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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. [ABSTRACT FROM AUTHOR]

Background: In 2017, the Food and Drug Administration approved pembrolizumab for treatment of any mismatch repair–deficient (dMMR) tumor making MMR immunohistochemistry (IHC) testing beneficial for all tumor types. For the first time, MMR IHC was not performed exclusively to screen for Lynch syndrome (LS). Methods: In this study, all MMR IHC reports issued between 2017 and 2021 at an academic hospital were reviewed and completion of genetic testing was determined through chart review. Colorectal cancers (CRCs), endometrial cancers (ECs), and noncancerous lesions were excluded. Results: Between 2017 and 2021, MMR IHC was completed in 1939 patients with a malignancy other than CRC or EC. Absent or weak staining for at least one MMR protein was detected in 115 (5.9%) patients and 59 (51%) of those completed germline genetic testing. Overall, the identification rate of LS in this cohort was 0.72%, which is similar to the rate in our previously reported CRC and EC universal screening cohort. A diagnosis of LS was most commonly made in patients with dMMR brain (18.75%) and small intestinal cancers (10.20%). Five additional patients were found to carry a pathogenic variant in a non‐LS gene. Conclusions: Pan‐cancer MMR testing for pembrolizumab consideration can identify LS cases at a rate similar to universal CRC and EC screening programs. A persistent challenge is subsequent uptake of genetic testing. MMR testing should be prioritized in brain and small intestinal tumors, and multigene panel testing is recommended in patients with dMMR, as unexpected pathogenic variants in non‐LS genes were found as frequently as LS gene variants. The use of mismatch repair immunohistochemistry testing across tumor types has increased significantly in the age of immune checkpoint inhibitors. Pan‐cancer mismatch repair–deficient immunohistochemistry testing has identified Lynch syndrome cases at a rate similar to the colorectal and endometrial cohorts. [ABSTRACT FROM AUTHOR]

Background: Lynch syndrome (LS) is a hereditary cancer syndrome caused by pathogenic germline variants in mismatch repair (MMR) genes, which predisposes to various types of cancers showing deficient MMR (dMMR). Identification of LS probands is crucial to reduce cancer-related deaths in affected families. Although universal screening is recommended for colorectal and endometrial cancers, and age-restricted screening is proposed as an alternative, LS screening covering a broader spectrum of cancer types is needed. In the current study, we elucidated the rate of dMMR tumors and evaluated the outcome of LS screening in young-onset extra-colorectal LS-associated cancers. Methods: Immunohistochemistry for MMR proteins were retrospectively performed in a total of 309 tissue samples of endometrial, non-mucinous ovarian, gastric, urothelial, pancreatic, biliary tract, and adrenal cancers in patients < 50 years of age. Clinicopathological information and the results of genetic testing were obtained from medical charts. Results: There were 24 dMMR tumors (7.8%) including 18 endometrial, three ovarian, two urothelial, and one gastric cancer. Co-occurrence of colorectal cancer and family history of LS-associated cancers was significantly enriched in patients with dMMR tumors. Among the 16 patients with dMMR tumors who were informed of the immunohistochemistry results, five with endometrial and one with urothelial cancer were diagnosed as LS with positive pathogenic variants in MMR genes. Conclusions: We report the outcome of immunohistochemistry for MMR proteins performed in multiple types of young-onset extra-colorectal LS-associated cancers. Our study demonstrates the feasibility of a comprehensive LS screening program incorporating young-onset patients with various types of extra-colorectal LS-associated cancers. [ABSTRACT FROM AUTHOR]

Objective: To perform a collaborative review of the literature exploring the microsatellite instability/deficient mismatch repair (MSI/dMMR) phenotype in patients with upper tract urothelial carcinoma (UTUC). Method: A collaborative review of the literature available on Medline was conducted by the Cancer Committee of the French Association of Urology to report studies describing the genetic mechanisms, investigation, prevalence and impact of the MSI/dMMR phenotype in UTUC patients. Results: The predominant genetic mechanism leading to the MSI/dMMR phenotype in UTUC patients is related to the constitutional mutation of one allele of the MMR genes MLH1, MSH2, MSH6 and PMS2 within Lynch syndrome. Indications for its investigation currently remain limited to patients with a clinical suspicion for sporadic UTUC to refer only those with a positive testing for germline DNA sequencing to screen for this syndrome. With regard to technical aspects, despite the interest of MSIsensor, only PCR and immunohistochemistry are routinely used to somatically investigate the MSI and dMMR phenotypes, respectively. The prevalence of the MSI/dMMR phenotype in UTUC patients ranges from 1.7% to 57%, depending on the study population, investigation method and definition of a positive test. Younger age and a more balanced male to female ratio at initial diagnosis are the main specific clinical characteristics of UTUC patients with an MSI/dMMR phenotype. Despite the conflicting results available in the literature, these patients may have a better prognosis, potentially related to more favourable pathological features. Finally, they may also have lower sensitivity to chemotherapy but greater sensitivity to immunotherapy. Conclusion: Our collaborative review summarises the available data from published studies exploring the MSI/dMMR phenotype in UTUC patients, the majority of which are limited by a low level of evidence. [ABSTRACT FROM AUTHOR]

• MSI-H/MMRd subtype: less responsive to fertility-sparing treatment; higher recurrence risk. • Patients with MSI-H/MMRd have low spontaneous conception and require assisted reproductive technology. • Cautiously recommend fertility-sparing treatment for MSI-H/MMRd patients. • Emphasize the need for comprehensive counseling. This systematic review and meta-analysis aimed to describe the oncological and reproductive outcomes of patients with MSI-H/MMRd endometrial carcinoma (EC) or atypical endometrial hyperplasia (AEH) undergoing fertility-sparing treatment. The study protocol was registered with the PROSPERO database (No: CRD42024530406). A systematic literature search in major electronic databases (PubMed, Embase, and Cochrane Library) was conducted from January 1, 2013 to August 10, 2024. The primary outcomes were complete remission (CR) rate and recurrence rate. Other outcomes included oncological outcomes in patients with Lynch syndrome and overall patient fertility status. The study included ten retrospective studies summarizing 66 patients with MSI-H/MMRd undergoing fertility-sparing treatment. The publication bias analysis was low. The length of follow-up varied from 3 to 164 months according to the different studies analyzed. After fertility-sparing treatment, 61.8 % of patients achieved CR, and 41.2 % of patients relapsed. Twelve patients were identified with germline mutations in Lynch syndrome, nine (75 %) achieved CR, and seven (77.8 %) relapsed. Only one study with active use of assisted reproductive technology reported a 1-year cumulative pregnancy rate of more than 60 % and more than half live births, while the remaining five studies assessed fertility outcomes and reported only one live birth. EC and AEH patients with the MSI-H/MMRd subtype had a low remission rate and high recurrence rate compared to conservative treatment. Caution is recommended when evaluating fertility-sparing therapy for patients with the MSI-H/MMRd subtype. [ABSTRACT FROM AUTHOR]

The discovery of "mismatch repair deficient (MMRd)-crypt foci" in non-neoplastic intestinal mucosa in Lynch syndrome (LS) has significantly enhanced our understanding of how tumors and tumor immunity form and evolve in LS. In this study, we report the frequent presence of "mismatch repair proficient (MMRp)-crypt foci" in both non-neoplastic and neoplastic intestinal mucosa in a patient with constitutional MMR deficiency (CMMRD), who carried a germline MSH6 pathogenic variant (c.3261dupC) in trans with an MSH6 likely pathogenic variant (c.3724_3726del) and whose tissues were otherwise deficient in MMR globally. The MMRp-crypts occurred at a rate of 1.1/100 crypts in non-neoplastic intestinal mucosa and were readily discernible in adenomas > 1 cm. Sequencing analysis revealed normalization of the MSH6c.3261dupC variant in MMRp-adenoma crypts, indicating reverse frameshifting of the exon 5 C8 microsatellite. Interestingly but not surprisingly, the MMRp-adenoma crypts remained microsatellite-instability-high (MSI-H), and shared oncogenic APC mutations with the background MMRd-adenoma. Contrasting with MSH6-CMMRD, no PMS2-CMMRD individuals (0/5) harbored MMRp-crypts. In conclusion, our study documents distinct MMRp-crypts in MSH6-CMMRD, a phenomenon in keeping with MSH6 being a frequent target of MSI-H due to its coding microsatellite and suggesting that MSH6-CMMRD can potentially serve as a unique model system to further our understanding of MSH6's role in MSI-H tumor formation and evolution. Our findings also bear diagnostic implications; when using MMR immunohistochemistry as an ancillary tool in detecting CMMRD, awareness of these MMRp crypts can help avoid diagnostic pitfalls. [ABSTRACT FROM AUTHOR]

While universal tumor testing for Lynch Syndrome (LS) is recommended in all new diagnoses of colorectal cancer (CC) and endometrial cancer (EC), the cost and availability of this test in low-resource settings poses challenges. The PREdiction Model for gene Mutations (PREMM5) is a clinical algorithm designed to assess the risk of an individual carrying estimates one's risk of carrying a LS mutation. This study aims to assess the feasibility of using PREMM5 to screen for LS risk in Guatemala. This cross-sectional pilot study enrolled 50 patients with colorectal or endometrial cancer receiving treatment at LIGA-INCAN, a cancer hospital in Guatemala City, between June 2022–July 2022. Patients were contacted by phone and administered the PREMM5 survey, followed by an additional feasibility questionnaire. Of the 50 participants, 62% of patients had a PREMM5 predicted probability of ≥ 2.5%, the threshold above which genetic testing is recommended. Almost all patients found the survey easy to complete (98%), were able to easily recall personal (90%) and family (88%) medical history, understood its purpose (94%), and reported an interest in (96%) and ability to (98%) act on the results if applicable. Our study shows the role of the PREMM5 as a feasible tool for identifying individuals at risk of carrying mutations associated with LS in this low-resource setting. By implementing the PREMM5 model, high risk individuals can be identified early, enabling timely interventions and improving outcomes in this at-risk population. [ABSTRACT FROM AUTHOR]

Lynch syndrome predisposes to a high risk of colorectal cancer and colonoscopy remains the primary preventive strategy. The prevention of colorectal cancer through colonoscopy relies on identifying and removing adenomas, the main precursor lesion. Nevertheless, colonoscopy is not an optimal strategy since post-colonoscopy colorectal cancer remains an important issue. In continuation of a 2021 journal review, the present article seeks to offer an updated perspective by examining relevant articles from the past 3 years. We place recent findings in the context of existing guidelines, with a specific focus on colonoscopy surveillance. Key aspects explored include colonoscopy quality standards, timing of initiation, and surveillance intervals. Our review provides a comprehensive analysis of adenoma-related insights in Lynch syndrome, delving into emerging technologies like virtual chromoendoscopy and artificial intelligence-assisted endoscopy. This review aims to contribute valuable insights into the topic of colonoscopy surveillance in Lynch syndrome. [ABSTRACT FROM AUTHOR]

PMS2, a Lynch Syndrome gene, presents challenges in genetic testing due to the existence of multiple pseudogenes. This study aims to describe a series of cases harboring a variant in the PMS2CL pseudogene that has been incorrectly assigned to PMS2 with different nomenclatures. We reviewed data from 647 Brazilian patients who underwent multigene genetic testing at a single center to identify those harboring the PMS2 V1:c.2186_2187delTC or V2:c.2182_2184delACTinsG variants, allegedly located at PMS2 exon 13. Gene-specific PCR and transcript sequencing was performed. Among the 647 individuals, 1.8% (12) carried the investigated variants, with variant allele frequencies ranging from 15 to 34%. By visually inspecting the alignments, we confirmed that both V1 and V2 represented the same variant and through gene-specific PCR and PMS2 transcript analysis, we demonstrated that V1/V2 is actually located in the PMS2CL pseudogene. Genomic databases (ExAC and gnomAD) report an incidence of 2.5 − 5.3% of this variant in the African population. Currently, V1 is classified as "uncertain significance" and V2 as "conflicting" in ClinVar, with several laboratories classifying them as "pathogenic". We identified a frequent African PMS2CL variant in the Brazilian population that is misclassified as a PMS2 variant. It is likely that V1/V2 have been erroneously assigned to PMS2 in several manuscripts and by clinical laboratories, underscoring a disparity-induced matter. Considering the limitations of short-read NGS differentiating between certain regions of PMS2 and PMS2CL, using complementary methodologies is imperative to provide an accurate diagnosis. [ABSTRACT FROM AUTHOR]

Background and study aims: Lynch syndrome (LS) is a hereditary autosomal dominant condition, with an increased lifetime risk of developing malignancies including colorectal cancer (CRC). Current guidelines differ in recommended colonoscopy-surveillance intervals from 1 to 2 years. Although colonoscopy is considered a safe procedure, there are risks of severe adverse events (SAEs), such as perforation and bleeding, as well as adverse events (AEs), such as abdominal discomfort and post-colonoscopy gastrointestinal infections. Colonoscopy-related bleeding and perforation rates have been reported 0.17% and 0.11%, respectively. However, there are insufficient data regarding complications of colonoscopy-surveillance for LS patients. This study aims to investigate the risk of AEs among LS patients during colonoscopy in the Stockholm region. Patients and methods: This retrospective cohort study includes 351 LS patients undergoing endoscopic surveillance at the Karolinska University Hospital, August 1989 – April 2021. Data from endoscopic surveillance colonoscopies were extracted from patients' medical records. Results: Of 1873 endoscopies in 351 LS patients, 12 complications (AEs) were documented within 30 days (0.64%) and with a total of 3 bleedings (SAEs, 0.16%). No perforations were identified. Conclusion: Colonoscopy surveillance for LS patients shows a comparatively low risk of AEs per-examination. Colonoscopy complications per-patient, including both SAEs and AEs, show a significantly higher risk. Colonoscopy complications only including SAEs, show a comparatively low risk. Understanding the lifetime risk of surveillance-related colonoscopy complications is important when designing targeted surveillance programmes. [ABSTRACT FROM AUTHOR]

Hormonal contraception (HC) is a well-recognized protection against endometrial cancer (EC) in the general population. It has not been established if this is also applicable to women with Lynch syndrome (LS), a condition associated with a up to 50% lifetime risk of developing EC. The objective of this study was to evaluate if the use of HC influences the incidence of endometrial hyperplasia and EC in women with LS by comparing the histology of annual endometrial biopsies obtained in patients with LS who are using HC versus non-users. This is a retrospective cohort study conducted with endometrial biopsies obtained in women 30 to 50 years of age with LS. The Pearson Chi-square test was performed to compare the prevalence of cancer and hyperplasia in the HC users and in the non-HC users groups. A total of 164 endometrial biopsies obtained among 75 women were suitable for analysis. Among the 86 biopsies obtained in the non-HC group, 81.4% (70/86) were normal. Two cases of endometrial carcinoma (2.3%) and 6 endometrial hyperplasia without atypia were found (7.0%). Among the 78 biopsies performed in patients using HC, 78.2% (61/78) were normal. Three endometrial hyperplasia without atypia (3.8%) and three cases of EC were diagnosed (3.8%). This study suggests that, in women of 30 to 50 years of age with LS, the use of hormonal contraception does not seem to decrease the occurrence of endometrial hyperplasia/carcinoma on annual endometrial histology. [ABSTRACT FROM AUTHOR]

Constitutional Mismatch Repair Deficiency (CMMRD) is a rare childhood cancer predisposition syndrome, caused by biallelic pathogenic germline variants in the mismatch repair genes. Diagnosis and management of this syndrome is challenging, especially in low-resource settings. This study describes a patient diagnosed with colorectal cancer and grade 3 astrocytoma at the age of 11 and 12 respectively. Immunohistochemistry analysis showed a loss of MSH2 and MSH6 protein expression in CRC tissues of the patient. We identified by Targeted Exome Sequencing a homozygous pathogenic germline variant in exon 9 of the MSH6 gene (c.3991 C > T; p.Ala1268Glyfs*6). Genetic investigation of the family showed that the father was heterozygous for the identified pathogenic variant while the brother was wild type for this variant. Our study highlights the importance of a correct and timely diagnosis of CMMRD which can have implications for treatment. It also underlines the imperative need to enhance awareness, diagnostic standards, and surveillance that are crucial for patients and their families. [ABSTRACT FROM AUTHOR]

Serrated polyposis syndrome (SPS) presents with multiple sessile serrated lesions (SSL) in the large intestine and confers increased colorectal cancer (CRC) risk. However, the etiology of SPS is not known. SSL-derived organoids have not been previously studied but may help provide insights into SPS pathogenesis and identify novel biomarkers and chemopreventive strategies. This study examined effects of EGFR and COX pathway inhibition in organoid cultures derived from uninvolved colon and polyps of SPS patients. We also compared with organoids representing the hereditary gastrointestinal syndromes, Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). Eighteen total organoid colon cultures were generated from uninvolved colon and polyps in SPS, FAP, LS, and non-syndromic screening colonoscopy patients. BRAF and KRAS mutation status was determined for each culture. Erlotinib (EGFR inhibitor) and sulindac (COX inhibitor) were applied individually and in combination. A 44-target gene custom mRNA panel (including WNT and COX pathway genes) and a 798-gene microRNA gene panel were used to quantitate organoid RNA expression by NanoString analysis. Erlotinib treatment significantly decreased levels of mRNAs associated with WNT and MAPK kinase signaling in organoids from uninvolved colon from all four patient categories and from all SSL and adenomatous polyps. Sulindac did not change the mRNA profile in any culture. Our findings suggest that EGFR inhibitors may contribute to the chemopreventive treatment of SSLs. These findings may also facilitate clinical trial design using these agents in SPS patients. Differentially expressed genes identified in our study (MYC, FOSL1, EGR1, IL33, LGR5 and FOXQ1) may be used to identify other new molecular targets for chemoprevention of SSLs. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS; HNPCC) patients carry heterozygous pathogenic germline variants in mismatch repair (MMR) genes, which have also been shown to play an important role in meiosis. Therefore, it was hypothesized, that LS might be associated with a higher risk for premature ovarian failure (POF) or earlier menopause. Data on medical gynaecological history, cancer diagnoses and therapy were collected from 167 female LS patients and compared to a population-based control cohort. There was no difference between the age of menopause in patients compared to controls and no evidence for a higher risk of POF in LS patients. However, around one third (35%) of the probands have already had premenopausal cancer and mostly cancer-related treatment affecting fertility before the age of 45 years. Therefore, childbearing time might still be limited in these patients, especially due to the premenopausal cancer risk. LS patients should be informed in time about the elevated premenopausal cancer risks and the possible impact on family planning. This is particularly relevant since the average childbearing age has increased during the last decades. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Lynch syndrome (LS) is an autosomal‐dominant, hereditary cancer predisposition syndrome caused by pathogenic variants (PVs) in one of the mismatch‐repair genes MLH1, MSH2/EPCAM, MSH6, or PMS2. Individuals who have MLH1 PVs have high lifetime risks of colorectal cancer (CRC) and endometrial cancer (EC). There is controversy regarding whether a younger age at diagnosis (or anticipation) occurs in MLH1‐associated LS. The objective of this study was to assess anticipation in families with MLH1‐associated LS by using statistical models while controlling for potential confounders.Data from 31 families with MLH1 PVs were obtained from an academic registry. Wilcoxon signed‐rank tests on parent–child‐pairs as well as parametric Weibull and semiparametric Cox proportional hazards and Cox mixed‐effects models were used to calculate hazard ratios or to compare mean ages at CRC/EC diagnosis by generation. Models were also corrected for ascertainment bias and birth‐cohort effects.A trend toward younger ages at diagnosis of CRC/EC in successive generations, ranging from 3.2 to 15.7 years, was observed in MLH1 PV carrier families. A greater hazard for cancer in younger generations was not precluded by the inclusion of birth cohorts in the model. Individuals who had MLH1 variants with no Mlh1 activity were at a 78% greater hazard for CRC/EC than those who retained Mlh1 activity.The current results demonstrated evidence in support of anticipation in families with MLH1‐associated LS across all statistical models. Mutational effects on Mlh1 activity influenced the hazard for CRC/EC. Screening based on the youngest age of cancer diagnosis in MLH1‐LS families is recommended. [ABSTRACT FROM AUTHOR]

Background: Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by mutations in mismatch repair genes. Genetic counseling is crucial for the prevention and treatment of LS, as individuals with these mutations have an increased lifetime risk of developing multiple cancers. MutS Homolog 2 (MSH2)is a protein-coding gene that plays a key role in LS. A significant number of LS cases are linked to harmful heterozygous mutations in the MSH2 gene. Case Presentation: The proband was a 50-year-old endometrial dedifferentiated carcinoma patient with a dMMR/MSI-H tumor negative for MSH2/MSH6 expression by immunohistochemistry. Genetic counseling and tumor gene testing were conducted using next-generation sequencing (NGS) technology, which revealed a previously unknown germline MSH2 gene nonsense mutation NM&lowbar;000251.2:exon2.354T>A (p.Y118*), leading to a diagnosis of LS. Further analysis of this variant in five family members of the patient confirmed its presence in all individuals, with one family member being diagnosed with colorectal cancer (CRC) at the age of 43. The proband received postoperative chemoradiotherapy and achieved a disease-free survival of 2 years, with ongoing follow-up. Conclusion: This study provides evidence that the MSH2 nonsense mutation c.354T>A is a highly likely pathogenic mutation and is responsible for typical LS-associated endometrial carcinoma. It emphasizes the importance of genetic counseling for proband family members to facilitate early diagnosis of LS- related carcinoma. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aim Methods Results Conclusions Trial Registration Non‐invasive biomarkers may reduce post‐colonoscopy colorectal cancer (CRC) rates and colonoscopy overuse in Lynch syndrome. Unlike faecal immunochemical test (FIT), faecal volatile organic compounds (VOCs) may accurately detect both advanced and non‐advanced colorectal neoplasia.The aim of this study was to evaluate the potential of faecal VOCs—separately and with FIT—to guide optimal colonoscopy intervals in Lynch syndrome.Prospective longitudinal multicentre study in which individuals with Lynch syndrome collected faeces before and after high‐quality surveillance colonoscopy. VOC‐patterns were analysed using field asymmetric ion mobility spectrometry (FAIMS) and gas chromatography‐ion mobility spectrometry (GC‐IMS) followed by machine learning pipelines, and combined with FIT at 2.55 μg Hb/g faeces. Gas chromatography time‐of‐flight mass spectrometry analysed individual VOC abundance.Among 200 included individuals (57% female, median 51 years), 62 had relevant neoplasia at colonoscopy: 3 CRC, 6 advanced adenoma (AA), 3 advanced serrated lesion (ASL), and 50 non‐advanced adenoma (NAA). Respective sensitivity and negative predictive value for CRC and AA (and also ASL in case of FAIMS) were 100% and 100% using FAIMS (54% specificity), and 89% and 99% using GC‐IMS (58% specificity). Respective sensitivity and specificity for any relevant neoplasia were 88% and 44% (FAIMS) and 84% and 28% (GC‐IMS); accuracy did not significantly improve upon VOC‐FIT. VOC‐patterns differed before and after polypectomy (AUC 0.70). NAA showed decreased faecal abundance of butanal, 2‐oxohexane, dimethyldisulphide and dimethyltrisulphide.In Lynch syndrome, faecal VOCs may be a promising strategy for postponing colonoscopy and for follow‐up after polypectomy. Our results serve as a stepping stone for large validation studies.NL8749 [ABSTRACT FROM AUTHOR]

Objective Background Method Results Conclusion Implications The goal was to explore how families communicate to cope with hereditary cancer conditions and identify factors that may enhance resilience and recommended decision‐making.Families with Hereditary Breast and Ovarian Cancer syndrome (HBOC), Lynch syndrome (LS), and Li‐Fraumeni syndrome (LFS) have an increased lifetime risk of developing cancer. We use the communication theory of resilience (CTR) to examine how families engage in resilience and make health decisions about hereditary cancer risks over time.We conducted 42 dyadic interviews with families with HBOC, LS, and LFS. Themes emerged through qualitative analysis for each of the resilience processes outlined by CTR (crafting normalcy, communication networks, identity anchors, alternative logics, and foregrounding productive action while legitimizing negative feelings), illustrating how family members manage stressors associated with hereditary cancer over time.Participants described enacting each of the five CTR processes to manage the acute and chronic stressors associated with hereditary cancer. We described themes that emerged within each of the five resilience processes.Findings demonstrate the ways in which families managing hereditary cancer risks enact resilience processes and how these processes may have a complex relationship to coping and medical decision‐making.Findings demonstrate areas for intervention to support familial resilience. [ABSTRACT FROM AUTHOR]

The application of immunotherapy for treating colorectal cancer (CRC) is currently a research hotspot, and neoadjuvant immunotherapy has shown initial success in treating CRC. The watch-and-wait (W&W) approach is often used after achieving a clinical complete response (cCR) following preoperative treatment of low rectal cancer. However, thus far, the W&W approach has not been reported for patients with colon cancer. Here, we report the case of a 64-year-old patient with heterogeneous multigenic CRC who achieved cCR after five sessions of neoadjuvant immunotherapy before surgery. A W&W approach was used to spare the patient from surgery. A 64-year-old male presented with intermittent abdominal pain. A colonoscopy examination detected an irregular cauliflower-like mass near the hepatic flexure of the ascending colon. The biopsy results indicated adenocarcinoma of the ascending colon. The patient was administered pembrolizumab (200 mg, ivgtt, q3w). After one cycle of treatment, the intestinal obstruction symptoms disappeared, and the treatment was continued for additional three sessions. After complete clinical remission of the tumor was confirmed, the W&W approach was adopted. Follow-up CT scans and colonoscopy examinations confirmed no local tumor regeneration or metastasis. Neoadjuvant immunotherapy is effective for patients with DNA mismatch repair gene deficiency and/or microsatellite instability high with a high rate of cCR or pathologic complete response. The W&W approach may also be suitable for patients with colon cancer. The safety and feasibility of watch and wait in patients with colon cancer need to be verified by more clinical data. [ABSTRACT FROM AUTHOR]

Growing evidence has demonstrated the role of mutations of tumor biomarkers in diagnosing and treating epithelial ovarian cancer. This review aims to analyze recent literature on the correlation between tumor biomarkers and chemotherapy in nonmucinous ovarian cancer, providing suggestions for personalized treatment approaches. An extensive literature search was conducted to identify relevant studies and trials. BRCA1/2 mutations are central in homologous recombination repair deficiency (HRD) in ovarian cancer, but several other genetic mutations also contribute to varying cancer risks. While the role of MMR testing in ovarian cancer is debated, it is more commonly linked to non-serous ovarian cancer, often associated with Lynch syndrome. A significant proportion of ovarian cancer patients have HRD, affecting treatment decisions in both first-line (especially in advanced stages) and second-line therapy due to HRD's connection with platinum-based therapy and PARP inhibitors' response. However, validated genetic tests to identify HRD have not yet been universally implemented. There is no definitive therapeutic algorithm for advanced ovarian cancer, despite ongoing efforts and multiple proposed tools. Future research should focus on expanding the utility of biomarkers, reducing resistance, and increasing the actionable biomarker pool. [ABSTRACT FROM AUTHOR]

Currently, there is no robust evidence demonstrating a clear association between Lynch syndrome and non-malignant breast pathology such as adenomyoepithelioma. We report a case of benign breast adenomyoepithelioma, which after recurrence was associated with ductal carcinoma in-situ (DCIS) in a 41-year-old woman with Lynch syndrome, who lacked significant family history of breast or ovarian cancer. Both, the adenomyoepithelioma and DCIS were found to have nuclear loss of MSH2/MSH6 by immunohistochemistry, while germline testing confirmed MSH2 gene mutation. Concordant loss of MSH2 in both lesions in the context of a MSH2 pathogenic variant in this patient with Lynch syndrome illustrates that the benign adenomyoepithelioma behaved as a likely precursor of DCIS. Our report provides a novel perspective that in some patients with Lynch syndrome adenomyoepithelioma may represent a pre-malignant precursor lesion of DCIS. [ABSTRACT FROM AUTHOR]

Lynch syndrome, also called hereditary non‐polyposis colorectal cancer, is an autosomal dominant disorder characterized by germline pathogenic mutations in DNA mismatch repair genes—resulting in increased susceptibility to colorectal, endometrial, and other tumors. This case report presents an incidental finding of endometrial cancer with Lynch syndrome during investigation for primary infertility. A 34‐year‐old woman presented to the fertility clinic with unexplained primary infertility. Investigations showed possible endometrial polyp, 13 × 11 mm in size. Hysteroscopic polypectomy and endometrial biopsy revealed complex endometrial hyperplasia amounting to endometroid adenocarcinoma. The case was discussed at the West of Scotland Gynecology‐Oncology MDT meeting—management options including fertility‐sparing treatment or radical surgery were presented to the patient and she opted for the latter. A total laparoscopic hysterectomy with bilateral salpingo‐oophorectomy was performed with pathology results consistent with well‐differentiated endometroid adenocarcinoma Stage 1A. Peritoneal washings showed no malignant cells. Genetic testing confirmed a diagnosis of Lynch syndrome. On further questioning, it was revealed that the patient had a strong family history of colon cancer but had not previously met the criteria for genetic testing. She was referred to colorectal surgeons and underwent colonoscopy. This showed no abnormality; she was therefore scheduled for 2‐yearly colonoscopic surveillance. Synopsis: Asymptomatic presentation of endometrial cancer in a patient found to have Lynch syndrome, discovered incidentally through workup for primary infertility. [ABSTRACT FROM AUTHOR]

Background: It is projected that, by 2040, the number of new cases of colorectal cancer (CRC) will increase to 3.2 million, and the number of deaths to 1.6 million, highlighting the need for prevention strategies, early detection and adequate follow-up. In this study, we aimed to provide an overview of the progress in personalized medicine of CRC in Serbia, with results and insights from the Institute for Oncology and Radiology of Serbia (IORS), and to propose guidance for tackling observed challenges in the future. Methods: Epidemiological data were derived from official global and national cancer registries and IORS electronic medical records. Germline genetic testing for Lynch syndrome was performed by Next Generation Sequencing. RAS and BRAF mutation analyses were performed using qPCR diagnostic kits. Results: Epidemiology and risk factors, prevention and early detection programs, as well as treatment options and scientific advances have been described in detail. Out of 103 patients who underwent germline testing for Lynch syndrome, 19 (18.4%) showed a mutation in MMR genes with pathogenic or likely pathogenic significance and 8 (7.8%) in other CRC-associated genes (APC, CHEK2, MUTYH). Of 6369 tested patients, 50.43% had a mutation in KRAS or NRAS genes, while 9.54% had the V600 mutation in the BRAF gene. Conclusions: Although significant improvements in CRC management have occurred globally in recent years, a strategic approach leading to population-based systemic solutions is required. The high incidence of young-onset CRC and the growing elderly population due to a rise in life expectancy will be especially important factors for countries with limited healthcare resources like Serbia. [ABSTRACT FROM AUTHOR]

Background: High variability in the age at cancer diagnosis in Lynch syndrome (LS) patients is widely observed, even among relatives with the same germline pathogenic variant (PV) in the mismatch repair (MMR) genes. Genetic polymorphisms and lifestyle factors are thought to contribute to this variability. We investigated the influence of previously reported genetic polymorphisms on the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene. Methods: A total of 359 LS variant heterozygotes (LSVH) from 60 different families were genotyped for specific genetic polymorphisms in GSTM1, GSTT1, CYP1A1, CYP17, PPP2R2B, KIF20A, TGFB1, XRCC5, TNF, BCL2, CHFR, CDC25C, ATM, TTC28, CDC25C, HFE, and hTERT genes using Multiplex Polymerase Chain Reaction and MassArray methods. Kaplan–Meier survival analysis, univariate and multivariate Cox proportional hazards gamma shared frailty models adjusted for sex were used to estimate the association between age at cancer diagnosis and polymorphism genotypes. A p-value < 0.05 after correcting for multiple testing using the Benjamini–Hochberg method was considered significant at a 95% confidence interval. Results: We identified three genotypes in the cell-cycle regulation, DNA repair, and xenobiotic-metabolism genes significantly associated with age at cancer diagnosis in this cohort. The CYP1A1 rs4646903 risk (GG) and CDC25C rs3734166 polymorphic (GA+AA) genotypes were significantly associated with an increased risk of a younger age at cancer diagnosis (Adj HR: 2.03 [1.01–4.08], p = 0.034 and Adj HR: 1.53 [1.09–2.14], p = 0.015, respectively). LSVH who were heterozygous for the XRCC5 rs1051685 SNP showed significant protection against younger age at cancer diagnosis (Adj HR: 0.69 [CI, 0.48–0.99], p = 0.043). The risk of a younger age at any cancer diagnosis was significantly high in LS carriers of one to two risk genotypes (Adj HR: 1.49 [CI: 1.06–2.09], corrected p = 0.030), while having one to two protective genotypes significantly reduced the risk of developing any cancer and CRC at a younger age (Adj HR: 0.52 [CI: 0.37–0.73], and Adj HR: 0.51 [CI: 0.36–0.74], both corrected p < 0.001). Conclusions: Polymorphism genotypes in the cell-cycle regulation, DNA repair, and xenobiotic metabolizing genes may influence the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene. [ABSTRACT FROM AUTHOR]

Objective: To investigate the clinical utility of Next Generation Sequencing (NGS) in molecular typing of endometrial carcinoma and its combined screening for Lynch Syndrome (LS). Methods: 90 patients diagnosed with endometrial carcinoma (EC) and receiving treatment at the Third Affiliated Hospital of Zhengzhou University between March 2022 and December 2023 were included in this study. Molecular typing and germline evaluation for LS were conducted using NGS on the Illumina platform. A retrospective analysis was performed to examine the clinical pathological characteristics, molecular mutation spectrum, and LS screening outcomes among patients with four distinct molecular subtyping categories. Results: Among the 90 cases of EC, 11 cases (12.2%) of POLE mut type, 19 cases (21.1%) of MMRd type, 6 cases (6.7%) of p53 abn type, and 54 cases (60%) of NSMP type were detected, with detailed analysis of their respective molecular characteristics. LS screening identified 9 cases (10%) of pathogenic germline mutations in MMR genes, including 3 cases of MLH1 germline mutations, 2 cases of PMS2, 2 of MSH2, and 2 of MSH6. Of the 9 LS patients, 7 were MMRd type and 2 NSMP type, with 7 cases showing abnormal MMR protein expression. Additionally, 6 cases with germline variants of uncertain significance in MMR genes were detected, including 2 MLH1, 1 MSH6, 2 MSH6, 1 PMS2, and 1 EPCAM. Conclusion: NGS enables precise molecular typing of endometrial carcinoma through the identification of mutations in the POLE, TP53, and MMR genes. Conducting germline mutation testing for MMR genes in all patients with endometrial carcinoma can effectively prevent instances of overlooked LS diagnoses. Nevertheless, the extensive expenses associated with NGS necessitate additional validation and investigation before its clinical implementation can be fully endorsed. [ABSTRACT FROM AUTHOR]

Survivors of colorectal cancer (CRC) are at risk of developing another primary colorectal cancer ‐ metachronous CRC. Understanding which pathological features of the first tumour are associated with risk of metachronous CRC might help tailor existing surveillance guidelines. Population‐based CRC cases were recruited from the United States, Canada and Australia between 1997 and 2012 and followed prospectively until 2022 by the Colon Cancer Family Registry. Metachronous CRC was defined as a new primary CRC diagnosed at least 1 year after the initial CRC. Those with the genetic cancer predisposition Lynch syndrome or MUTYH mutation carriers were excluded. Cox regression models were fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the associations. Of 6085 CRC cases, 138 (2.3%) were diagnosed with a metachronous CRC over a median follow‐up time of 12 years (incidence: 2.0 per 1000 person‐years). CRC cases with a synchronous CRC were 3.4‐fold more likely to develop a metachronous CRC (adjusted HR: 3.36, 95% CI: 1.89–5.98) than those without a synchronous tumour. CRC cases with MMR‐deficient tumours had a 72% increased risk of metachronous CRC (adjusted HR: 1.72, 95% CI: 1.11–2.64) compared to those with MMR‐proficient tumours. Compared to cases who had an adenocarcinoma histologic type, those with an undifferentiated histologic type were 77% less likely to develop a metachronous CRC (adjusted HR: 0.23, 95% CI: 0.06–0.94). Existing surveillance guidelines for CRC survivors could be updated to include increased surveillance for those whose first CRC was diagnosed with a synchronous CRC or was MMR‐deficient. [ABSTRACT FROM AUTHOR]

Background: Lynch syndrome represents the most common hereditary cause of both colorectal and endometrial cancer. It is caused by defects in mismatch repair genes, as well as EPCAM. Universal screening of colon tumors for Lynch syndrome via microsatellite instability (MSI) and/or immunohistochemistry (IHC) can identify patients and families at risk to develop further cancers and potentially impact surveillance and treatment options. The approach to implementation of universal screening, taking ethical considerations into account, is critical to its effectiveness, with patient perspectives providing valuable insight. Methods: Patients whose colon tumors underwent universal screening at Penn State Hershey Medical Center over a period of 2.5 years were mailed a survey on universal screening in 2017. Along with the survey, they received a recruitment letter and a summary explanation of research. The survey included both multiple choice and free-response questions that covered topics including respondent knowledge of Lynch syndrome, attitudes toward universal screening and experiences with the screening protocol as implemented. Results: Sixty-six of 297 possible patients (22.2%) responded to the survey, including 13 whose screening results raised concern for Lynch syndrome. 75.8% of respondents supported universal tumor screening without informed consent. 92.4% preferred receiving screening results regardless of outcome. Respondents described benefits to screening for themselves and their families. Conclusions: While broadly supporting universal tumor screening without informed consent, respondents also wanted more information shared about the screening policy, as well as their results. These patient preferences should be one of many factors considered when implementing universal screening and can also inform practices regarding both tumor profiling and universal genetic testing, which is becoming more prevalent. [ABSTRACT FROM AUTHOR]

Pembrolizumab and other immunotherapies have become central in treating metastatic colon cancer, particularly effective in patients with mismatch repair deficiencies. We report a case involving a man who initially underwent radical surgery for sigmoid colon cancer on April 27, 2011, followed by hepatic tumor resection on September 21, 2017. Post-surgery, he received eight cycles of adjuvant chemotherapy with the CAPEOX regimen and was regularly monitored through CT and MRI scans. On August 24, 2022, liver metastases were detected, and he was diagnosed with Lynch syndrome (LS) due to germline mutation in the MSH2 and EPCAM genes. He commenced treatment with 200mg of pembrolizumab intravenously every three weeks on September 2, 2022, and demonstrated a sustained response. However, after 17 cycles, he developed a treatment related adverse event (TRAE) of pancreatic endocrine dysfunction, leading to type 1 diabetes, managed with subcutaneous insulin injections. After 30 cycles of treatment, no evidence of disease was observed. This case underscores the significant clinical benefits of first-line pembrolizumab in managing hepatic metastasis in colonic carcinoma associated with LS, despite the occurrence of TRAEs. It raises critical questions regarding the optimal duration of immunotherapy following a complete or partial response and whether treatment should be discontinued upon the emergency of TRAEs. Continued research and forthcoming clinical trials with checkpoint inhibitors are expected to refine treatment protocols for LS-associated carcinoma. [ABSTRACT FROM AUTHOR]

Introduction: Penile squamous cell carcinoma (PSCC) is a rare malignancy in men with poor survival in metastatic disease. Lynch syndrome (LS) is a cancer predisposition, autosomal-dominant, inherited disorder that arises from loss of function variants in mismatch repair genes. Case Presentation: Here, we reported a PSCC patient who was suspected with LS caused by a heterozygous PMS2 D526Afs*69 variant. A 57-year-old male with PSCC underwent pelvic lymph node dissection and bilateral groin lymph node dissection due to metastatic disease. He has a family history of colon cancer and brain cancer. Comprehensive genomic sequencing of his tumor specimen identified 19 somatic mutations with a high tumor mutation burden (14.03 mutations per Mb) and a high frequency of microsatellite instability. Additionally, a germline PMS2 D526Afs*69 mutation was identified in the peripheral blood sample. Immunohistochemistry analysis showed complete loss of PMS2 and MLH1 expression in his tumor. Conclusion: These observations provided evidence suggesting that PSCC could be part of the LS spectrum. [ABSTRACT FROM AUTHOR]

This document provides summaries of research studies on colorectal surgery, covering various topics such as surgical outcomes, predictors of patient outcomes, diagnostic tools, and management approaches. The studies suggest that robotic surgery is a safe and effective option for colorectal resections, potentially leading to shorter hospital stays and improved patient outcomes. Additionally, the studies indicate that body composition may be a predictor of preoperative fitness and that nurse-led clinics can offer timely diagnoses. However, more research is needed to validate these findings and investigate other aspects of colorectal surgery. [Extracted from the article]

This document contains summaries of several articles related to colorectal disease. The first article discusses the adoption of a hybrid alternative to single-use laparoscopic ports in order to reduce the carbon footprint of laparoscopic surgery. The second article explores surgeons' experiences and practices in the primary repair of obstetric anal sphincter injuries. The third article introduces an AI-powered endoscopic analysis tool that improves the detection of precancerous lesions in colorectal cancer screening. The fourth article examines the impact of colonoscopy key performance indicators on the risk of colorectal cancer and advanced polyps. The fifth article investigates the association between psoas sarcopenia and mortality in patients with per rectal bleeding. The sixth article outlines a Phase III study evaluating the efficacy and safety of perioperative dostarlimab monotherapy in patients with resectable colon adenocarcinoma. The seventh article assesses the incidence, healthcare resource use, and costs associated with incisional hernia repair. The final article discusses the use of innovative techniques in restorative prophylactic surgery for familial adenomatous polyposis. [Extracted from the article]

Background: Endometrial hyperplasia, characterized by excessive growth leading to endometrial thickening, is commonly observed in the premenopausal period. Its prevalence in postmenopausal women is approximately 15%, peaking between ages 50 and 60. This condition often manifests as abnormal uterine bleeding and can progress to malignancy, with varying risks depending on the type of hyperplasia. Purpose: This study aims to investigate the factors influencing endometrial thickness during the perimenopausal period and raise awareness among healthcare professionals about the importance of evaluating and caring for individuals with endometrial hyperplasia. Methods: Studies examining the association between various factors such as diabetes mellitus, hypertension, age, estrogen replacement therapy, anovulatory disorders, smoking, medications, genetic factors, and endocrine-related proteins and the development of endometrial hyperplasia were reviewed. The literature search encompassed relevant databases, including PubMed, Scopus, and Web of Science. Results: Research findings indicate significant associations between changes in gene expression of several factors and the development of endometrial hyperplasia. Notably, the risk of progression to cancer varies between non-atypical and atypical hyperplasia cases. Factors such as diabetes mellitus, hypertension, age, estrogen replacement therapy, anovulatory disorders, smoking, medications, Lynch syndrome, tamoxifen use, and alterations in gene expression of TNF-α, EGF, IGF-1, IGF-1R, and PTEN have been implicated in the pathogenesis of endometrial hyperplasia. Conclusion: This study underscores the importance of understanding the factors influencing endometrial thickness during the perimenopausal period. It emphasizes the pivotal role of healthcare professionals in evaluating and caring for individuals with this condition. [ABSTRACT FROM AUTHOR]

Background & Aims: Lynch Syndrome, a hereditary disorder characterized by germline mutations in mismatch repair (MMR) genes, is a major contributor to colorectal cancers. It has also been identified in endometrial cancer. Despite the established role of MMR deficiency in tumorigenesis, the specific genomic alterations driving Lynch syndrome-associated endometrial cancer, and their overlap with colorectal cancer, remain incompletely understood. This study aims to fill this gap by performing a detailed comparative analysis of germline and somatic mutations in endometrial cancer within the context of Lynch syndrome. Methods: We conducted whole exome sequencing on matched germline and somatic DNA from 13 patients diagnosed with Lynch syndrome-associated endometrial cancer. High-depth sequencing was performed, followed by rigorous bioinformatics analysis to identify and annotate variants, focusing on their potential pathogenicity and relevance to both endometrial and colorectal cancer. Results: Our analysis revealed 1,118 germline and 14,051 somatic variants, with 493 variants common to both. Recurrent pathogenic mutations in MLH1, MSH2, and MSH6 were confirmed, highlighting their critical role in Lynch syndrome. Notably, frequent somatic mutations in the PIK3CA and PTEN genes were identified, implicating the PI3K/AKT/mTOR pathway as a key oncogenic driver in these cancers. Additionally, novel somatic mutations in genes related to the extracellular matrix such as FBN1 and SPARC were uncovered, suggesting a possible unique role in endometrial tumor progression. Conclusions: This study provides new insights into the molecular basis of Lynch syndrome-associated endometrial cancer, emphasizing the overlap in oncogenic pathways with colorectal cancer. The discovery of shared and unique genetic mutations highlights the importance of developing combined treatment strategies and suggests that targeting these specific mutations could improve therapy for patients with Lynch syndromeassociated cancers. [ABSTRACT FROM AUTHOR]

Background: Lynch syndrome carriers ('carriers') are presented with complex, emotionally laden choices regarding management of increased genetic cancer risks. Decision aids encourage active involvement in values‐based health decisions. This paper aimed to address the research question: How do Lynch syndrome carriers make sense of their chances of developing cancer, and what are the implications for providing support with decision making about genetic cancer risk management? Methods: Adult carriers were recruited through a genetics service or involvement with Lynch Syndrome UK. Semi‐structured interviews explored lived experiences of carriers' access to care with a focus on decision support. Themes were constructed using framework analysis. These were developed into a conceptual model with recommendations for codevelopment of improved information and support including a tailored decision aid to complement integrated healthcare. Results: Twenty participants included 12 women and eight men, half with a history of cancer. Six overarching themes were: (1) finding balance with Lynch; (2) living 'on higher alert'; (3) managing uncertainty: 'I've thought about it a lot'; (4) burden of responsibility: 'It's on me'; (5) access to joined‐up care and support: 'There's something missing'; and (6) influence/pressure from others. Conclusions: This qualitative interview study provided in‐depth insights from Lynch syndrome carriers about their lived experiences, informed by their values. Recommendations to empower carriers to make sense of genetic cancer risks and support decisions included accessible, trusted information, educated healthcare professionals, shared decision making, and joined‐up integrated care pathways complemented by tailored decision aids. [ABSTRACT FROM AUTHOR]

Simple Summary: Hereditary colorectal cancer syndromes (HCCS) and inflammatory bowel disease (IBD) carry a high risk of developing colorectal cancer (CRC). The co-occurrence of IBD and HCCS is extremely rare. Individuals with HCCS and IBD are prone to developing CRC at a younger age compared to those without IBD, with patients who have ulcerative colitis at such an especially high risk. The interplay between chronic inflammation and genetic predispositions remains poorly understood. Background and aims: Hereditary colorectal cancer syndromes (HCCS), including familial adenomatous polyposis (FAP) and Lynch syndrome (LS), are the two most important high-risk conditions for colorectal cancer (CRC). Inflammatory bowel disease (IBD) increases the risk by two to six times compared with that in the general population. The intersection of these two conditions has rarely been documented in literature. We aimed to summarize the prevalence, pathogenesis, and current evidence-based management of IBD and HCCS and the underlying molecular mechanisms of accelerated carcinogenesis due to combined inflammation and genetic predisposition. Methods: PubMed and Scopus were searched until June 2024 to identify relevant studies investigating the epidemiology, pathogenesis, and management of IBD and coexisting hereditary CRC syndromes. Results: Co-occurrence of IBD and hereditary CRC syndromes is exceptionally uncommon. Individuals with LS and IBD tend to develop CRC at a younger age than those without IBD, with patients with ulcerative colitis facing particularly elevated risks. The interaction between mismatch deficiency and chronic inflammation requires further investigation. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the risk of metachronous colorectal cancer (CRC) after resection of index (first) rectal cancer in patients with Lynch syndrome (LS). Methods: 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). Results: 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Fifteen percent of all colorectal cancers have detectable defects in the mismatch repair system (dMMR). MMR status is used to identify possible Lynch Syndrome (LS) and to determine prognosis and choice of treatment. Two standard techniques for determining MMR status are immunohistochemistry (IHC) and analysis for microsatellite instability (MSI) by PCR. Recently, our department introduced Idylla™ MSI assay as an alternative option to IHC, and as part of this, we introduced a decision algorithm. The purpose of this study was to review the use of the new method and our algorithm and to assess possible false‐positive results. Retrospectively, we identified 629 cases of colorectal cancer in which either IHC (336 cases) or Idylla™ MSI (293 cases) was performed. Similar results were obtained by the two methods. IHC detected dMMR in 55 cases (16%) and Idylla™ MSI in 52 cases (18%). In all 52 cases of MSI, subsequent IHC was performed. One case was not confirmed by IHC, but was confirmed by another PCR‐based method. Overall, we found that the Idylla™ MSI works well as a screening method for dMMR with no false‐positive cases detected. The proposed algorithm was useful and easily applicable. [ABSTRACT FROM AUTHOR]

Background: Lynch syndrome (LS) is the most frequent hereditary tumor syndrome and is associated with an increased risk of colorectal cancer (CRC). While gene-specific and age-specific differences are considered in patient surveillance, gender-specific risks in the development of CRC have been reported in many studies but are not consistently documented. Objective: This systematic review aims to investigate gender-specific differences in CRC development among LS patients. Material and methods: A systematic literature search following PRISMA 2020 guidelines was conducted in the PubMed, Ovid, The Cochrane Library and Web of Science databases. A total of 688 studies were screened, and 41 met the inclusion criteria. Results: Men have a higher risk of CRC and develop CRC earlier compared to women. Conclusion: These findings indicate gender-specific differences in the risk of CRC among LS patients, although they do not currently justify separate surveillance strategies. [ABSTRACT FROM AUTHOR]

Why you should read this article: • To be aware of national guidance recommending that all people with endometrial cancer should be tested for Lynch syndrome • To recognise that after a diagnosis of endometrial cancer, patients should be informed of their screening result for Lynch syndrome • To understand the importance of healthcare professionals providing patients with information about Lynch syndrome, and making clinical genetics referrals where appropriate. Lynch syndrome is an autosomal dominant inherited condition which predisposes individuals to developing certain cancers, including endometrial, colorectal and/or ovarian cancer. However, most people with Lynch syndrome are not aware that they have the condition. National Institute for Health and Care Excellence (NICE) guidance recommends that all patients with endometrial cancer should be tested for Lynch syndrome and that healthcare professionals should inform patients of the possible implications of test results for themselves and their relatives, and should make clinical genetics referrals where appropriate. This article details a cross-sectional survey that was undertaken to determine the level of awareness and understanding of Lynch syndrome among patients with endometrial cancer in the UK and to identify best practice and areas for improvement. Of the 144 eligible respondents, most were neither aware of Lynch syndrome before their cancer diagnosis nor that NICE recommends testing for the syndrome. Many respondents diagnosed with Lynch syndrome did not receive verbal or written information on the condition or referral to a clinical geneticist. This is necessary to increase patient uptake of testing and support them in sharing information with their relatives. [ABSTRACT FROM AUTHOR]

Identifying Lynch syndrome significantly impacts cancer risk management, treatment, and prognosis. Validation of mutation risk predictive models for mismatch repair (MMR) genes is crucial for guiding genetic counseling and testing, particularly in the understudied Asian population. We evaluated the performance of four MMR mutation risk predictive models in a Chinese cohort of 604 patients with colorectal cancer (CRC), endometrial cancer (EC), or ovarian cancer (OC) in Taiwan. All patients underwent germline genetic testing and 36 (6.0%) carried a mutation in the MMR genes (MLH1, MSH2, MSH6, and PMS2). All models demonstrated good performance, with area under the receiver operating characteristic curves comparable to Western cohorts: PREMM5 0.80 (95% confidence interval [CI], 0.73–0.88), MMRPro 0.88 (95% CI, 0.82–0.94), MMRPredict 0.82 (95% CI, 0.74–0.90), and Myriad 0.76 (95% CI, 0.67–0.84). Notably, MMRPro exhibited exceptional performance across all subgroups regardless of family history (FH+ 0.88, FH‐ 0.83), cancer type (CRC 0.84, EC 0.85, OC 1.00), or sex (male 0.83, female 0.90). PREMM5 and MMRPredict had good accuracy in the FH+ subgroup (0.85 and 0.82, respectively) and in CRC patients (0.76 and 0.82, respectively). Using the ratio of observed and predicted mutation rates, MMRPro and PREMM5 had good overall fit, while MMRPredict and Myriad overestimated mutation rates. Risk threshold settings in different models led to different positive predictive values. We suggest a lower threshold (5%) for recommending genetic testing when using MMRPro, and a higher threshold (20%) when using PREMM5 and MMRPredict. Our findings have important implications for personalized mutation risk assessment and counseling on genetic testing. [ABSTRACT FROM AUTHOR]

Objective: Lynch syndrome (LS) is a hereditary condition associated with an increased risk of colorectal and endometrial cancer. This study aimed to assess the knowledge, attitudes, and beliefs of women with LS regarding combined hormonal contraceptive (CHC) use compared to a control group of healthy women. Methods: Pre-menopausal women with LS (n=43) and an age-matched control group of healthy women (n=128) participated in this prospective, cross-sectional study (NCT05909410). Participants completed an electronic questionnaire evaluating perceptions of CHC use and its impact on various cancers, medical conditions, and symptoms. Statistical analysis compared responses between the two groups, with reported p-values. Results: Women with LS were less likely to use CHCs compared to the control group (p=0.03) and had a more negative perception of CHCs' impact on colorectal cancer (p=0.023) and endometrial cancer (p=0.028). Limited knowledge was observed in both groups regarding the protective effects of CHCs against colorectal and ovarian cancer. Perceptions of CHC use and its impact on symptoms and chronic diseases did not significantly differ between the groups (p>0.05). CHC use was not associated with greater awareness of the protective effect against colorectal (p=0.89) and endometrial cancer (p=0.47), but it was associated with a desire for contraception (OR 21.25; 95% CI 1.16 to 388.21; p=0.039). Conclusion: This study highlights contrasting perceptions of CHCs and their implications in oncology between women with LS and healthy women. Tailored counselling and support strategies are crucial for empowering women with LS to make informed decisions about their gynaecologic health. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to test a universal screening strategy on endometrial cancer to evaluate its effectiveness to find Lynch Syndrome (LS) cases to two established clinical criteria: Amsterdam II criteria, and the revised Bethesda criteria to select cases for prescreening with immunohistochemistry (IHC). Cases were subsequently screened for germline disease causing variants regarding the DNA mismatch repair (MMR) genes. Methods: IHC was performed on 221 endometrial cancer (EC) cases, using antibodies against the DNA mismatch repair proteins MLH1, PMS2, MSH2, and MSH6. MMR loss was found in 54 cases, and gene mutation screening was undertaken in 52 of those. Results: In this set of patients, the use of Amsterdam II criteria detected two (0.9%), the Bethesda criteria two (0.9%), and universal testing five (2.3%) cases of LS. The combination of universal testing and family history criteria resulted in detection of five patients (2.3%) with LS. Conclusions: Based on our results and other similar studies to date we propose a screening protocol for LS on EC tumors with prescreening using IHC for the four MMR proteins on all new EC cases diagnosed before 70 years of age, followed by mutation screening of all tumors with loss of MSH2 and/or MSH6 or only PMS2, plus consideration for mutation screening of all LS genes in cases fulfilling the clinical Amsterdam II criteria regardless of MMR status on IHC. [ABSTRACT FROM AUTHOR]

Endometrial cancer in Lynch syndrome is characterized by a higher incidence, younger age at onset, and increased recurrence rates compared to sporadic cases, while the safety and efficacy of fertility-sparing treatments remain uncertain. This case report presents the oncology outcome of fertilitypreserving treatment in a 39-year-old woman diagnosed with Lynch syndrome and atypical endometrial hyperplasia. Initially, she responded favorably to fertility-preserving treatment but subsequently experienced disease relapse and rapid progression during retreatment. Final pathology revealed endometrial cancer with metastasis to the right ovary, categorized as FIGO 2023 stage IIIA1. This population's unique molecular mechanisms and genetic mutations warrant special consideration when opting for fertility-sparing treatment. We have reviewed and summarized the oncology and pregnancy outcomes among Lynch syndrome and MMR-deficient patients through previous literature. However, no studies have investigated retreatment after recurrence in Lynch syndrome. Our case highlights the potential risks associated with retreatment following relapse. Vigilant monitoring and prompt consideration of surgical intervention are recommended upon disease relapse. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally. It's recognized that the molecular subtype of CRC, characterized by mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H), plays a critical role in determining appropriate treatment strategies. This review examines the current molecular classifications, focusing on dMMR/MSI-H CRC and its subtypes: Lynch syndrome (LS), Lynch-like syndrome (LLS), and sporadic cases. Despite advances in understanding of these genetic backgrounds, clinical trials have not conclusively differentiated the efficacy of immune checkpoint inhibitors among these subgroups. Therefore, while this review details the molecular characteristics and their general implications for treatment and prognosis, it also highlights the limitations and the need for more refined clinical studies to ascertain tailored therapeutic strategies for each subtype. Furthermore, this review summarizes completed and ongoing clinical studies, emphasizing the importance of developing treatments aligned more closely with molecular profiles. By discussing these aspects, the review seeks to provide a comprehensive analysis of oncological characteristics, presenting a detailed understanding of their implications for treatment and prognosis in dMMR/MSI-H CRC. [ABSTRACT FROM AUTHOR]

Introduction: The Implementing Universal Lynch Syndrome Screening (IMPULSS) study explained institutional variation in universal tumor screening (UTS) with the goal of identifying ways to aid organizational decision-makers in implementing and optimizing Lynch syndrome UTS programs. Methods: After applying the Consolidated Framework for Implementation Research (CFIR 1.0) to analyze interviews with 66 stakeholders across 9 healthcare systems to develop a toolkit for implementation, we adapted the International Patient Decision Aid Standards (IPDAS) to assess toolkit potential to aid decision-making consistent with organizational values. We then conducted user testing with two experienced and four non-experienced implementers of UTS to improve the content and functionality of the toolkit and assess its acceptability and appropriateness. Results: Toolkit components were organized to address findings related to CFIR 1.0 constructs of evidence strength and quality, relative advantage, cost, engaging, planning, executing, and reflecting and evaluating. A home page was added to direct users to different sections based on whether they are deciding to implement UTS, planning for implementation, improving an existing UTS program, or considering a different approach to identify patients with Lynch syndrome. Upon initial evaluation, 31 of 64 IPDAS criteria were met by the original toolkit. All users rated the toolkit as acceptable and appropriate for assisting organizational decision-making and identified multiple areas for improvement. Numerous iterative changes were made to the toolkit, resulting in meeting 17 of the previously unmet IPDAS criteria. Conclusion: We demonstrate the rigorous development of a toolkit guided by the CFIR and show how user testing helped improve the toolkit to ensure it is acceptable, appropriate, and meets most IPDAS criteria relevant to organizational values-based decision-making. [ABSTRACT FROM AUTHOR]

The incidence of colorectal carcinoma (CRC) is increasing among individuals younger than 50, and some studies suggest the presence of differences in CRC among old and young individuals regarding clinical and histopathological features. The aim of this study was to compare clinicopathological features, mismatch repair protein status, and expression of certain immunohistochemical stains between young and old groups. The study included 180 cases and found significant histological and immunohistochemical differences between the two groups. CRC in the young tends to be more right-sided and has a higher percentage of dMMR proteins, but less expression of p53 mutations. These features are commoner in Lynch syndrome, and more investigations to study the relationship between young-onset CRC and hereditary syndromes are needed. Young-onset CRC also tends to show higher expression of tumor cell PD-L1, which is an expected finding, as dMMR cases are more likely to be immunogenic. Two other significant differences are the higher percentage of mucinous carcinoma and the higher tumor grade in young-onset CRC. These two features suggest a more advanced disease with possibly worse outcomes; however, there is no difference in disease stage between the two age groups. [ABSTRACT FROM AUTHOR]

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

Lynch syndrome, a hereditary cancer susceptibility syndrome, arises from pathogenic mutations in mismatch repair genes. This syndrome is strongly linked to colorectal and endometrial cancers, as well as an elevated risk for other cancers such as gastric, ovarian, renal pelvis/ureter, and prostate. Notably, Lynch syndrome is rarely associated with cholangiocarcinoma (CCA). In this case study, we present a unique instance of Lynch syndrome-related CCA resulting from a singular MSH6 mutation. Notably, our findings reveal discrepancies between immunohistochemistry (IHC) and microsatellite stability results compared to genetic testing outcomes. This discrepancy underscores the limitations of solely relying on IHC analysis and microsatellite stability testing for the detection of hereditary tumors, emphasizing the crucial role of genetic testing in such cases. This insight enhances our comprehension of the mechanisms involved in cancer development and underscores the significance of thorough analysis integrating immunohistochemistry and genetic testing for diagnosing Lynch syndrome-related cancers. [ABSTRACT FROM AUTHOR]

Women with Lynch Syndrome (LS) have a high risk of colorectal and endometrial cancer. They are recommended regular colonoscopies, and some choose prophylactic hysterectomy. The aim of this study was to determine the impact of hysterectomy on subsequent colonoscopy in these women. A total of 219 LS women >30 years of age registered in the clinical registry at Section for Hereditary Cancer, Oslo University Hospital, were included. Data included hysterectomy status, other abdominal surgeries, and time of surgery. For colonoscopies, data were collected on cecal intubation rate, challenges, and level of pain. Observations in women with and without hysterectomy, and pre- and post-hysterectomy were compared. Cecal intubation rate was lower in women with hysterectomy than in those without (119/126 = 94.4% vs 88/88 = 100%, p = 0.025). Multivariate regression analysis showed an increased risk of challenging colonoscopies (OR,3.58; CI: 1.52–8.43; p = 0.003), and indicated a higher risk of painful colonoscopy (OR, 3.00; 95%CI: 0.99–17.44, p = 0.052), in women with hysterectomy compared with no hysterectomy. Comparing colonoscopy before and after hysterectomy, we also found higher rates of reported challenging colonoscopies post-hysterectomy (6/69 = 8.7% vs 23/69 = 33.3%, p < 0.001). Women with hysterectomy had a lower cecal intubation rate and a higher number of reported challenging colonoscopy than women with no hysterectomy. However, completion rate in the hysterectomy group was still as high as 94.4%. Thus, LS women who consider hysterectomy should not be advised against it. [ABSTRACT FROM AUTHOR]