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PubMed2004

Lynch Syndrome

CLINICAL CHARACTERISTICS: Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, prostate, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous epithelioma, sebaceous carcinomas, and keratoacanthomas), and pancreas. Cancer risks and age of onset vary depending on the associated gene. Several other cancer types have been reported to occur in individuals with Lynch syndrome (e.g., sarcomas, adrenocortical carcinoma). However, the data are not sufficient to demonstrate that the risk of developing these cancers is increased in individuals with Lynch syndrome. DIAGNOSIS/TESTING: The diagnosis of Lynch syndrome is established in a proband with a germline heterozygous pathogenic variant in MLH1, MSH2, MSH6, or PMS2 or a 3' EPCAM deletion identified by molecular genetic testing, or, rarely, constitutional inactivation of the MLH1 promotor due to methylation identified by DNA methylation analysis. MANAGEMENT: Treatment of manifestations: Polypectomy at the time of colonoscopy; referral to advanced endoscopist for lesions requiring advanced resection techniques; surgical resection of polyps when needed; individualized surgical management for colon cancer based on tumor location, stage, Lynch syndrome-associated gene, age, comorbidity, bowel function, anticipated quality of life, and risk of metachronous CRC; mismatch repair (MMR) testing, microsatellite instability (MSI) testing, and multidisciplinary evaluation for rectal cancer prior to treatment; consider immune checkpoint inhibitor therapy for metastatic or unresectable MMR-deficient or MSI-high tumors; other tumors are managed as in the general population. Prevention of primary manifestations: Risk-reducing hysterectomy with bilateral salpingo-oophorectomy can be considered after childbearing is completed. Prophylactic colectomy prior to the development of colon cancer is generally not recommended for individuals known to have Lynch syndrome because screening colonoscopy with polypectomy is an effective preventive measure. Aspirin therapy has been shown to decrease the risk for CRC in individuals with Lynch syndrome. Surveillance: Colonoscopy with removal of precancerous polyps with frequency and initial screening based on gene involved and family history; annual education for females regarding the symptoms of endometrial and ovarian cancers; consider transvaginal ultrasound examination and endometrial biopsy every one to two years beginning at age 30 to 35 years; consider upper endoscopy examination particularly for individuals with a family history of gastric cancer and those of Asian ancestry with frequency and initial screening based on gene involved and family history; biopsies should be evaluated for H pylori infections so that appropriate treatment can be given as needed; consider capsule endoscopy and small bowel enterography for distal small bowel cancers in symptomatic persons; consider urinalysis with urine cytology annually beginning between ages 30 and 35 years; consider pancreatic cancer screening in individuals with a family history of pancreatic cancer; follow population screening guidelines and maintain awareness for signs and symptoms of other cancers. Agents/circumstances to avoid: Obesity, physical inactivity, cigarette smoking, alcohol consumption, and type 2 diabetes may increase CRC risk in individuals with Lynch syndrome. Evaluation of relatives at risk: Molecular genetic testing for the familial Lynch syndrome-related pathogenic variant is recommended for all first-degree relatives (parents, sibs, and offspring) of an affected individual in order to identify as early as possible those who would benefit from surveillance, risk-reducing interventions, and other preventive measures. Testing for constitutional MLH1 hypermethylation is recommended for all first-degree relatives of individuals with Lynch syndrome caused by constitutional MLH1 methylation. GENETIC COUNSELING: Lynch syndrome caused by a heterozygous germline Lynch syndrome-related pathogenic variant (i.e., a pathogenic variant in MLH1, MSH2, MSH6, or PMS2 or a 3' EPCAM deletion) is inherited in an autosomal dominant manner. Individuals with Lynch syndrome caused by constitutional inactivation of MLH1 by methylation typically represent simplex cases, although affected individuals from a few families have been reported with inherited MLH1 promoter methylation. The majority of individuals with a heterozygous germline Lynch syndrome-related pathogenic variant inherited the pathogenic variant from a parent who may or may not have had cancer. Each child of an individual with Lynch syndrome has a 50% chance of inheriting the Lynch syndrome-related pathogenic variant and the related cancer risks. If the reproductive partner of an individual with Lynch syndrome has a germline heterozygous pathogenic variant in the same Lynch syndrome-related gene, offspring are at risk of inheriting biallelic pathogenic variants and having constitutional mismatch repair deficiency. Once a germline Lynch syndrome-related pathogenic variant has been identified in an affected family member, predictive testing for at-risk asymptomatic family members and prenatal/preimplantation genetic testing are possible.

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)↗
PubMed2026

Artificial intelligence-assisted detection and optical differentiation of colorectal lesions in Lynch syndrome surveillance (CADLY2): a multicentre, open-label, randomised controlled superiority trial.

BACKGROUND: Artificial intelligence (AI)-based computer-aided detection (CADe) systems improve adenoma detection in average-risk colorectal cancer screening. Meanwhile, evidence in Lynch syndrome surveillance is sparse and inconsistent. We assessed the effect of CADe on adenoma detection during Lynch syndrome surveillance. Computer-aided optical diagnosis (CADx) performance for optical differentiation of colorectal lesions was evaluated as a secondary aim. METHODS: CADLY2 was an international, multicentre, open-label, randomised controlled superiority trial at nine specialised hereditary cancer surveillance centres in Belgium, Germany, the Netherlands, and Spain. Adults aged 18 years or older with genetically confirmed Lynch syndrome scheduled for surveillance colonoscopy were randomly assigned (1:1) to high-definition white-light (HD-WL) colonoscopy alone or to HD-WL colonoscopy with computer-aided assistance from CAD EYE (Fujifilm, Tokyo, Japan). CAD EYE was used for CADe during withdrawal and for CADx after lesion detection. Randomisation was done centrally through a secure web-based system using Pocock's minimisation algorithm with a stochastic component and was stratified by centre, sex, previous colorectal cancer, underlying pathogenic variant, and interval since previous colonoscopy. Allocation concealment was ensured through the centralised web-based system. Patients were masked to group allocation until the start of withdrawal in procedures with mild sedation, or until completion of the procedure in procedures with propofol-based sedation. Endoscopists were not masked. The primary outcome was adenoma detection rate, defined as the proportion of patients with at least one histopathologically confirmed adenoma, analysed in the full analysis set (defined as all randomly allocated patients with available data for the primary outcome). The diagnostic performance of the CADx system was evaluated as a secondary outcome. The safety analysis set comprised all randomly allocated patients who underwent a study colonoscopy. This study is registered with the German Clinical Trials Register, DRKS00030695, and is completed. FINDINGS: Between May 9, 2023, and Oct 30, 2025, 757 patients were randomly allocated to HD-WL colonoscopy (377 patients) or to AI-assisted colonoscopy (380 patients); 733 patients were included in the full analysis set (369 HD-WL and 364 AI-assisted). The median age was 49 years (IQR 38-59) in the HD-WL group and 50 years (38-59) in the AI-assisted group; 213 (58%) were female and 156 (42%) male in the HD-WL group, and 207 (57%) were female and 157 (43%) male in the AI-assisted group. The adenoma detection rate was 30·9% (114 of 369 patients) with HD-WL versus 33·8% (123 of 364 patients) with CADe assistance (odds ratio 1·14 [95% CI 0·83-1·57], p=0·41). For CADx differentiation of neoplastic versus non-neoplastic lesions in the paired lesion-level analysis, with histopathology as the reference standard and sessile serrated lesions and traditional serrated adenomas classified as non-neoplastic, CADx sensitivity was 85·9% (95% CI 82·0-89·1) and specificity was 91·4% (89·4-93·0). Three adverse events occurred in the AI-assisted group: two mild post-polypectomy bleedings and one serious pulmonary embolism or deep venous thrombosis unrelated to the procedure. No adverse events occurred in the HD-WL group. INTERPRETATION: CADe-assisted colonoscopy did not show the absolute improvement in adenoma detection rate that was assumed in the prespecified sample-size calculation. CADx did not clearly improve lesion differentiation beyond expert optical diagnosis in expert Lynch syndrome surveillance settings. FUNDING: Third-party research funding of the National Center for Hereditary Tumor Syndromes, University Hospital Bonn.

Humans↗
PubMed2026

Lynch syndrome-associated urothelial carcinoma: clinical and molecular findings from a single-institution cohort.

Lynch syndrome-associated urothelial carcinoma (LS-UC) is a rare and undercharacterized clinical entity. While FGFR3 alterations are well described in sporadic urothelial carcinoma, their prevalence and clinical implications in LS-UC remain unclear. We aimed to provide a comprehensive clinical and molecular characterization of LS-UC. We conducted a retrospective single-center study including patients with Lynch syndrome (LS) and histologically confirmed urothelial carcinoma (UC). Clinical, pathological, treatment, and follow-up data were collected. Targeted next-generation sequencing was performed on available tumor samples to assess genomic alterations, with particular attention to FGFR3 mutations. A total of 27 patients with LS-UC were identified, with a predominance of upper urinary tract involvement (70%). Most tumors were diagnosed at an early stage and initially managed with local treatment. During a median follow-up of 92 months, 48% of patients experienced recurrence, with a median time to recurrence of 37 months. Recurrences were predominantly local and were mainly managed with additional surgical or intravesical treatments. No deaths were attributable to UC at last follow-up. Molecular analysis was feasible in 9 cases. FGFR3 mutations were detected in 67% of evaluable samples, with the recurrent p.Arg248Cys hotspot identified in 55% of cases. Additional alterations involved TP53, SWI/SNF complex genes, and PIK3CA, which co-occurred with FGFR3 p.Arg248Cys. No gene fusions were identified. This study expands the limited molecular and clinical evidence on Lynch syndrome-associated urothelial carcinoma. Beyond confirming the recurrent role of FGFR3 (notably p.Arg248Cys), our comprehensive multigene profiling enriches the current genomic knowledge for this rare population. Multi-center collaborative efforts remain essential to aggregate larger datasets and ultimately guide personalized patient management.

Humans↗
PubMed2026

Clinical and genetic characterization of constitutional MLH1 promoter hypermethylation: Implications for Lynch syndrome diagnosis.

PURPOSE: Constitutional MLH1 promoter hypermethylation (CMPH) is a relatively rare cause of Lynch syndrome. While most cases appear to be sporadic, some result from secondary epimutations, mainly caused by germline variants in the MLH1 promoter region. This study describes the clinical phenotype and genetic etiology of CMPH in the largest clinical cohort to date. METHODS: A retrospective analysis was conducted for 422 individuals who underwent clinical CMPH testing. Promoter sequencing was used to identify the underlying variants. Long-read sequencing further characterized MLH1 promoter methylation. RESULTS: CMPH was identified in 15.6% of the study cohort participants. Of these, 63 exhibited clinical features consistent with Lynch syndrome. The most common associated cancers were colorectal cancer, followed by endometrial cancer, breast cancer, and sebaceous neoplasms. Mendelian inheritance of CMPH was observed in 5 families in the study cohort, indicating secondary epimutations. Promoter sequencing identified 8 unique germline variants, including 3 novel variants. Methylation analysis by long-read sequencing revealed mutant allele-specific promoter methylation for these variants. CONCLUSION: Our findings provide the most comprehensive review of the clinical phenotype associated with CMPH and highlight the significant contribution of promoter variants to its etiology. These results underscore the need to include the assessment of constitutional MLH1 promoter methylation for Lynch syndrome diagnosis.

Humans↗
PubMed2026

Uptake of germline testing for Lynch Syndrome in patients with deficient mismatch repair/ microsatellite-high colorectal cancer in the public hospital system in South Australia.

Lynch syndrome (LS) accounts for approximately 4% of colorectal cancer (CRC) cases and arises from pathogenic variants in mismatch repair (MMR) genes. Australian guidelines recommend universal MMR or microsatellite instability (MSI) screening in all CRC patients; however, real-world uptake remains variable. This study evaluated rates of MMR/MSI screening, germline testing, and genetics referrals across two major public hospitals in South Australia. A retrospective review of 1775 patients discussed at colorectal multidisciplinary team meetings in the Royal Adelaide and Queen Elizabeth hospitals between January 2021 and December 2023 was conducted to identify rates of MMR/MSI screening and subsequent referral of eligible patients to genetics. Of the 1129 colorectal cancer cases identified, MMR/MSI testing was performed in 93.2% (1052/1129), with deficiency detected in 12.5% (131/1052). Of these, 37% (49/131) were eligible for genetics referral after exclusion of somatic causes. Among eligible patients, 73.5% (36/49) were referred, and 43% (21/49) underwent germline testing. LS was confirmed in 12 patients (9% of deficient MMR CRC), while 9 patients (6.9%) were classified as having Lynch-like syndrome. Despite high screening rates, gaps remain in genetics referral and testing. Barriers included lack of reflex testing, loss to follow-up, and patient refusal. Targeted system-level interventions and improved genomic education are needed to enhance adherence to guidelines and optimise patient outcomes.

Humans↗
PubMed2025

Uveal Melanoma and the Lynch Syndrome Tumor Spectrum.

IMPORTANCE: To date, no environmental factors and few therapeutic options are known for uveal melanoma (UM), the most common malignant intraocular primary tumor in adults. Identification of new predisposition factors could lead to better monitoring and possibly improved treatments of patients with UM. OBJECTIVE: To identify new genetic alterations predisposing for UM. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study conducted at Institut Curie in Paris, France, among 381 consecutive patients diagnosed with UM between July 2021 and February 2023. UM was diagnosed clinically by ophthalmologists, and a senior pathologist confirmed the diagnosis when tumor or biopsy was available. All participants received genetic counseling and consented to extended genetic testing. A panel of 122 genes predisposing to cancer were analyzed by targeted sequencing on germline DNA from these patients. MAIN OUTCOMES AND MEASURES: Frequency of pathogenic variants (PVs) in genes from a targeted panel, with classification of germline PVs done according to the American College of Medical Genetics and Genomics guidelines and the French Unicancer Genetics Group. RESULTS: A total of 79 PVs were identified in 70 participants (41 female and 29 male; mean [SD] age, 60.6 [15.3] years). Among them, 21 were found in clinically relevant genes, with an enrichment in the mismatch repair (MMR) genes, involved in Lynch syndrome, a frequent predisposition to colon and endometrial cancers. This finding suggested MMR germline PVs could also predispose to UM. One tumor was available from a participant carrying a MLH1 germline PV. The tumor exhibited a monosomy 3 with loss of the wild-type allele of MLH1, located on chromosome 3. Loss of expression of MLH1 was observed by immunohistochemistry, and MMR variant signatures SBS6, ID1, and ID2 were identified from the whole-genome sequencing of this tumor, supporting the possibility that MLH1 contributes to the oncogenesis of this UM. CONCLUSIONS AND RELEVANCE: This prospective germline study on patients with UM provided evidence supporting the notion that MMR germline alterations are enriched among patients with UM and may contribute to oncogenesis of UM, and that UM may therefore be a rare tumor manifestation of Lynch syndrome.

Humans↗
PubMed2024

Cost-effectiveness of population-wide genomic screening for Lynch Syndrome and polygenic risk scores to inform colorectal cancer screening.

PURPOSE: Genomic screening to identify individuals with Lynch Syndrome (LS) and those with a high polygenic risk score (PRS) promises to personalize colorectal cancer (CRC) screening. Understanding its clinical and economic impact is needed to inform screening guidelines and reimbursement policies. METHODS: We developed a Markov model to simulate individuals over a lifetime. We compared LS+PRS genomic screening with standard of care (SOC) for a cohort of US adults at age 30. The Markov model included health states of no CRC, CRC stages (A-D), and death. We estimated incidence, mortality, and discounted economic outcomes of the population under different interventions. RESULTS: Screening 1000 individuals for LS+PRS resulted in 1.36 fewer CRC cases and 0.65 fewer deaths compared with SOC. The incremental cost-effectiveness ratio was $124,415 per quality-adjusted life year; screening had a 69% probability of being cost-effective using a willingness-to-pay threshold of $150,000/quality-adjusted life year . Setting the PRS threshold at the 90th percentile of the LS+PRS screening program to define individuals at high risk was most likely to be cost-effective compared with 95th, 85th, and 80th percentiles. CONCLUSION: Population-level LS+PRS screening is marginally cost-effective, and a threshold of 90th percentile is more likely to be cost-effective than other thresholds.

Humans↗
PubMed2026

Exercise-associated epigenetic remodeling and TCR repertoire dynamics in Lynch syndrome carriers.

Lynch syndrome (LS) carriers are at elevated cancer risk. Emerging evidence suggests that exercise may serve as a non-pharmacologic preventive strategy, yet the epigenetic and immunological mechanisms underlying its protective effects in this population remain unclear. Here, we perform integrative multi-omics profiling of DNA methylation, gene expression, and the T cell receptor (TCR) repertoire in LS carriers undergoing a 52-week aerobic cycling intervention. We identify compartment-specific DNA methylation changes, including innate immune activation in cfDNA and oncogenic pathway repression in tissue. Integrative transcriptomic analysis highlights ISL1 as a key exercise-repressed, epigenetically regulated gene, and identifies FLCN as a colorectal cancer (CRC)-associated methylation target. TCR analysis reveals an exercise-associated increase in systemic repertoire diversity and tissue-specific clonal convergence, thus suggesting antigen-driven recruitment. Collectively, these findings uncover epigenetic and immune remodeling as potential mechanisms of exercise-mediated protection in LS.

Lynch syndrome↗
PubMed2026

Uncertainty and information management for Lynch syndrome in a genomic screening cohort: Connections to clinical engagement.

OBJECTIVE: Lynch syndrome (LS) is a common hereditary cancer predisposition syndrome. This study explores how individuals learning about LS-related cancer risk through a population genomic screening program appraise, reappraise, and manage uncertainty and engage in medical management. METHODS: We recruited participants with an LS result from a population genomic screening study, purposively sampling based on the characteristics of sex, age, LS gene, and family history of cancer. Semi-structured interviews and chart reviews focused on participants' experiences of learning about the LS result and making management decisions. Thematic analysis and heatmapping were used to explore participant characteristics related to uncertainty management and clinical engagement. RESULTS: Seventeen participants completed interviews, describing uncertainty discrepancies or ambivalent appraisals. Most participants who appraised their LS risk as a threat had high clinical engagement. All participants who had lower clinical engagement received misinformation, had little support from clinicians, or had misunderstandings about LS. CONCLUSION: Accurate information from trusted sources is critical to support uncertainty management and subsequent engagement in clinical risk management choices. PRACTICE IMPLICATIONS: Ensuring primary care providers have the information and tools to provide patients with accurate information may support recommended clinical engagement, thereby improving health outcomes for this population.

Clinical Engagement↗
PubMed2026

Heterozygous germline mutations in MSH3, and probably MLH3, act as classical tumour suppressors, leading to excess somatic deletion mutations, signature ID4 and increased colorectal cancer risk.

BACKGROUND: MSH3 and MLH3 are non-canonical DNA mismatch repair genes, involved in repairing insertion-deletion mutations. Colorectal cancer (CRC) and adenomas have been reported in patients with bi-allelic germline MSH3 mutations, and in a very few bi-allelic MLH3 mutation carriers. OBJECTIVES: We hypothesised that germline loss-of-function MSH3 and MLH3 mutations were akin to constitutional mismatch repair deficiency (cMMRd) and Lynch syndrome, such that CRC could result from either bi-allelic germline mutations or heterozygous germline mutations after second hits. DESIGN: About 12 000 CRC and multiple polyp cases and 460&#x2009;000 controls were studied. 2023 patients underwent cancer genome sequencing. RESULTS: One CRC/multiple polyp case had bi-allelic MSH3 mutations and another, bi-allelic MLH3 mutations. MSH3 and MLH3 germline heterozygotes had an increased risk of CRC (2.2-fold, p=6.6&#xd7;10-5&#x2009;and 1.6-fold, p=0.028, respectively), owing to somatic 'second hits' that inactivated the wildtype allele. Single second hits sometimes inactivated both MSH3 and the nearby APC gene. All CRCs with MSH3 or MLH3 deficiency were microsatellite-stable but hypermutant. Deletions of &#x2265;2&#x2009;bp were particularly increased (~12-fold) and signature ID4 was usually present (p<0.0001). CRCs from heterozygotes without 'second hits' showed no hypermutation. CONCLUSION: The phenotypes of bi-allelic MSH3 and MLH3 mutation carriers resemble some patients with cMMRd. Heterozygous germline MSH3 and MLH3 alleles have incomplete penetrance, but increase CRC risk via hypermutation, phenotypically resembling PMS2-mutant Lynch syndrome. A causal association with specific mutations has not previously been reported for ID4 in human tumours. ID4 probably does not have a single aetiology, but can result from MSH3 or MLH3 deficiency.

COLONIC POLYPS↗
PubMed2024

Adult-Onset Cancer Predisposition Syndromes in Children and Adolescents-To Test or not to Test?

With the increasing use of comprehensive germline genetic testing of children and adolescents with cancer, it has become evident that pathogenic variants (PV) in adult-onset cancer predisposition genes (aoCPG) underlying adult-onset cancer predisposition syndromes, such as Lynch syndrome or hereditary breast and ovarian cancer, are enriched and reported in 1% to 2% of children and adolescents with cancer. However, the causal relationship between PVs in aoCPGs and childhood cancer is still under investigation. The best-studied examples include heterozygous PVs in mismatch repair genes associated with Lynch syndrome in children with mismatch repair deficient high-grade glioma, heterozygous PVs in BARD1 in childhood neuroblastoma, and heterozygous PVs in BRCA2 in children with rhabdomyosarcoma. The low penetrance for pediatric cancers is considered to result from a combination of the low baseline risk of cancer in childhood and the report of only a modest relative risk of disease in childhood. Therefore, we do not advise that healthy children empirically be tested for PVs in an aoCPG before adulthood outside a research study. However, germline panel testing is increasingly being performed in children and adolescents with cancer, and exome and genome sequencing may be offered more commonly in this population in the future. The precise pediatric cancer risks and spectra associated with PVs in aoCPGs, underlying cellular mechanisms and somatic mutational signatures, as well as treatment response, second neoplasm risks, and psycho-oncological aspects require further research.

Adolescent↗
PubMed2026

Paired Exome-Based Comprehensive Genomic Profiling and Germline Genetic Testing for Unselected Patients With Colorectal Cancer in a Multicenter Prospective Study.

BACKGROUND AND AIMS: Comprehensive genomic profiling (CGP) for tumors and germline genetic testing (GGT) inform precision therapy and clinical management of patients with colorectal cancer (CRC), and evidence is growing in support of universal paired CGP-GGT patient testing. However, the utility of combining CGP and GGT for early-stage CRC (ESC) and early-onset CRC (EOC) is unclear. METHODS: We performed a prospective, multisite study featuring GGT using an 80+ gene next-generation sequencing platform and exome-based CGP among CRC patients (unselected for age, stage, family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020. RESULTS: A total of 150 CRC patients had GGT and exome-based CGP performed. ESC patients had an enrichment of high microsatellite instability and high tumor mutation burden. High microsatellite instability was also enriched in those with smoking history, and in tumors with mutated BRAF, homologous recombination deficiency, or at least 1 variant in the rat sarcoma virus pathway. Moreover, patients with smoking history were enriched in BRAF and other Tier 1 or 2 variants overall. Sixteen percent of patients harbored a pathogenic germline variant, most frequent being in Lynch syndrome genes. Paired GGT and CGP testing had high rates of clinically significant findings (&#x2248;70%) with the most frequent being high tumor mutation burden status. Pathway and mutational signature analysis revealed frequent CGP mutations in DNA repair and cell cycle pathways. CONCLUSION: These data suggest that universal, combined GGT-CGP increases clinical utility for EOC and ESC patients. This is key for EOC patients who tend to experience poorer outcomes. CGP-GGT expedites germline resolution for tumor mutations in hereditary cancer genes, reducing delays and facilitating identification of relevant therapies, clinical trials, and management recommendations.

Colorectal Cancer↗
PubMed2026

Primary mismatch repair deficient glioma, IDH-wildtype and H3-wildtype: A giant cell tumor with potential for long-term survival occurring at all ages.

BACKGROUND: Replication repair deficiency is associated with increased risk of developing malignant gliomas. The aim of this study was to investigate primary mismatch repair deficient gliomas (PMMRDGs), a group of IDH-wildtype and H3-wildtype gliomas that is enriched among patients with CMMRD and Lynch syndrome. METHODS: We investigated how PMMRDGs differ from other gliomas with respect to DNA methylation profile, genomic alterations, histopathology, and clinical outcomes. RESULTS: PMMRDGs occur in pediatric, adolescents and the elderly, falling in two related methylation clusters and are characterized by a high frequency of replication repair deficiency. Histology showed multinucleated giant cells, and immunohistochemistry demonstrated loss of MMR protein expression. Survival analysis revealed long-term survival in patients with high mutational burden (>50 mut/Mb) and an intact chromosome 9p region, which was validated in an independent reference cohort. CONCLUSIONS: Overall, our findings indicate that PMMRDGs represent a distinct type of IDH-wildtype gliomas with potential for long-term survival likely driven by immune activation.

Humans↗
PubMed2026

Systemic immune activation in hereditary cancer predisposition syndromes: a cross-sectional study.

BACKGROUND: Immune surveillance mechanisms contribute to the elimination of precancerous lesions in hereditary cancer predisposition syndromes (HCPSs). METHODS: By combining single-cell transcriptomics, multiparametric mass cytometry and cytokine profiling of the systemic immune environment in 391 individuals among whom 227 are living with HCPSs we investigated phenotypic alterations in cancer-free individuals with HCPS. RESULTS: A decrease in peripheral B cell abundance and their more differentiated phenotype have been confirmed both in breast cancer patients with germline pathogenic variants in BRCA1 (gpath(BRCA1)) and in patients living with Lynch syndrome (LS). Pre-cancer women with gpath(BRCA1) exhibited an activated phenotype of multiple immune cell lineages, similar to those with manifest disease. In LS, B cell phenotypes exhibited the largest changes in response to cancer eradication, while increased peripheral IL-6 levels was detected even in presymptomatic individuals with LS. CONCLUSIONS: HCPS-specific differences in the phenotype of the systemic immune system might be leveraged in future risk-reducing strategies.

Humans↗
PubMed2026

The work of specialist nurses in the mainstreaming of germline genomic testing in cancer: an investigation.

BACKGROUND: Specialist nurses are increasingly working in the mainstreaming of germline genomic testing in cancer. AIMS: The study aimed to investigate the work of specialist nurses in the mainstreaming of germline genomic testing in cancer, with a focus on Lynch syndrome, and to consider the future of genomics in nursing. METHODS: Semi-structured interviews were conducted with a purposive sample of 12 specialist nurses and three genetic counsellors, and thematic analysis was carried out. FINDINGS: Prominent themes arising from the data were: the capability and capacity of specialty-based clinical nurse specialists, for whom genomics is an added part of their wider role, to deliver genomic testing; and whether these specialty-based nurses or specialist genomic nurses, who work only in genomics, are best placed to deliver genomic testing. CONCLUSION: When planning service provision in the mainstreaming of genetic testing, the capacity and capability of specialty-based clinical nurse specialists should be considered alongside the possible need for specialist genomic nurses.

Humans↗
PubMed2026

Incidental MSH6 Germline Pathogenic Variant Identified through Tumor-only Comprehensive Genomic Profiling in a Patient with Small Cell Lung Cancer.

A 55-year-old woman was diagnosed with limited-disease small cell lung cancer (LD-SCLC) after incidental detection of a lung nodule. First-line chemotherapy achieved partial response, but recurrence occurred after one year. During second-line therapy, comprehensive genomic profiling (CGP) revealed a germline MSH6 frameshift mutation. Although lung tumor immunohistochemistry showed the retained expression of mismatch repair (MMR) protein, a prior colon cancer specimen showed the loss of MSH6 expression and deficient MMR expression. Germline genetic testing confirmed Lynch syndrome. Cascade testing identified the same mutation in her daughter. This case outlines a tumor-to-germline workflow with testing of at-risk relatives and highlights the importance of prudent interpretation of presumed germline variants.

Humans↗
PubMed2026

Genetic Ancestry and Colorectal Cancer in the All of Us Dataset.

IMPORTANCE: Genetic ancestry may complement biological, behavioral, and clinical factors in understanding colorectal cancer (CRC) disparities; yet, ancestry-informed analyses in CRC remain limited. OBJECTIVE: To characterize associations of genetic ancestry with CRC burden, age at diagnosis, and age-specific risk, and to develop a multiethnic CRC risk-prediction model. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used All of Us data from July 1986 to October 2023, with follow-up through last visit or death (median [IQR], 133.1 [57.1-186.5] months); analyses were conducted from February to June 2026. All of Us is a US research cohort with linked electronic health record (EHR) and short-read whole-genome sequencing (srWGS) data. All of Us Research Program participants with srWGS and linked EHR data were included, except those with hereditary polyposis or Lynch syndrome. EXPOSURES: Genetically inferred ancestry categories and principal components. MAIN OUTCOMES AND MEASURES: Any CRC was the primary outcome. Associations were evaluated using Fisher exact tests, cumulative incidence functions with Gray tests, cause-specific and Fine-Gray subdistribution hazard models, and pooled multivariable logistic regression. Prediction models used penalized least absolute shrinkage and selection operator and extreme gradient boosting (XGBoost). RESULTS: Among 316&#x202f;624 participants (median [IQR] age, 56.3 [40.2-68.2] years; 172&#x202f;327 [54.4%] of European ancestry; 191&#x202f;705 female [61.2%]; 121&#x202f;585 male [38.8%]), 2914 (0.9%) developed CRC. European ancestry was associated with higher odds of CRC vs all other ancestries combined (odds ratio, 1.50; 95% CI, 1.39-1.62). The median age at CRC diagnosis was older in European (63.4 [53.9-71.2] years) than in American admixed-Latino, African, East Asian, and Other ancestry groups. In cause-specific hazard models on the attained-age scale, American admixed-Latino (hazard ratio, 1.30; 95% CI, 1.14-1.47) and East Asian (hazard ratio, 1.43; 95% CI, 1.06-1.94) ancestry had higher age-specific CRC hazard than European ancestry, with consistent findings on the subdistribution scale accounting for competing death. The multiethnic XGBoost model performed best (receiver operating characteristic area under the curve, 0.898; 95% CI, 0.882-0.912; precision-recall area under the curve, 0.338; 95% CI, 0.296-0.379) and was well calibrated. CONCLUSIONS AND RELEVANCE: In this cohort study, genetic ancestry was associated with meaningful differences in CRC burden and age-specific risk. These findings suggest that a multiethnic XGBoost model may complement CRC screening as a risk-enrichment tool.

Aged↗