such as intraductal carcinoma. PARP inhibitors, due to the induction of synthetic lethality, have been therapeutically approved for mCRPC with HRD alterations. Mutations are detected in metastatic tissue, while a liquid biopsy is utilized during follow-up, recognizing acquired resistance mechanisms. The mismatch repair (MMR) pathway is another DNA repair mechanism implicated in carcinogenesis, although only 5% of metastatic PCa is affected. It is associated with aggressive disease. PD-1 inhibitors have been used in MMR-deficient tumors; thus, the MMR status should be tested in all metastatic PCa cases. A surrogate marker of defective DNA repair mechanisms is the tumor mutational burden. PDL-1 expression and intratumoral lymphocytes have ambivalent predictive value. Few experimental molecules have been so far proposed as potential biomarkers. Future research may further elucidate the role of DNA damage pathways in PCa, revealing new therapeutic targets and predictive biomarkers.

The N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) is the only writer responsible for DNA 6mA modifications. At present, its role in cancer is still unclear, and further systematic pan-cancer analysis is needed to explore its value in diagnosis, prognosis and immunological function.

The subcellular localization of N6AMT1 was explored by UniProt and HPA database. The expression data and prognosis data of N6AMT1 were downloaded from the UCSC (cohort: TCGA pan-cancer), and the diagnostic and prognostic value of N6AMT1 in pan-cancer was explored. The value of N6AMT1-guided immunotherapy was explored through three cohorts (GSE168204, GSE67501 and IMvigor210 cohort). The correlation between N6AMT1 expression and tumor immune microenvironment was explored using CIBERSORT and ESTIMATE calculation methods, combined with TISIDB database. The biological role of N6AMT1 in specific tumors was explored by GSEA method. Finally, we explored chemicals affecting N6AMT1 expression through the CTD.

N6AMT1 is mainly localized in the nucleus and differentially expressed in 9 cancer types. In addition, N6AMT1 showed early diagnostic value in 7 cancers and showed potential prognostic value in multiple cancer types. We also demonstrated that N6AMT1 expression was significantly associated with immunomodulator-related molecules, infiltration of lymphocyte subsets, and biomarkers of immunotherapy response. Furthermore, we show that N6AMT1 is differentially expressed in the immunotherapy cohort. Finally, we explored 43 chemicals that can affect N6AMT1 expression.

N6AMT1 has shown excellent diagnostic and prognostic capabilities in a variety of cancers, and it may reshape the tumor microenvironment and contribute to the ability to predict response to immunotherapy.

ADAR is an enzyme involved in adenosine-inosine RNA editing. However, the role of ADAR in tumorigenesis, progression, and immunotherapy has not been fully elucidated.

The TCGA, GTEx and GEO databases were extensively utilized to explore the expression level of ADAR across cancers. Combined with the clinical information of patients, the risk profile of ADAR in various cancers was delineated. We identified pathways enriched in ADAR and their related genes and explored the association between ADAR expression and the cancer immune microenvironment score and response to immunotherapy. Finally, we specifically explored the potential value of ADAR in the treatment of the bladder cancer immune response and verified the critical role of ADAR in the development and progression of bladder cancer through experiments.

ADAR is highly expressed in most cancers at both the RNA and protein level. ADAR is associated with the aggressiveness of some cancers, especially bladder cancer. In addition, ADAR is associated with immune-related genes, especially immune checkpoint genes, in the tumor immune microenvironment. Moreover, ADAR expression is positively correlated with tumor mutation burden and microsatellite instability in a variety of cancers, indicating that ADAR could be used as a biomarker of immunotherapy. Finally, we demonstrated that ADAR is a key pathogenic factor in bladder cancer. ADAR promoted proliferation and metastasis of bladder cancer cells.

ADAR regulates the tumor immune microenvironment and can be used as a biomarker of the tumor immunotherapy response, providing a novel strategy for the treatment of tumors, especially bladder cancer.

Gastric cancer has been categorized into molecular subtypes including Epstein-Barr virus (EBV)-positive tumors, which provide clinicopathological and prognostic information. In this study, we investigated the EBV infection status of patients with gastric cancer and its correlation with the clinicopathological characteristics and multiple genes related to gastric carcinogenesis. The data of 460 gastric cancer patients who underwent curative gastrectomy with D2 lymph node dissection between January 2017 and February 2022 were analyzed. The clinicopathological features and prognosis of the patients with EBV-positive gastric cancers were compared with those of EBV-negative gastric cancers. Immunohistochemistry for epidermal growth factor receptor (EGFR), C-erb B2, Ki-67, and p53 was performed. Additionally, in situ hybridization was conducted to detect EBV, and microsatellite instability (MSI) analysis was used to assess the deficiency in mismatch repair (MMR) genes. EBV-positivity and MSI were identified in 10.4% and 37.3% of gastric cancer patients, respectively. EBV positivity was associated with male gender (P = 0.001), proximal location (P = 0.004), poorly differentiated histological type (P = 0.048), moderate to severe lymphoid stroma (P = 0.006), high Ki-67 expression (P = 0.02), and a shorter resection margin. EGFR was more often expressed in EBV-negative gastric cancers (P < 0.001). MSI tumors were associated with older age (P = 0.01), the presence of lymphatic invasion (P = 0.02), less perineural invasion (P = 0.05), and the presence of H. pylori infection (P = 0.05). EBV positive gastric cancer is associated with increased Ki-67 and decreased EGFR expression and a shorter resection margin due to the prominent lymphoid stroma. However, MMR deficiency is not associated with EBV status even though MSI gastric cancer is related to H. pylori status.

The Four Jointed Box 1 (FJX1) gene has been implicated in the upregulation of various cancers, highlighting its crucial role in oncology and immunity. In order to better understand the biological function of FJX1 and identify new immunotherapy targets for cancer, we conducted a comprehensive analysis of this gene.

We analyzed the expression profiles and prognostic value of FJX1 using data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). Copy number alterations (CNAs), mutations, and DNA methylation were analyzed through cBioPortal. The Immune Cell Abundance Identifier (ImmuCellAI) was used to examine the correlation between FJX1 expression and immune cell infiltration. The relationship between FJX1 expression and immune-related genes and immunosuppressive pathway-related genes was analyzed using The Tumor Immune Estimation Resource version 2 (TIMER2). Tumor mutational burden (TMB) and microsatellite instability (MSI) were obtained from TCGA pan-cancer data. The effect of immunotherapy and the IC50 were assessed using IMvigor210CoreBiologies and Genomics For Drug Sensitivity in Cancer (GDSC). Finally, we evaluated the impact of FJX1 on colon cancer cell proliferation and migration through in vitro functional experiments.

Our study indicated that FJX1 expression was high in most cancers and was significantly associated with poor prognosis. High FJX1 expression was also linked to significant alterations in CNA, DNA methylation, TMB, and MSI. Positive correlations were found between FJX1 expression and tumor-associated macrophages (TAMs) and with immune-related genes such as TGFB1 and IL-10 and immunosuppressive pathway-related genes such as TGFB1 and WNT1. On the other hand, FJX1 expression showed a negative relationship with CD8+ T cells. Furthermore, high FJX1 expression led to reduced effectiveness of immunotherapy and drug resistance. In colon cancer cells, FJX1 knockdown was found to decrease cell proliferation and migration.

Our research findings demonstrate that FJX1 is a new prognostic factor with a significant role in tumor immunity. Our results highlight the importance of further exploring the potential of targeting FJX1 as a therapeutic strategy in cancer.

Metastasis-associated protein 2 (MTA2) is a member of the metastasis-associated transcriptional regulator family and is a core component of the nucleosome remodeling and histone deacetylation complex. Despite growing evidence that MTA2 plays a crucial role in the tumorigenesis of certain cancers, no systematic pan-cancer analysis of MTA2 is available to date. Therefore, the aim of our study is to explore the prognostic value of MTA2 in 33 cancer types and to investigate its potential immune function.

by comprehensive use of databases from TCGA, GTEx, GEO, UCSC xena, cBioPortal, comPPI, GeneMANIA, TCIA, MSigDB, and PDB, we applied various bioinformatics approaches to investigate the potential role of MTA2, including analyzing the association of MTA2 with MSI, prognosis, gene mutation, and immune cell infiltration in different tumors. We constructed a nomogram in TCGA-LIHC, performed single-cell sequencing (scRNA-seq) analysis of MTA2 in hepatocellular carcinoma (HCC), and screened drugs for the treatment of HCC. Finally, immunohistochemical experiments were performed to verify the expression and prognostic value of MTA2 in HCC. In vitro experiments were employed to observe the growth inhibition effects of MK-886 on the HCC cell line HepG2.

The results suggested that MTA2 was highly expressed in most cancers, and MTA2 expression was associated with the prognosis of different cancers. In addition, MTA2 expression was associated with Tumor Mutation Burden (TMB) in 12 cancer types and MSI in 8 cancer types. Immunoassays indicated that MTA2 positively correlated with activated memory CD4 T cells and M0 macrophage infiltration levels in HCC. ScRNA-seq analysis based on the GEO dataset discovered that MTA2 was significantly expressed in T cells in HCC. Finally, the eXtreme Sum (Xsum) algorithm was used to screen the antitumor drug MK-886, and the molecular docking technique was utilized to reveal the binding capacity between MK-886 and the MTA2 protein. The results demonstrated excellent binding sites between them, which bind to each other through Π-alkyl and alkyl interaction forces. An immunohistochemistry experiment showed that MTA2 protein was highly expressed in HCC, and high MTA2 expression was associated with poor survival in HCC patients. MK-886 significantly inhibited the proliferation and induced cell death of HepG2 cells in a dose-dependent manner.

Our study demonstrated that MTA2 plays crucial roles in tumor progression and tumor immunity, and it could be used as a prognostic marker for various malignancies. MK-886 might be a powerful drug for HCC.

In a post hoc analysis of the MAGIC trial, patients with curatively resected gastric cancer (GC) and mismatch repair (MMR) deficiency (MMRd) had better median overall survival (OS) when treated with surgery alone but worse median OS when treated with additional chemotherapy. Further data are required to corroborate these findings.

Between April 2013 and December 2018, 458 patients with curatively resected GC, including cancers of the esophagogastric junction Siewert type II and III, were identified in the German centers of the staR consortium. Tumor sections were assessed for expression of MLH1, MSH2, MSH6 and PMS2 by immunohistochemistry. The association between MMR status and survival was assessed. Similar studies published up to January 2021 were then identified in a MEDLINE search for a meta-analysis.

MMR-status and survival data were available for 223 patients (median age 66 years, 62.8% male), 23 patients were MMRd (10.3%). After matching for baseline clinical characteristics, median OS was not reached in any subgroup. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd and MMRp had a HR of 0.67 (95% CI 0.13-3.37, P = 0.63) and 1.44 (95% CI 0.66-3.13, P = 0.36), respectively. The meta-analysis included pooled data from 385 patients. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd had an improved OS with a HR of 0.36 (95% CI 0.14-0.91, P = 0.03), whereas those with MMRp had a HR of 1.18 (95% CI 0.89-1.58, P = 0.26).

Our data support a positive prognostic effect for MMRd in GC patients treated with surgery only and a differentially negative prognostic effect in patients treated with perioperative chemotherapy. MMR status determined by preoperative biopsies may be used as a predictive biomarker to select patients for perioperative chemotherapy in curatively resectable GC.

Patients with the heritable cancer disease, Lynch syndrome, carry germline variants in the MLH1, MSH2, MSH6 and PMS2 genes, encoding the central components of the DNA mismatch repair system. Loss-of-function variants disrupt the DNA mismatch repair system and give rise to a detrimental increase in the cellular mutational burden and cancer development. The treatment prospects for Lynch syndrome rely heavily on early diagnosis; however, accurate diagnosis is inextricably linked to correct clinical interpretation of individual variants. Protein variant classification traditionally relies on cumulative information from occurrence in patients, as well as experimental testing of the individual variants. The complexity of variant classification is due to (1) that variants of unknown significance are rare in the population and phenotypic information on the specific variants is missing, and (2) that individual variant testing is challenging, costly and slow. Here, we summarise recent developments in high-throughput technologies and computational prediction tools for the assessment of variants of unknown significance in Lynch syndrome. These approaches may vastly increase the number of interpretable variants and could also provide important mechanistic insights into the disease. These insights may in turn pave the road towards developing personalised treatment approaches for Lynch syndrome.

Most patients with sporadic colorectal cancer (SCRC) develop microsatellite instability because of defects in mismatch repair (MMR). Moreover, the gut microbiome plays a vital role in the pathogenesis of SCRC. In this study, we assessed the microbial composition and diversity of SCRC tumors with varying MutL protein homolog 1 (MLH1) status, and the effects of functional genes related to bacterial markers and clinical diagnostic prediction.

The tumor microbial diversity and composition were profiled using high-throughput sequencing of the 16S ribosomal RNA (rRNA) gene V4 region. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt2) software and BugBase tool were used to predict the functional roles of the microbiome. We aimed to construct a high-accuracy model to detect and evaluate the area under the receiver operating characteristic curve with candidate biomarkers.

The study included 23 patients with negative/defective MLH1 (DM group) and 22 patients with positive/intact MLH1 (IM group). Estimation of alpha diversity indices showed that the Shannon index (p = 0.049) was significantly higher in the DM group than in the controls, while the Simpson index (p = 0.025) was significantly lower. At the genus level, we observed a significant difference in beta diversity in the DM group versus the IM group. Moreover, the abundance of Lachnoclostridium spp. and Coprococcus spp. was significantly more enriched in the DM group than in the IM group (q < 0.01 vs. q < 0.001). When predicting metagenomes, there were 18 Kyoto Encyclopedia of Genes and Genomes pathways and one BugBase function difference in both groups (all q < 0.05). On the basis of the model of diagnostic prediction, we built a simplified optimal model through stepwise selection, consisting of the top two bacterial candidate markers (area under the curve = 0.93).

In conclusion, the genera Lachnoclostridium and Coprococcus as key species may be crucial biomarkers for non-invasive diagnostic prediction of DM in patients with SCRC in the future.

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.