Contemporary diagnostic and therapeutic strategies for many solid tumors rely on understanding the Mismatch Repair (MMR) system, a fundamental DNA repair mechanism responsible for correcting errors introduced during DNA replication. Pathology reports written for tumors excised in surgery, often indicate the expression status of MMR proteins. This is of significant clinical value, as loss of MMR protein expression is associated with the accumulation of DNA replication errors. The MMR system recognizes and replaces mismatched nucleotides, particularly in microsatellite regions. These are short, repetitive non-coding DNA sequences prone to replication errors. When MMR proteins are inactivated by genetic or epigenetic alterations, MMR deficiency (dMMR) occurs, preventing repair and leading to microsatellite instability (MSI). MSI is a hallmark of Lynch syndrome, which is commonly associated with colorectal cancer (CRC) and endometrial cancer. This work highlights the clinical utility of MMR protein and MSI status as molecular signatures and discusses diagnostic, prognostic, and therapeutic implications. Understanding these molecular changes supports clinicians in making informed therapeutic decisions and may improve patient outcomes by providing personalized treatments to fit individual tumor profiles.

Background and Objectives: Lynch syndrome (LS), an autosomal dominant condition arising from germline mutations in mismatch repair (MMR) genes, is a major cause of hereditary early-onset colorectal cancer (CRC). Although patients diagnosed before age 50 represent a critical subgroup where Lynch syndrome might be more prevalent, data on the precise frequency, clinical outcomes, and molecular correlates remain heterogeneous across studies. This systematic review was conducted to (1) estimate the prevalence of MMR deficiency (dMMR) and confirmed LS in patients diagnosed with CRC before the age of 50, and (2) examine immunohistochemistry (IHC) mismatch repair testing patterns and associated molecular findings (BRAF mutations, MLH1 promoter hypermethylation, somatic MMR gene alterations). Methods: Following a predefined search strategy in PubMed, Scopus, and Web of Science, five relevant studies were identified (n = 5). Each study comprised patients younger than 50 who underwent IHC-based tumor screening. Data extraction covered demographic details, number of patients tested, proportion with abnormal IHC, frequency of somatic or germline MMR gene mutations, and method of classification into sporadic dMMR vs. LS. Quality assessment was performed using recommended scales for observational studies. Results: Among 5 studies totaling 960 early-onset CRC patients, the frequency of dMMR CRC ranged from 8.4% to 19.1%. The confirmed prevalence of LS among all young-onset CRC was between 5.0% and 5.9% in three studies but reached 8.9% in another and 5.1% in yet another. Across all studies, the presence of right-sided tumors and histopathological features such as tumor-infiltrating lymphocytes were more common in dMMR cancers. Incorporation of MLH1-promoter hypermethylation and/or BRAF V600E mutation testing aided discrimination of sporadic dMMR CRC from germline LS cases. Conclusions: The prevalence of LS in CRC patients younger than 50 is clinically significant, at approximately 5-9%. Routine IHC-based MMR screening is both feasible and effective for detecting LS in early-onset CRC. Further research is needed to standardize universal testing protocols, delineate the role of additional molecular assays, and ensure comprehensive genetic counseling for at-risk individuals.

We herein report a patient with Lynch-like syndrome in whom a brain tumor (glioblastoma) developed after repeated resection of colorectal cancer. The patient had a significant family history of cancer. Immunohistochemical expression of mismatch repair proteins was decreased in both brain and colon tumors, but no pathogenic variant of the related genes was detected. Although brain tumors occasionally develop in Lynch syndrome, they have not been reported in cases of Lynch-like syndrome. This first report of Lynch-like syndrome with the development of glioblastoma suggests the need for further investigation on the surveillance of brain tumors in patients with this syndrome.

Hereditary cancer syndromes account for 6-10% of all colorectal cancer (CRC) cases and 20% of early-onset CRC. Identifying novel pathogenic germline variants can impact genetic testing, counseling, and surveillance. This study aimed to determine the prevalence of germline variants associated with hereditary CRC in the Iranian population.

Whole exome sequencing (WES) was conducted on DNA from 101 patients in the Iranian Hereditary Colorectal Cancer Registry (IHCCR). The cohort included 63 high-risk Lynch Syndrome (LS) patients and 38 colorectal polyposis patients. Germline variants and phenotype spectrum were assessed. Relatives of individuals with the mutations received counseling and cascade testing. Gene ontology and protein-protein interaction (PPI) analyses were conducted to elucidate gene roles on protein function.

Pathogenic/likely pathogenic (P/LP) variants were identified in Lynch-related genes in 36.51% of patients. P/LP variants in non-Lynch genes (ATM, FH (mono-allelic), MSH3, PMS1, and TP53) were identified in 26.98% of patients. Among polyposis patients, 50% had P/LP variants in the APC gene, and 15.79% had P/LP variants in the MUTYH gene. Additionally, 7.89% carried P/LP variants in non-FAP/MAP genes (BLM, BRCA2, and PTEN). MLH1 variants were most common in exons 10 and 18, MSH2 in exon 12, and APC gene in exon 16. Cascade testing identified 50% of the tested relatives (40/80). Topology analysis of the protein-protein interaction networks in high-risk LS cases highlighted stronger connections among nodes for genes such as TP53, ATM, POLD1, CDH1, MUTYH, WRN, NOTCH1, SMAD4, ERCC4, ERCC1, and MSH3. These genes were associated with high penetrance in CRC. The protein-protein interaction analyses of polyposis patients indicated that genes like POLE, MSH6, MSH2, BRCA2, BRCA1, MLH1, TOPBP1, BLM, RAD50, MUTYH, MSH3, MLH3, PTEN, BRIP1, and POLK had a higher degree value and were also associated with high penetrance. Gene ontology and protein-protein interaction (PPI) analysis showed that some of the top-scoring non-Lynch genes were TP53, ATM, POLD1, CDH1, MUTYH, WRN, NOTCH1, SMAD4, ERCC4, ERCC1, and MSH3.

The study identified crucial germline variants for hereditary polyposis and non-polyposis CRC pathogenesis in the Iranian population. A selective strategy and cascade genetic testing are recommended for the diagnosis of hereditary colorectal cancer syndromes.

Lynch syndrome (LS), a hereditary condition caused by germline mutations in mismatch repair (MMR) genes, significantly elevates the lifetime risk of endometrial cancer (EC) (40-60%) and ovarian cancer (8-10%) in affected women. Despite advances in colorectal cancer screening for LS patients, optimal strategies for gynecologic cancer prevention remain under debate. Current recommendations for EC surveillance, including annual transvaginal ultrasound and endometrial biopsy starting at age 30-35, lack robust evidence for effectiveness. Risk-reducing hysterectomy with bilateral salpingo-oophorectomy (BSO) is frequently advised after childbearing to mitigate cancer risk. Emerging data suggest that hormonal interventions, such as oral contraceptives and progestin-based therapies, may reduce EC risk by up to 50%, offering non-surgical preventive options. Lifestyle modifications, including weight management and physical activity, further complement risk reduction strategies. Molecular diagnostic advancements, including immunohistochemistry and microsatellite instability testing, enhance early identification of LS-associated gynecologic malignancies. For patients with advanced or recurrent EC, the integration of immunotherapy into treatment regimens has demonstrated significant efficacy. Agents such as pembrolizumab and dostarlimab, particularly in combination with carboplatin and paclitaxel, have improved progression-free and overall survival rates for patients with MMR-deficient tumors. This review highlights the need for personalized, evidence-based approaches to gynecologic cancer screening and prevention in LS, emphasizing the importance of integrating genetic testing, patient education, and novel therapeutic options. Future research should focus on refining screening protocols and expanding non-invasive preventive strategies to improve outcomes for this high-risk population.

Understanding the genetic heterogeneity of Lynch syndrome (LS) cancers has led to significant scientific advancements. However, these findings are widely dispersed across various resources, making it difficult for clinicians and researchers to stay informed. Furthermore, the uneven quality of studies and the lack of effective translation of knowledge into clinical practice create challenges in delivering optimal patient care. To address these issues, we developed and launched the Precision Lynch Syndrome Knowledge Base (PLSKB), a specialized, interactive web-based platform that consolidates comprehensive information on LS.

To create the PLSKB, we conducted an extensive literature review and gathered data from reliable sources. Through an extensive literature review and survey of other reliable sources, we have extracted prominent and relevant content with a high level of accuracy, transparency, and detailed provenance. To enhance usability, we implemented an evidence-leveling framework, categorizing studies on the basis of the type of research, reliability, and applicability to clinical care. The platform is designed to be dynamic, with updates performed monthly to incorporate the latest research.

The PLSKB integrates a broad spectrum of data related to LS, including biomarkers, cancer types, screening and prevention strategies, diagnostic methods, and therapeutics options. This centralized resource is intended to support clinicians and researchers in making evidence-based decisions throughout surveillance and care processes. Its interactive design and frequent updates ensure that users have access to the most current and relevant findings.

The PLSKB bridges the gap between research and clinical practice by offering a reliable, up-to-date repository of evidence-based information. This tool empowers clinicians and researchers to deliver precision care and advance research for LS and related conditions, ultimately improving patient outcomes.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide. The leading risk factors for CRC include male gender, age over 50, family history, obesity, tobacco smoking, alcohol consumption, and unhealthy diet. CRC screening methods vary considerably between countries and depend on incidence, economic resources and healthcare structure. Important aspects of screening include adherence, which can vary significantly across ethnic and socioeconomic groups. Basic concepts of CRC screening include pre-stratification of patients by identifying risk factors and then using fecal immunochemical test or guaiac-based fecal occult blood test and/or colonoscopy or radiologic imaging techniques. Technological capabilities for CRC screening are rapidly evolving and include stool DNA test, liquid biopsy, virtual colonography, and the use of artificial intelligence. A CRC prevention strategy should be comprehensive and include active patient education along with targeted implementation of screening.

This review addresses the current treatment paradigm and new advancements in the management of microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) esophagogastric cancer (EGC).

While chemotherapy and surgery remain the cornerstone of EGC treatment, MSI-H/dMMR tumors harbor high tumor mutational burden and represent a subset of patients who benefit from immune checkpoint inhibitors (ICI). ICI has been incorporated in the front line setting with and without chemotherapy for advanced disease. Recently, ICI has been studied in the perioperative setting for resectable disease. Though perioperative ICI results in improved response rates, it is not yet clear whether this translates to a survival benefit. Despite high response rates with ICI in this patient population, many do not respond to therapy, representing a major challenge in treatment. Preclinical studies have highlighted potential mechanisms of resistance which will guide drug development and clinical trials.

Lynch syndrome is a genetic condition predisposing to cancer, particularly colorectal cancer and endometrial cancer, due to germline mutations in MisMatch Repair genes. More rarely, Lynch syndrome is the result of a constitutional MLH1 promoter methylation. This review summarizes the current knowledge about the role of this epigenetic mechanism in the Lynch syndrome. Universal Tumor Screening, performed on tumoral specimens to identify features suggestive of Lynch syndrome, shows the same features both in the case of sporadic cancers and Lynch syndrome-cancers due to a constitutional MLH1 methylation: microsatellite instability, deficiency of MisMatch Repair proteins, and methylation of MLH1 gene. Over the last few years, identifying methylation of MLH1 promoter on tumors was used to discern sporadic tumors from Lynch syndrome tumors: the methylation of the MLH1 promoter was usually explained as a somatic event and this could lead to a missed diagnosis of some Lynch syndrome cases. Therefore, establishing criteria to decide when to test patients for constitutional MLH1 methylation is urgent. In the case of microsatellite instability/deficiency of MisMatch Repair tumors with MLH1 methylation, a germline genetic test could be requested for all colorectal cancer patients aged 55 years or younger and all endometrial cancer patients younger than 50 years old, independently from family history. The prevalence of germline MLH1 epimutations is not precisely known and possibly underestimated. The associated cancer risk could be similar to that due to a MLH1 sequence variant. MLH1 epimutations could be secondary to other genetic defects and follow an autosomal dominant inheritance. On the contrary, primary epimutations are often "de novo" events, and their transmission does not follow Mendelian rules.

In today's world, with its continuing advancements in genetics, the identification of Lynch syndrome (LS) increasingly relies on sophisticated genetic testing techniques. Most guidelines recommend a tailored surveillance program, as well as personalized prophylactic and therapeutic approaches, according to the type of dMMR gene mutation. Carriers of path_MLH1 and path_MSH2 genes have a higher risk of developing colorectal cancer (CRC), despite intensive colonoscopic surveillance. Conversely, carriers of path_MSH6 and path_PMS2 genes have a lower risk of developing CRC, which may be due to their lower penetrance and later age of onset. Thus, carriers of path_MLH1 or path_MSH2 would theoretically derive greater benefits from total colectomy, compared to low-risk carriers (path_MSH6 and path_PMS2), in which colonoscopic surveillance might achieve an efficient prophylaxis. Furthermore, regarding the risk of endometrial/ovarian cancer development, there is a global agreement to offer both hysterectomy and bilateral salpingo-oophorectomy to path_MLH1, path_MSH2 and path_MSH6 carriers after the age of 40. In patients with CRC, preoperative knowledge of the diagnosis of LS is of tremendous importance, due to the high risk of metachronous CRC. However, this risk depends on the type of dMMR gene mutation. For carriers of the high-risk variants (MLH1, MSH2 and EPCAM) who have already developed colon cancer, it is strongly recommended a subtotal or total colectomy is performed, while partial colectomy followed by endoscopic surveillance is an appropriate management approach to treat colon cancer in carriers of the low-risk variants (MSH6 and PMS2). On the other hand, extended surgery for index rectal cancer (such as total proctocolectomy) is less effective than extended surgery for index colon cancer from the point of view of metachronous CRC risk reduction, and is associated with a decreased quality of life.

Gliomas are a major cause of cancer-related death among children, adolescents, and young adults (age 0-40 years). Primary mismatch repair deficiency (MMRD) is a pan-cancer mechanism with unique biology and therapeutic opportunities. We aimed to determine the extent and impact of primary MMRD in gliomas among children, adolescents, and young adults.

Clinical and molecular data were collected from a population-based cohort of children, adolescents, and young adults with gliomas from Toronto (TOR-Ped, age 0-18 years, collected Jan 1, 2000, to Dec 31, 2021; and TOR-AYA, age 18-40 years, collected Jan 1, 2000, to June 30, 2019). Additional validation paediatric cohorts from St Jude Children's Research Hospital (0-18 years, 2015-21) and the Children's Brain Tumor Network (0-18 years, 1981-2021) were used. Functional genomic tools were applied with the primary aim of assessing primary MMRD prevalence among glioma subgroups and germline impact. To evaluate the effect of primary MMRD on therapy and overall survival, Kaplan-Meier estimates were used on an additional cohort of patients with primary MMRD gliomas treated with immunotherapy.

1389 gliomas were included in the study. The prevalence of primary MMRD ranged between 3·7% and 12·4% in high-grade gliomas (overall 30 of 483; 6·2%, 95% CI 4·2-8·7) and less than 1% in low-grade gliomas (four of 899; 0·4%, 0·1-1·1; p<0·0001 by χ2 test). Specific molecular analysis for all gliomas showed that primary MMRD was absent among oligodendrogliomas (none of 67) and uncommon in BRAFV600E gliomas (one of 110) and histone mutant-driven gliomas (one of 150). In the paediatric age group (<18 years), primary MMRD was common in IDHWT and H3WT gliomas harbouring pathogenic TP53 variants (21 of 61; 34·4%, 22·7-47·7) and in malignant IDHmut gliomas (five of eight; 62·5%, 24·5-91·5). Germline aetiology accounted for 33 (94·3%) of 35 primary MMRD gliomas, including children, adolescents, and young adults with previously unrecognised Lynch syndrome. Survival was poor for patients with primary MMRD gliomas. Particularly poor survival was observed for those with IDHmut astrocytomas with primary MMRD when compared with those with mismatch repair-proficient gliomas (HR 12·6, 95% CI 2·8-57·5; p=0·0011 by multivariable Cox regression). Immune checkpoint blockade was associated with improved survival for patients with primary MMRD gliomas compared with conventional chemoradiotherapy regimens (HR 0·4, 0·3-0·7; p=0·0017 by multivariable Cox regression), regardless of age or germline status.

Primary MMRD is more common than previously reported in gliomas in children, adolescents, and young adults, is enriched in specific molecular subgroups, and is associated with poor outcomes. Accurate detection, genetic testing, early diagnosis through surveillance, and implementation of immunotherapy might improve survival for these patients.

The Canadian Institutes for Health Research, Stand Up to Cancer-Bristol Myers Squibb Catalyst, US National Institutes of Health, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Canada's Immunotherapy Network, Harry and Agnieszka Hall, Meagan's Hug, BRAINchild Canada, and the LivWise Foundation.

Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition syndrome whereby the lifetime risk of developing gastrointestinal and genitourinary cancers rises by to over 50%. It is caused by heterozygous variants in the DNA mismatch repair genes- MLH1, MSH2, MSH6 and PMS2, with the majority detected in MLH1 and MSH2. Recurrently observed LS-associated variants in apparently unrelated individuals have either arisen de novo in different families due to mutation hotspots or are inherited from a common ancestor (founder) that lived several generations back. Testing for founder variants can facilitate molecular diagnosis of LS more efficiently and cost effectively than screening for all possible variants in the MMR genes. Here, we report a study of the missense variant c.306G > T in the MLH1 gene, the first potential founder variant identified in LS patients of Indian ethnicity. Haplotype analysis consisting of 25 LS carriers with the MLH1 c.306G > T variant and 100 healthy controls confirmed a shared haplotype in cases spanning a 27.8 kb region encompassing the c.306G > T variant (𝝌2 = 96.418; p = < 0.0001). Age of variant analysis suggests the variant to have arisen in the population approximately 800 years (95% CI: 670-934 years) ago. Furthermore, it is estimated that c.306G > T variant is likely to be observed in 6.4% of all LS patients of Indian ethnicity. These findings have important implications for genetic counselling and molecular diagnosis of Lynch syndrome.

Colorectal cancer (CRC), with a growing incidence trend, is one of the most diagnosed cancers and the second cause of cancer-related deaths worldwide. The literature has frequently focused attention on the correlation between the gut microbiota imbalance and CRC. The genera Lactobacillus and Bifidobacterium have recently received increasing attention because of their potential in restoring alterations in the gut microflora. Therefore, this study aimed to quantitatively evaluate the presence of lactobacilli and bifidobacterial strains in the fecal samples of CRC patients compared to healthy volunteers.

From 2018 to 2019, 25 confirmed CRC patients and 25 age- and gender-matched control subjects were enrolled in the study. Bacterial DNA was extracted from the fecal samples and the presence of lactobacilli and bifidobacterial strains were quantitatively determined using quantitative real-time PCR using genus-specific 16S rDNA primers.

A significant decline in the abundance of bifidobacteria in CRC patients compared to healthy individuals (p value<0.003) was observed; however, no significant difference was observed between the two groups regarding the abundance of lactobacilli (p value<0.163). Correlation analysis showed a positive association between the lack of genetic history of CRC and the numbers of gut bifidobacteria and lactobacilli.

As a putative gut probiotic, depletion of bifidobacteria showed significant correlation to the development and progression of CRC; therefore, therapeutic use of these probiotic bacteria could be considered a possible adjuvant approach in disease management through modulation of the microbiota.

Trivariate joint modeling for longitudinal count data, recurrent events, and a terminal event for family data has increased interest in medical studies. For example, families with Lynch syndrome (LS) are at high risk of developing colorectal cancer (CRC), where the number of polyps and the frequency of colonoscopy screening visits are highly associated with the risk of CRC among individuals and families. To assess how screening visits influence polyp detection, which in turn influences time to CRC, we propose a clustered trivariate joint model. The proposed model facilitates longitudinal count data that are zero-inflated and over-dispersed and invokes individual-specific and family-specific random effects to account for dependence among individuals and families. We formulate our proposed model as a latent Gaussian model to use the Bayesian estimation approach with the integrated nested Laplace approximation algorithm and evaluate its performance using simulation studies. Our trivariate joint model is applied to a series of 18 families from Newfoundland, with the occurrence of CRC taken as the terminal event, the colonoscopy screening visits as recurrent events, and the number of polyps detected at each visit as zero-inflated count data with overdispersion. We showed that our trivariate model fits better than alternative bivariate models and that the cluster effects should not be ignored when analyzing family data. Finally, the proposed model enables us to quantify heterogeneity across families and individuals in polyp detection and CRC risk, thus helping to identify individuals and families who would benefit from more intensive screening visits.

Lynch syndrome (LS) is an autosomal dominant disorder characterized by increased risks of colorectal and endometrial cancers. LS is defined by pathogenic variants in mismatch repair (MMR) genes, including MLH1, MSH2, and MSH6. Data on the prevalence and associated cancer risks of LS in the Han Chinese population remain limited. In this study, using a broad biobank approach through the Taiwan Precision Medicine Initiative (TPMI), we identified LS-associated MMR gene variants within a cohort of 42,828 participants from a Taiwanese medical center. A total of 89 individuals were found to carry pathogenic MMR variants: MLH1 (n = 22, 25%), MSH2 (n = 47, 53%), and MSH6 (n = 20, 22%). The overall prevalence of MMR variants was calculated, and cancer incidence rates among carriers were determined. The prevalence of MMR variants in the study population was 1 in 481. The distribution of MLH1, MSH2, and MSH6 variants were 24.7%, 52.8%, and 22.5%, respectively. Cumulative cancer incidence rates of carriers were 40.9% for MLH1 carriers, 29.8% for MSH2, and 40% for MSH6. Among the 19 individuals who underwent colonoscopy screening, the prevalence of polyps was similar to that of the control group (adenoma detection rate: 32% vs 26%, p = 0.585). A meticulous analysis of the detected polyps in seven participants, considering factors such as location, size, morphology, and pathological features, showed no significant differences from controls. A significant cancer risk is associated with LS-related MMR variants in the Taiwanese population. The apparent under diagnosis of LS highlights the urgent need for enhanced surveillance and genetic counseling in this demographic. Our findings suggest that adjustments in the current screening protocols may be warranted to better identify and manage at-risk individuals.

In Norway, we have offered testing of PMS2 since 2006, and have a large national cohort of carriers. The aim of this study was to describe all PMS2 variants identified, and to describe frequency, spectrum and penetrance of cancers in carriers of class 4/5 variants.

All detected PMS2 variants were collected from the diagnostic laboratories and reclassified according to ACMG criteria and gene specific guidelines. Data on variant, gender, cancer diagnosis, age at diagnosis, and age at last known follow-up was collected on all carriers of class 4/5 variants from electronic patient records. The Kaplan-Meier algorithm was used to calculate cumulative risk of any cancer, colorectal cancer and endometrial cancer.

In total, 220 different PMS2 variants were detected. Twenty nine class 4/5 variants were identified in 482 carriers. The most common pathogenic variant was the founder mutation c.989-1G > T, detected in 204 patients from 58 families. Eighty seven out of 482 (18.0%) had been diagnosed with colorectal cancer, 10 of these (11.8%) before 40 years. Cumulative risk at 70 years in our cohort was 34.7% for colorectal cancer and 26.1% for endometrial cancer.

After 15 years of genetic testing, 29 different class 4/5 variants have been detected in Norway. Almost half of Norwegian PMS2 carriers have the founder variant 989-1G > T. Penetrance of colorectal cancer in our cohort was moderate but variable, as 11.5% of those diagnosed were younger than 40 years.

This study evaluated the risk of metachronous colorectal cancer (CRC) after resection of index (first) rectal cancer in patients with Lynch syndrome (LS).

Clinicopathological data of patients with genetically proven LS were retrospectively analyzed in this multicenter Japanese study. The cumulative incidence of metachronous CRC and the overall survival were compared between patients with index rectal cancer (rectal group) and those with index colon cancer (colon group).

The median age at index CRC surgery was lower in the rectal group than in the colon group (37 vs. 46 years old, P = 0.01). The cumulative 5-, 10-, and 20-year incidences of metachronous CRC were 3.5%, 13.9%, and 21.1%, respectively, in the rectal cancer group and 14.9%, 22.0%, and 57.9%, respectively, in the colon cancer group (P = 0.02). The overall survival curves were not significantly different between two groups (P = 0.23).

This is the first report from an East Asian country to report the risk of metachronous CRC after resection of index rectal cancer in patients with LS. Despite this study having several limitations, we cannot recommend extended resection, such as total proctocolectomy, for index rectal cancer as a standard surgical treatment in patients with LS.

Lynch syndrome is an inherited condition which leads to an increased risk of colorectal, endometrial and ovarian cancer. Risk-reducing surgery is generally recommended to manage the risk of gynaecological cancer once childbearing is completed. The value of gynaecological colonoscopic surveillance as an interim measure or instead of risk-reducing surgery is uncertain. We aimed to determine whether gynaecological surveillance was effective and cost-effective in Lynch syndrome.

We conducted systematic reviews of the effectiveness and cost-effectiveness of gynaecological cancer surveillance in Lynch syndrome, as well as a systematic review of health utility values relating to cancer and gynaecological risk reduction. Study identification included bibliographic database searching and citation chasing (searches updated 3 August 2021). Screening and assessment of eligibility for inclusion were conducted by independent researchers. Outcomes were prespecified and were informed by clinical experts and patient involvement. Data extraction and quality appraisal were conducted and results were synthesised narratively. We also developed a whole-disease economic model for Lynch syndrome using discrete event simulation methodology, including natural history components for colorectal, endometrial and ovarian cancer, and we used this model to conduct a cost-utility analysis of gynaecological risk management strategies, including surveillance, risk-reducing surgery and doing nothing.

We found 30 studies in the review of clinical effectiveness, of which 20 were non-comparative (single-arm) studies. There were no high-quality studies providing precise outcome estimates at low risk of bias. There is some evidence that mortality rate is higher for surveillance than for risk-reducing surgery but mortality is also higher for no surveillance than for surveillance. Some asymptomatic cancers were detected through surveillance but some cancers were also missed. There was a wide range of pain experiences, including some individuals feeling no pain and some feeling severe pain. The use of pain relief (e.g. ibuprofen) was common, and some women underwent general anaesthetic for surveillance. Existing economic evaluations clearly found that risk-reducing surgery leads to the best lifetime health (measured using quality-adjusted life-years) and is cost-effective, while surveillance is not cost-effective in comparison. Our economic evaluation found that a strategy of surveillance alone or offering surveillance and risk-reducing surgery was cost-effective, except for path_PMS2 Lynch syndrome. Offering only risk-reducing surgery was less effective than offering surveillance with or without surgery.

Firm conclusions about clinical effectiveness could not be reached because of the lack of high-quality research. We did not assume that women would immediately take up risk-reducing surgery if offered, and it is possible that risk-reducing surgery would be more effective and cost-effective if it was taken up when offered.

There is insufficient evidence to recommend for or against gynaecological cancer surveillance in Lynch syndrome on clinical grounds, but modelling suggests that surveillance could be cost-effective. Further research is needed but it must be rigorously designed and well reported to be of benefit.

This study is registered as PROSPERO CRD42020171098.

This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR129713) and is published in full in Health Technology Assessment; Vol. 28, No. 41. See the NIHR Funding and Awards website for further award information.

The optimal interval of colonoscopy (CS) surveillance in cases with Lynch syndrome (LS), and stratification according to the causative mismatch repair gene mutation, has received much attention. To verify a feasible and effective CS surveillance strategy, we investigated the colorectal cancer (CRC) incidence at different intervals and the characteristics of precancerous colorectal lesions of LS cases.

This retrospective multicenter study was conducted in Japan. CRCs and advanced adenomas (AAs) in 316 LS cases with germline pathogenic variants (path_) were analyzed according to the data of 1,756 registered CS.

The mean time interval for advanced CRCs (ACs) detected via CS surveillance was 28.7 months (95% confidence interval: 13.8-43.5). The rate of AC detection within (2.1%) and beyond 2 years (8.7%) differed significantly (p = 0.0003). AAs accounted for 43%, 46%, and 41% of lesions < 10 mm in size in the MLH1-, MSH2-, and MSH6-groups, respectively. The lifetime incidence of metachronous CRCs requiring intestinal resection for path_MLH1, path_MSH2, and path_MSH6 cases was 34%, 23%, and 14% in these cases, respectively. The cumulative CRC incidence showed a trend towards a 10-year delay for path_MSH6 cases as compared with that for path_MLH1 and path_MSH2 cases.

In cases with path_MLH1, path_MSH2, and path_MSH6, maintaining an appropriate CS surveillance interval of within 2 years is advisable to detect of the colorectal lesion amenable to endoscopic treatment. path_MSH6 cases could be stratified with path_MLH1 and MSH2 cases in terms of risk of metachronous CRC and age of onset.

Lynch syndrome (LS) is under-diagnosed. UK National Institute for Health and Care Excellence guidelines recommend multistep molecular testing of all colorectal cancers (CRCs) to screen for LS. However, the complexity of the pathway has resulted in limited improvement in diagnosis.

One-step multiplex PCR was used to generate sequencing-ready amplicons from 14 microsatellite instability (MSI) markers and 22 BRAF, KRAS, and NRAS mutation hotspots. MSI and BRAF/RAS variants were detected using amplicon-sequencing and automated analysis. The assay was clinically validated and deployed into service in northern England, followed by regional and local audits to assess its impact.

MSI analysis achieved 99.1% sensitivity and 99.2% specificity and was reproducible (r = 0.995). Mutation hotspot analysis had 100% sensitivity, 99.9% specificity, and was reproducible (r = 0.998). Assay-use in service in 2022-2023 increased CRC testing (97.2% (2466/2536) versus 28.6% (601/2104)), halved turnaround times, and identified more CRC patients at-risk of LS (5.5% (139/2536) versus 2.9% (61/2104)) compared to 2019-2020 when a multi-test pathway was used.

A novel amplicon-sequencing assay of CRCs, including all biomarkers for LS screening and anti-EGFR therapy, achieved >95% testing rate. Adoption of this low cost, scalable, and fully automatable test will complement on-going, national initiatives to improve LS screening.

In this editorial, I commented on the paper by Lin et al, published in this issue of the World Journal of Gastrointestinal Oncology. The work aimed at analysing the clinicopathologic characteristics and prognosis of synchronous and metachronous cancers in patients with dual primary gastric and colorectal cancer (CRC). The authors concluded the necessity for regular surveillance for metachronous cancer during postoperative follow-up and reported the prognosis is influenced by the gastric cancer (GC) stage rather than the CRC stage. Although surveillance was recommended in the conclusion, the authors did not explore this area in their study and did not include tests used for such surveillance. This editorial focuses on the most characterized gastrointestinal cancer susceptibility syndromes concerning dual gastric and CRCs. These include hereditary diffuse GC, familial adenomatous polyposis, hereditary nonpolyposis colon cancer, Lynch syndrome, and three major hamartomatous polyposis syndromes associated with CRC and GC, namely Peutz-Jeghers syndrome, juvenile polyposis syndrome, and PTEN hamartoma syndrome. Careful assessment of these syndromes/conditions, including inheritance, risk of gastric and colorectal or other cancer development, genetic mutations and recommended genetic investigations, is crucial for optimum management of these patients.

Given the crucial predictive implications of microsatellite instability (MSI) in colorectal cancer (CRC), MSI screening is commonly performed in those with and at risk for CRC. Here, we compared results from immunohistochemistry (IHC) and the droplet digital PCR (ddPCR) MSI assay on formalin-fixed paraffin-embedded tumor samples from 48 patients who underwent surgery for colon and rectal cancer by calculating Cohen's kappa measurement (k), revealing high agreement between the methods (k = 0.915). We performed Kaplan-Meier survival analyses and univariate and multivariate Cox regression to assess the prognostic significance of ddPCR-based MSI and to identify clinicopathological features associated with CRC outcome. Patients with MSI-high had better overall survival (OS; p = 0.038) and disease-free survival (DFS; p = 0.049) than those with microsatellite stability (MSS). When stratified by primary tumor location, right-sided CRC patients with MSI-high showed improved DFS, relative to those with MSS (p < 0.001), but left-sided CRC patients did not. In multivariate analyses, MSI-high was associated with improved OS (hazard ratio (HR) = 0.221, 95% confidence interval (CI): 0.026-0.870, p = 0.042), whereas the loss of DNA mismatch repair protein MutL homolog 1 (MLH1) expression was associated with worse OS (HR = 0.133, 95% CI: 0.001-1.152, p = 0.049). Our results suggest ddPCR is a promising tool for MSI detection. Given the opposing effects of MSI-high and MLH1 loss on OS, both ddPCR and IHC may be complementary for the prognostic assessment of CRC.

Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are distinct cancer syndromes caused, respectively, by mono- and bi-allelic germline mismatch repair (MMR) variants. LS predisposes to mainly gastrointestinal and genitourinary cancers in adulthood. CMMRD predisposes to brain, haematological, and LS-spectrum cancers from childhood. Two suspected LS patients with first cancer diagnosis aged 27 or 38 years were found to be homozygous for an MMR (likely) pathogenic variant, MSH6 c.3226C>T (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G>A (p.(Glu102=)). MLH1 c.306G>A was shown to cause leaky exon 3 skipping. The apparent genotype-phenotype conflict was resolved by detection of constitutional microsatellite instability in both patients, a hallmark feature of CMMRD. A hypomorphic effect of these and other variants found in additional late onset CMMRD cases, identified by literature review, likely explains a LS-like phenotype. CMMRD testing in carriers of compound heterozygous or homozygous MMR VUS may find similar cases and novel hypomorphic variants. Individualised management of mono- and bi-allelic carriers of hypomorphic MMR variants is needed until we better characterise the associated phenotypes.

Panel germline testing allows for the efficient detection of deleterious variants for multiple conditions, but the benefits and harms of identifying these variants are not always well understood. We present a multi-gene, multi-disease aggregate utility formula that allows the user to consider adding or removing each gene in a panel based on variant frequency, estimated penetrances, and subjective disutilities for testing positive but not developing the disease and testing negative but developing the disease. We provide credible intervals for utility that reflect uncertainty in penetrance estimates. Rare, highly penetrant deleterious variants tend to contribute positive net utilities for a wide variety of user-specified disutilities, even when accounting for parameter estimation uncertainty. However, the clinical utility of deleterious variants with moderate, uncertain penetrance depends more on assumed disutilities. The decision to include a gene on a panel depends on variant frequency, penetrance, and subjective utilities and should account for uncertainties around these factors.

Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes.

We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms.

Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers.

Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.

This article is a summary of the French intergroup guidelines regarding the management of non-metastatic colon cancer (CC), revised in November 2022.

These guidelines represent collaborative work of all French medical and surgical societies involved in the management of CC. Recommendations were graded in three categories (A, B, and C) according to the level of evidence found in the literature published up to November 2022.

Initial evaluation of CC is based on clinical examination, colonoscopy, chest-abdomen-pelvis computed tomography (CT) scan, and carcinoembryonic antigen (CEA) assay. CC is usually managed by surgery and adjuvant treatment depending on the pathological findings. The use of adjuvant therapy remains a challenging question in stage II disease. For high-risk stage II CC, adjuvant chemotherapy must be discussed and fluoropyrimidine monotherapy or oxaliplatin-based chemotherapy proposed according to the type and number of poor prognostic features. Oxaliplatin-based chemotherapy (FOLFOX or CAPOX) is the current standard for adjuvant therapy of patients with stage III CC. However, these regimens are associated with significant oxaliplatin-induced neurotoxicity. The results of the recent IDEA study provide evidence that 3 months of treatment with CAPOX is as effective as 6 months of oxaliplatin-based therapy in patients with low-risk stage III CC (T1-3 and N1). A 6-month oxaliplatin-based therapy remains the standard of care for high-risk stage III CC (T4 and/or N2). For patients unfit for oxaliplatin, fluoropyrimidine monotherapy is recommended.

French guidelines for non-metastatic CC management help to offer the best personalized therapeutic strategy in daily clinical practice. Each individual case must be discussed within a multidisciplinary tumor board and then the treatment option decided with the patient.

Understanding service user preferences is key to effective health care decision making and efficient resource allocation. It is of particular importance in the management of high-risk patients in whom predictive genetic testing can alter health outcomes.

This review aims to identify the relative importance and willingness to pay for attributes of genetic testing in hereditary cancer syndromes.

Searches were conducted in Medline, Embase, PsycINFO, HMIC, Web of Science, and EconLit using discrete choice experiment (DCE) terms combined with terms related to hereditary cancer syndromes, malignancy synonyms, and genetic testing.

Following independent screening by 3 reviewers, 7 studies fulfilled the inclusion criteria, being a DCE investigating patient or public preferences related to predictive genetic testing for hereditary cancer syndromes.

Extracted data included study and respondent characteristics, DCE attributes and levels, methods of data analysis and interpretation, and key study findings.

Studies covered colorectal, breast, and ovarian cancer syndromes. Results were summarized in a narrative synthesis and the quality assessed using the Lancsar and Louviere framework.

This review focuses only on DCE design and testing for hereditary cancer syndromes rather than other complex diseases. Challenges also arose from heterogeneity in attributes and levels.

Test effectiveness and detection rates were consistently important to respondents and thus should be prioritized by policy makers. Accuracy, cost, and wait time, while also important, showed variation between studies, although overall reduction in cost may improve uptake. Patients and the public would be willing to pay for improved detection and clinician over insurance provider involvement. Future studies should seek to contextualize findings by considering the impact of sociodemographic characteristics, health system coverage, and insurance policies on preferences.

Test effectiveness and detection rates are consistently important to respondents in genetic testing for hereditary cancer syndromes.Reducing the cost of genetic testing for hereditary cancer syndromes may improve uptake.Individuals are most willing to pay for a test that improves detection rates, identifies multiple cancers, and for which results are shared with a doctor rather than with an insurance provider.

To review the literature with reference to counselling and management of women with genetic predisposition to gynaecological cancers.

Histochemical analysis, ultrasound, blood investigations, genetic testing, screening and risk-reducing surgery (RRS) are important tools for the management of gynaecological cancers and mortality reduction. Counselling can assist in timely management of gynaecological cancers. Systematic reviews, review articles, observational studies and clinical trials on PubMed, published in the English language, were included in this review.

The management of women with genetic predisposition to gynaecological cancers through screening tests and RRS has led to a significant decrease in the risk of malignancy through RRS in cases with BRCA1 and BRCA2 gene mutations. RRS and screening have also been found to reduce the mortality rate and increase the survival rate in women with BRCA1 and BRCA2 gene mutations. The efficacy of endometrial cancer surveillance in women with Lynch syndrome is still unproven. RRS has not been reported to be effective in women with Cowden syndrome. The risk of ovarian malignancies in individuals with germline mutations remains minimal in the general population in comparison with genetic mutations.

Genetic testing and RRS should be implemented in addition to genetic counselling for proper management and mortality reduction of women predisposed to gynaecological cancers.

Currently, no standard workflow exists for managing patients with pathogenic variants that put them at higher risk for hereditary cancers. Therefore, follow-up care for individuals with pathogenic variants is logistically challenging and results in poor guideline adherence. To address this challenge, authors created clinical management strategies for individuals identified at high risk for hereditary cancers.

An implementation mapping approach was used to develop and evaluate the establishment of a Hereditary Cancer Clinic at the Medical University of South Carolina throughout in 2022. This approach consisted of 5 steps: conduct a needs assessment, identify objectives, select implementation strategies, produce implementation protocols, and develop an evaluation plan. The needs assessment consisted of qualitative interviews with patients (n=11), specialists (n=9), and members of the implementation team (n=4). Interviews were coded using the Consolidated Framework for Implementation Research to identify barriers and facilitators to establishment of the Hereditary Cancer Clinic. Objectives were identified, and then the team selected implementation strategies and produced implementation protocols to address concerns identified during the needs assessment. Authors conducted a second round of patient interviews to assess patient education materials.

The research team developed a long-term evaluation plan to guide future assessment of implementation, service, and clinical/patient outcomes.

This approach provides the opportunity for real-time enhancements and impact, with strategies for care specialists, patients, and implementation teams. Findings support ongoing efforts to improve patient management and outcomes while providing an opportunity for long-term evaluation of implementation strategies and guidelines for patients at high risk for hereditary cancers.

Lynch syndrome is an inherited tumor syndrome caused by a pathogenic germline variant in DNA mismatch repair genes. As the leading cause of hereditary endometrial cancer, international guidelines recommend universal screening in women with endometrial cancer. However, testing for Lynch syndrome is not yet well established in clinical practice. The aim of this study was to evaluate adherence to our Lynch syndrome screening algorithm. A retrospective, single-center cohort study was conducted of all endometrial cancer patients undergoing surgical treatment at the Bern University Hospital, Switzerland, between 2017 and 2022. Adherence to immunohistochemical analysis of mismatch repair status, and, if indicated, to MLH1 promoter hypermethylation and to genetic counseling and testing was assessed. Of all 331 endometrial cancer patients, 102 (30.8%) were mismatch repair-deficient and 3 (0.9%) patients were diagnosed with Lynch syndrome. Overall screening adherence was 78.2%, with a notable improvement over the six years from 61.4% to 90.6%. A major reason for non-adherence was lack of provider recommendation for testing, with advanced patient age as a potential patient risk factor. Simplification of the algorithm through standardized reflex screening was recommended to provide optimal medical care for those affected and to allow for cascading testing of at-risk relatives.

The purpose of this article was to provide an overview of syndromic gliomas.

The authors conducted a nonsystematic literature review.

Cancer predisposition syndromes (CPSs) are genetic conditions that increase one's risk for certain types of cancer compared with the general population. Syndromes that can predispose one to developing gliomas include neurofibromatosis, Li-Fraumeni syndrome, Lynch syndrome, and tuberous sclerosis complex. The standard treatment for sporadic glioma may involve resection, radiation therapy, and/or alkylating chemotherapy. However, DNA-damaging approaches, such as radiation and alkylating agents, may increase the risk of secondary malignancies and other complications in patients with CPSs. In some cases, depending on genetic aberrations, targeted therapies or immunotherapeutic approaches may be considered. Data on clinical characteristics, therapeutic strategies, and prognosis of syndromic gliomas remain limited.

In this review, we provide an overview of syndromic gliomas with a focus on management for patients with CPSs and the role of novel treatments that can be considered.

With advancements in treatment and screening techniques, we have been witnessing an era where more cancer survivors harbor multiple primary cancers (MPCs), affecting approximately one in six patients. Identifying MPCs is crucial for tumor staging and subsequent treatment choices. However, the current clinicopathological criteria for clinical application are limited and insufficient, making it challenging to differentiate them from recurrences or metastases. The emergence of next-generation sequencing (NGS) technology has provided a genetic perspective for defining multiple primary cancers. Researchers have found that, when considering multiple tumor pairs, it is crucial not only to examine well-known essential mutations like MLH1/MSH2, EGFR, PTEN, BRCA1/2, CHEK2, and TP53 mutations but also to explore certain pleiotropic loci. Moreover, specific deleterious mutations may serve as regulatory factors in second cancer development following treatment. This review aims to discuss these susceptibility genes and provide an explanation of their functions based on the signaling pathway background. Additionally, the association network between genetic signatures and different tumor pairs will be summarized.