Lynch Syndrome Research Articles

Lynch syndrome – a case report and literature review

Lynch syndrome – a case report and literature review

Addressing sexual health in the care of patients with hereditary breast and ovarian cancer and Lynch syndrome: Patient perspectives

Addressing sexual health in the care of patients with hereditary breast and ovarian cancer and Lynch syndrome: Patient perspectives

Imaging of Upper Tract Urothelial Carcinoma.

Upper tract urothelial carcinoma (UTUC) originates in the renal pelvis or ureters and typically affects elderly patients, with its incidence increasing over the past few decades. UTUC is a distinct clinical entity with more aggressive clinical behavior than that of lower tract urothelial carcinoma. Due to the significant challenge of acquiring an adequate tissue sample for biopsy, comprehensive risk stratification is required for treatment planning, including radical nephroureterectomy and kidney-sparing management. Imaging plays an important integrated role in risk assessment along with endoscopy and pathologic examination. Lifelong surveillance is required after treatment due to the high incidence of recurrent and metachronous tumors. Lynch syndrome is a frequently unrecognized genetic disorder associated with UTUC that warrants specific attention in patient management. UTUC may manifest with diverse imaging findings, including filling defects, wall thickening, and mass-forming lesions. CT urography is the preferred modality for diagnosis and staging or restaging of UTUC, with numerous technical variations. Efforts have been made to optimize image quality and radiation exposure. Due to its poor sensitivity for small lesions, use of MR urography is limited to special clinical scenarios (eg, when patients have contraindications to iodinated contrast agents). Fluorine 18 fluorodeoxyglucose PET helps to detect metastatic lesions. Image-guided biopsy may be considered for uncertain lesions. Radiologists need to be familiar with the imaging findings and their differential diagnoses. ©RSNA, 2024 Supplemental material is available for this article.

One-stop Colon and Endometrial screening (OnCE): A prospective study of combined cancer screening for Lynch syndrome

One-stop Colon and Endometrial screening (OnCE): A prospective study of combined cancer screening for Lynch syndrome

Upfront tumor next-generation sequencing for diagnosis of Lynch syndrome in endometrial cancer

Upfront tumor next-generation sequencing for diagnosis of Lynch syndrome in endometrial cancer

Characteristics of Cancer in Subjects Carrying Lynch Syndrome-Associated Gene Variants in Taiwanese Population: A Hospital-Based Study in Taiwan

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.

Elucidating the roles of SOD3 correlated genes and reactive oxygen species in rare human diseases using a bioinformatic-ontology approach.

Superoxide Dismutase 3 (SOD3) scavenges extracellular superoxide giving a hydrogen peroxide metabolite. Both Reactive Oxygen Species diffuse through aquaporins causing oxidative stress and biomolecular damage. SOD3 is differentially expressed in cancer and this research utilises Gene Expression Omnibus data series GSE2109 with 2,158 cancer samples. Genome-wide expression correlation analysis was conducted with SOD3 as the seed gene. Categorical SOD3 Pearson Correlation gene lists incrementing in correlation strength by 0.01 from ρ≥|0.34| to ρ≥|0.41| were extracted from the data. Positively and negatively SOD3 correlated genes were separated for each list and checked for significance against disease overlapping genes in the ClinVar and Orphanet databases via Enrichr. Disease causal genes were added to the relevant gene list and checked against Gene Ontology, Phenotype Ontology, and Elsevier Pathways via Enrichr before the significant ontologies containing causal and non-overlapping genes were reviewed with a literature search for possible disease and oxidative stress associations. 12 significant individually discriminated disorders were identified: Autosomal Dominant Cutis Laxa (p = 6.05x10-7), Renal Tubular Dysgenesis of Genetic Origin (p = 6.05x10-7), Lethal Arteriopathy Syndrome due to Fibulin-4 Deficiency (p = 6.54x10-9), EMILIN-1-related Connective Tissue Disease (p = 6.54x10-9), Holt-Oram Syndrome (p = 7.72x10-10), Multisystemic Smooth Muscle Dysfunction Syndrome (p = 9.95x10-15), Distal Hereditary Motor Neuropathy type 2 (p = 4.48x10-7), Congenital Glaucoma (p = 5.24x210-9), Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (p = 3.77x10-16), Classical-like Ehlers-Danlos Syndrome type 1 (p = 3.77x10-16), Retinoblastoma (p = 1.9x10-8), and Lynch Syndrome (p = 5.04x10-9). 35 novel (21 unique) genes across 12 disorders were identified: ADNP, AOC3, CDC42EP2, CHTOP, CNN1, DES, FOXF1, FXR1, HLTF, KCNMB1, MTF2, MYH11, PLN, PNPLA2, REST, SGCA, SORBS1, SYNPO2, TAGLN, WAPL, and ZMYM4. These genes are proffered as potential biomarkers or therapeutic targets for the corresponding rare diseases discussed.

Lynch syndrome: Diagnosis based on immunomicroscopy and family history of a young patient with colorectal carcinoma

Lynch syndrome is a genetic condition that alters the production of DNA compatibility genes, which are responsible for monitoring the process of new cell formation in the body. Once compromised, this watchdog system fails and allows abnormal cells to develop, which sometimes initiates a process of malignization, resulting in the appearance of malignant tumours, especially in the colon and endometrial tissue. This text reports the clinical case of a young patient who was diagnosed with colorectal carcinoma and, after extensive outpatient and anatomopathological research, associated with a positive family history, was diagnosed with Lynch syndrome.

Diagnostic Performance of Faecal Immunochemical Testing (FIT) in Patients with Lynch Syndrome Scheduled for Colonoscopic Surveillance

Background and Aims: Lynch syndrome (LS) carries a substantial lifetime risk of colorectal cancer which is currently mitigated by biennial colonoscopy surveillance. Paramount to the surveillance programme is the removal of adenomas before malignant transformation but there is an associated service burden and morbidity of repeated endoscopy. We investigated if faecal immunochemical testing (FIT) for faecal haemoglobin has the diagnostic performance to replace colonoscopy. Methods: In this retrospective cohort study, patients due to undergo planned surveillance for LS between November 2020 and April 2022 were sent two FIT kits prior to colonoscopy. Test diagnostic performance of colorectal cancer (CRC), advanced and non-advanced adenoma detection was calculated for single and double FIT strategies. A faecal-Hb of 10 µg Hb/g was considered positive. Results: In total, 78 patients, with 45 (57.7%) female, median age 52 years (IQR 41–63), completed at least one FIT and colonoscopy. The median time from FIT to colonoscopy was 47 days. A single FIT was positive in 7/30 cases of adenoma (2/3 advanced, 5/27 non-advanced). A total of 64 (82.1% of FIT1T returners) completed a second FIT. Using the greatest of the two FITs (FIT2TMAX) 8/26 (2/3 advanced, 4/23 non-advanced), patients with adenomas were identified. There were no cases of CRC. The sensitivity for adenoma detection was 23.3% and 23.1%, respectively. Conclusions: In patients with LS awaiting colonoscopy, FIT has a low sensitivity for detecting adenomas and advanced adenomas. This is not improved by the addition of a second FIT test.

Upper tract urothelial carcinoma: epidemiology, presentation, and high-risk endemic populations.

Upper tract urothelial carcinoma (UTUC) only accounts for 5-10% of all urothelial cancers but these patients present with high stage disease and 2 out of 3 patients have evidence of muscle-invasion at time of diagnosis. Furthermore, 10% of UTUC patients have associated Lynch syndrome and therefore diagnosis of UTUC should prompt timely evaluation and familial counseling. The purpose of this review is to outline the current evidence on the epidemiology, presentation, and high-risk endemic populations of UTUC through review of contemporary publications occurring over the preceding 18 months. Both the American Urological Association (AUA) and European Association of Urology (EAU) have published updated guidelines within the last 18 months for the management of UTUC. Of note, the updated guidelines give special consideration to identifying patients with risk factors for Lynch syndrome and recommend universal histologic testing for those with high probability of having Lynch syndrome cancers as well as referral for genetic counseling and germline testing. UTUC is an overall rare malignancy but tends to present with advanced stage and muscle-invasion. A proper understanding of the epidemiology, presentation, and high-risk endemic populations is necessary to develop preventive and interventional strategies.

"Should I let them know I have this?": Multifaceted genetic discrimination and limited awareness of legal protections amongst individuals with hereditary cancer syndromes.

Hereditary cancer syndromes (HCS), such as Hereditary Breast and Ovarian Cancer Syndrome (HBOC) and Lynch Syndrome (LS), represent approximately 10% of all cancers. Along with medical burdens associated with the genetic risk of developing cancer, many individuals face stigma and discrimination. Genetic discrimination refers to negative treatment, unfair profiling or harm based on genetic characteristics, manifesting as "felt" stigma (ostracization without discriminatory acts) or "enacted" stigma (experiencing discriminatory acts). This study aimed to describe concerns and experiences of genetic discrimination faced by individuals with HCS. Semi-structured qualitative interviews were conducted with individuals with molecularly-confirmed HCS residing in Ontario, British Columbia and Newfoundland & Labrador, Canada. Purposive sampling was applied to obtain a diverse sample across demographic characteristics. Study procedures were informed by interpretive description; data were thematically analyzed using constant comparison. 73 participants were interviewed (39 HBOC, 34 LS; 51 females, 21 males, 1 gender-diverse; aged 25-80). Participants described multifaceted forms of genetic discrimination across healthcare, insurance, employment, and family/social settings. Participants valued the Genetic Non-Discrimination Act's protective intent, but demonstrated limited knowledge of its existence and provisions. Limited knowledge, coupled with policy constraints in non-legislatable settings and third-party use of proxy genetic information, hindered participants' ability to whistleblow or seek recourse. Our results illuminate a disconnect between intended protective effects of genetic non-discrimination legislation and ongoing genetic discrimination faced by individuals with hereditary conditions. To better support these individuals, this study encourages public outreach and knowledge translation efforts to increase awareness of non-discrimination legal protections.

Intraoperative rapid immunohistochemistry of microsatellite instability using non-contact alternating current electric field mixing.

Tumors caused by failure of the DNA-mismatch repair system generally show microsatellite instability (MSI). High-frequency MSI cancers have been shown to be susceptible to immuno-oncology therapies. The aim of this study was to evaluate the clinical reliability of a rapid immunohistochemistry (IHC) technique for intraoperatively assessing molecular status through detection of tumoral deficiencies in the expression of mismatch repair proteins (dMMR; MLH1, MSH2, MSH6, and PMS2). The rapid IHC method uses non-contact alternating current (AC) mixing to achieve more rapid/stable staining within a minimum of 13min during surgery. Sixteen formalin-fixed paraffin-embedded (FFPE) tumor samples from 3 dMMR patients with Lynch syndrome and 6 FFPE samples from 6 dMMR-cancer patients were collected to establish an IHC protocol for MMR proteins. Next, 26 surgical patients treated and whose MSI status was determined using PCR-based tests were retrospectively analyzed. The concordance of dMMR diagnoses for thoracic tumors between the conventional (frozen section (FS)- and FFPE-IHCs) and rapid AC-mixing IHC with FSs were compared. A rapid IHC protocol using primary antibodies against four MMR proteins (mixed 5-10min) was established (entire process within 40min). The concordance rate for MMR-IHC between the conventional and rapid IHC was 100%. dMMR diagnoses including an MSI-high pulmonary sarcoma patient entirely matched between FS- and FFPE-IHC. Rapid MMR-IHC could potentially serve as a clinical tool for intraoperative determination of tumor MSI/dMMR status. AC-mixing technology will contribute to improving pathological diagnostic capability through the development of an original and innovative rapid IHC.

Frameshift mutation spectra overlap between constitutional mismatch repair deficiency tumors and Lynch syndrome tumors.

Frameshift mutation spectra overlap between constitutional mismatch repair deficiency tumors and Lynch syndrome tumors.

Lynch syndrome diagnostic testing pathways in endometrial cancers: a nationwide English registry-based study

BackgroundFor female patients with Lynch syndrome (LS), endometrial cancer (EC) is often their first cancer diagnosis. A testing pathway of somatic tumour testing triage followed by germline mismatch repair (MMR)...

The Role of Tumor Biomarkers in Tailoring the Approach to Advanced Ovarian Cancer

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.

Faecal Volatile Organic Compounds to Detect Colorectal Neoplasia in Lynch Syndrome-A Prospective Longitudinal Multicentre Study.

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.

The Current State-or Lack Thereof-of Screening and Prevention for Gynecologic Malignancies for Patients With Lynch Syndrome.

Lynch syndrome (LS) is an autosomal dominant genetic disorder that results in an increased risk of ovarian and endometrial cancers. The aim of this paper was to explore the management of this risk through screening and prevention. Published materials and evidence were explored and summarized. This paper demonstrated that while there has been increased awareness and advances in the identification and diagnosis of patients with LS, recommendations for screening and prevention remain less evidence-based. In decisions of management of patients with LS, a shared decision-making model should be used considering individual patient goals.

Abstract B058: Nous-209 off-the-shelf vaccine targets neoantigens mutations well represented both in primary and metachronous incident CRCs from Lynch syndrome patients

Abstract Lynch Syndrome (LS) is the most common hereditary cancer syndrome, caused by germline mutations in one of the four DNA mismatch repair (MMR) genes. LS patients have a high risk to develop microsatellite instable (MSI) colorectal cancers. Tumors developed by LS carriers display high levels of microsatellite instability, which leads to the accumulation of large numbers of mutations, among which frameshift insertion/deletions (indels) within microsatellite (MS) loci are very common and shared among different tumors. When indels occur in coding genes they give rise to frameshift peptides (FSPs) with a very high potential to act as safe and potent neoantigens for a vaccine. NOUS-209 is a genetic vaccine encoding 209 neoantigens, shared across sporadic and hereditary MSI tumors, developed for interception and treatment of MSI tumors. Phase 1b trial evaluating NOUS-209 monotherapy in healthy LS carriers showed the induction of a potent and broad immune response. Here, we characterize indels encoding FSPs in a cohort of 50 incident MSI CRC from LS patients detected during routine screening (38 primary tumors; 22 metachronous tumors) by whole Exomeseq NGS. Overall, primary and metachronous tumors have a similar number of indels in coding genes. The repertoire of detected indels is only partially shared (27%) between the two categories of tumors. The 209 indels selected for the NOUS-209 vaccine are instead highly shared (95%) between primary and metachronous tumors. Moreover, the analysis of 8 patients for which both the primary and the metachronous tumor were available confirmed the presence of the 209 mutations both in the first and the second tumor. Therefore, the NOUS 209 vaccine has the potential to prevent tumor occurrence both in previvors and survivors by inducing a broad T cell immune response against recurrent FSP. Citation Format: Lorenzo De Marco, Elisa Micarelli, Joni Panula, Anna Morena D'Alise, Guido Leoni, Kalle E. Hokkanen, Eija Hämäläinen, Jukka-Pekka Mecklin, Elisa Scarselli, Toni Seppälä. Nous-209 off-the-shelf vaccine targets neoantigens mutations well represented both in primary and metachronous incident CRCs from Lynch syndrome patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B058.

Abstract PR-05: Nous-209 off-the-shelf vaccine targets neoantigens mutations well represented both in primary and metachronous incident CRCs from Lynch syndrome patients

Abstract PR-05: Nous-209 off-the-shelf vaccine targets neoantigens mutations well represented both in primary and metachronous incident CRCs from Lynch syndrome patients

Communicatively constructing resilience: Exploring family resilience in the experience of hereditary cancer

AbstractObjectiveThe goal was to explore how families communicate to cope with hereditary cancer conditions and identify factors that may enhance resilience and recommended decision‐making.BackgroundFamilies 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.MethodWe 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.ResultsParticipants 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.ConclusionFindings 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.ImplicationsFindings demonstrate areas for intervention to support familial resilience.