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Results for “DNA MICROSATELLITE INSTABILITY”

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PubMed2026

Microsatellite instability in penile cancer: comparative analysis of primary tumors and metastases.

BACKGROUND: Penile cancer (PeCA) presents high morbidity and mortality and is more prevalent in underdeveloped countries. The presence of nodal metastasis at diagnosis or as early recurrence carries a worse prognosis, making it important to determine whether clinically relevant biomarkers are maintained between primary tumors and corresponding lymph node metastases. We aim to describe the presence of DNA microsatellite instability (MSI) in primary PeCA tumors and locoregional lymph nodes affected by metastatic cells, as well as to assess HPV status through p16 expression. METHODS: A total of 116 patients were comparatively evaluated between the primary tumor and lymph node metastases. The evaluation of p16 and mismatch repair proteins was done by immunohistochemistry, and MSI status was assessed using a hexa-plex marker by polymerase chain reaction, followed by fragment analysis. RESULTS: All patients underwent a standard lymphadenectomy (inguinal or pelvic), with a pN0 frequency of 33.6%. MSI-H was found in three patients (2.6%), with correspondence between the presence of the biomarker in the primary tumors and the lymph node metastases. A second validation was performed using IHC for MMR, with MLH1/PMS2 loss in MSI-H cases. 22.8% of patients expressed p16 by immunohistochemistry. p16 positivity was associated with a 55% reduction in the risk of death. All MSI-H patients were p16 positive. CONCLUSION: MSI-H occurs in 2,6% of the sample and is associated predominantly with MLH1/PMS2 loss and p16 positivity. Together, these findings suggest potential interactions between HPV- associated carcinogenesis and genomic instability. Further prospective, biomarker-driven trials are warranted to define their prognostic and therapeutic relevance in PeCA.

HPV↗

PubMed2026

Novel immunotherapeutic strategies for colorectal cancer treatment: Advances, challenges, and future directions.

Immunotherapy has reshaped the treatment landscape of colorectal cancer (CRC), with the clearest and most durable benefit established in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) disease. However, framing CRC immunotherapy simply as "MSI-H responsive versus microsatellite stable (MSS) resistant" is no longer sufficient. Recent studies indicate that a subset of proficient mismatch repair (pMMR) colon cancers, particularly in the neoadjuvant setting, can mount clinically meaningful responses to immune checkpoint blockade, suggesting that disease stage, local immune organization, and treatment timing critically influence immunotherapy sensitivity. In parallel, emerging evidence has expanded the relevant immune landscape beyond the tumor bed itself, showing that spatially organized stromal and adipose niches can actively divert tumor-reactive lymphocytes and promote immune escape. These advances shift the central challenge in CRC immunotherapy from simply identifying new agents to defining when and in whom immune resistance is reversible, and which biological bottlenecks-such as vascular dysfunction, myeloid suppression, and spatial immune exclusion-must be overcome. In this context, alternative checkpoint inhibitors, bispecific antibodies, cellular therapies, vaccines, nanotechnology-enabled platforms, and microbiome-targeted approaches remain important, but their translational maturity and evidentiary support differ substantially. Biomarker development is likewise evolving from static genomic classification toward dynamic and mechanism-informed stratification incorporating circulating tumor DNA (ctDNA), chromosomal instability, immune architecture, and treatment-induced response trajectories. This review synthesizes recent advances in CRC immunotherapy while emphasizing evidence hierarchy, biomarker-guided patient selection, and the mechanistic basis of combination strategies. We argue that the next phase of CRC immunotherapy will depend less on the indiscriminate addition of novel agents and more on the rational deployment of immunotherapy across molecularly, spatially, and temporally defined disease states.

Humans↗

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 460 000 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=6.6×10-5 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 ≥2 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↗

PubMed2026

Integrated pan-cancer profiling highlights OSR2 as a prognostic indicator and immune-associated biomarker.

BACKGROUND: Odd-skipped-related 2 (OSR2), encoded by the OSR2 gene, has been reported to function as a checkpoint associated with CD8⁺ T-cell exhaustion in the tumor microenvironment of solid malignancies, suggesting its potential as a therapeutic target to improve immunotherapeutic responses. Nevertheless, the molecular and clinical significance of OSR2 across diverse cancer types has not yet been systematically investigated, and its pan-cancer expression profile, prognostic implications, and associations with tumor immunity remain to be fully elucidated. METHODS: In this study, we integrated datasets from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) portal, and the Human Protein Atlas to construct a systematic pan-cancer profile of OSR2. The prognostic value of OSR2 was comprehensively assessed using univariate Cox regression, survival analysis, and receiver operating characteristic (ROC) curve analysis. In addition, we performed an in-depth analysis of the relationships between OSR2 and multiple molecular and immunological features, including copy number variation (CNV), DNA methylation, tumor mutational burden (TMB), microsatellite instability (MSI), immune-related gene expression, immune cell infiltration, and drug sensitivity, with the aim of exploring its potential immunological associations with the tumor microenvironment. RESULTS: OSR2 expression was significantly upregulated or downregulated in the majority of tumor tissues relative to normal counterparts and exhibited distinct cancer-type-specific patterns across clinical stages. CNV alterations and aberrant DNA methylation were closely associated with abnormal OSR2 mRNA expression in multiple cancers. Prognostic analyses indicated that OSR2 expression was significantly associated with overall survival, disease-specific survival, disease-free interval, and progression-free interval across multiple cancer types, showing either risk-associated or protective associations in a tumor-context-dependent manner. Furthermore, OSR2 expression showed strong associations with immune cell infiltration, particularly T-cell subsets, and was significantly correlated with the expression of multiple immune checkpoint-related genes across diverse malignancies. OSR2 expression was also closely associated with TMB, MSI, and sensitivity to multiple anticancer agents. CONCLUSION: Taken together, these findings suggest that OSR2 is associated with prognosis and immune-related features across multiple cancer types. OSR2 may be linked to features of the tumor immune microenvironment through its relationships with immune cell infiltration, immune checkpoint gene expression, and genomic instability, and thus may serve as a candidate biomarker for further investigation in cancer immunotherapy.

CD8⁺ T-cell↗

PubMed2025

The protective role of γδ T cells in endometrial cancer.

Γδ T cells are non-conventional T cells that are not MHC restricted and have T cell receptors (TCRs) that are stimulated by phosphoantigens, stress-induced proteins, lipids, and other antigens. These cells are prognostic across cancer types in The Cancer Genome Atlas (TCGA) but have not been well studied in endometrial cancer, which has a rising incidence and mortality rate. Endometrial cancer patients have variable responses to checkpoint inhibitors which are related to the molecular subtype of their cancer. As such, there is a pressing need to understand the immune microenvironment in endometrial cancer. This study addresses this gap in knowledge by investigating γδ T cell repertoires and transcriptomes in this disease site. γδ T cell repertoires were obtained for 543 endometrial cancer patients within the TCGA and from 5 endometrial cancer patients in the single cell dataset SRP349751 using TRUST4. GLIPH2 was used to identify TCRs predicted to bind the same antigen. Transcriptomes were investigated in the single cell dataset. DNA Polymerase Epsilon Exonuclease (POLE) and Microsatellite Instability High (MSI-H) endometrial cancer subtypes had the most γδ T cell infiltration. Vδ1 and Vδ3 γδ T cell infiltration was prognostic independent of stage and molecular subtype. GLIPH2 analysis revealed TCRδ motifs for TDK, YTD, and GEL were public across all four molecular subtypes and were present in the single cell data set. Vδ1 γδ T cell transcriptomes were associated with cytotoxicity and recent TCR stimulation. These data support further investigation of immunotherapies targeting γδ T cells in endometrial cancer.

Humans↗

PubMed2026

Identification and validation of a previously missed mutational signature in colorectal cancer.

Mutational signature analysis has enhanced our understanding of mutagenic processes. In a recent study, we analyzed 802 microsatellite-stable colorectal cancers (CRC) and identified a de novo signature, SBS_D, which was decomposed into SBS18. Here, we re-evaluate this decomposition and provide evidence that SBS_D represents a distinct mutational process from SBS18. Through an analysis of 2,616 CRCs across three independent cohorts, we demonstrate that SBS_D is consistently present, suggesting this signature may have been previously overlooked. We illustrate that the pattern of SBS_D better aligns with signatures associated with deficiencies in DNA repair, despite evidence that SBS_D is not driven by canonical defects in these DNA repair pathways. Overall, this study identifies a previously unrecognized mutational signature in DNA repair-proficient CRC and proposes that its etiology may be linked to DNA repair infidelity emerging late in tumor development. SBS_D has been submitted to the COSMIC database and provisionally designated as SBS111.

Colorectal Neoplasms↗

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↗

PubMed2026

DHX9 Inhibition Enhances Paclitaxel Sensitivity by Inducing Mitotic Failure in Ovarian and Endometrial Cancers.

Recurrent high-grade serous ovarian carcinoma (HGSOC) and endometrial cancer remain major clinical challenges with limited effective treatment options. DExH-box helicase 9 (DHX9), a DNA/RNA helicase essential for genomic stability, has not yet been explored as a therapeutic target in gynecologic cancers. In this study, we show that a selective DHX9 inhibitor (DHX9i) suppresses proliferation in a subset of HGSOC and endometrial cancer cell lines by inducing DNA damage, chromosomal instability, and mitotic failure. This effect was independent of microsatellite instability status and prior resistance to platinum or PARP inhibitors. Genomic analysis indicated that DHX9i resistance was unlikely to be driven by single-gene mutations but was instead associated with copy-number alterations in mitotic spindle and microtubule-regulating genes in both HGSOC and endometrial cancer. Transcriptomic profiling further revealed consistent alterations in microtubule- and spindle-associated pathways in DHX9i-resistant models following DHX9i treatment. Mechanistically, DHX9i induced mitotic defects in DHX9i-sensitive models, whereas resistant lines maintained mitotic integrity. Given the convergence of resistance-associated features on microtubule-related pathways, we combined DHX9i with the microtubule-stabilizing agent paclitaxel to enhance mitotic stress. This combination triggered mitotic disruption and enhanced cytotoxicity in DHX9i-resistant cells. In vivo, the combination led to sustained tumor regression and prolonged survival in both DHX9i-sensitive and DHX9i-resistant models without notable toxicity. Overall, our findings define genomic, transcriptomic, and phenotypic characteristics associated with differential responses to DHX9i and support the clinical evaluation of the DHX9i-paclitaxel combination as a therapeutic strategy in recurrent gynecologic cancers.

Female↗

PubMed2025

DNA damage repair gene alterations influence the tumor immune microenvironment in advanced non-small cell lung cancer.

PURPOSE: DNA damage response and repair (DDR) gene alterations contribute to genomic instability and increased tumor immunogenicity, yet their clinical significance in non-small cell lung cancer (NSCLC) remains unclear. Using a large real-world dataset, we evaluated the prevalence of DDR alterations and their relation to the tumor immune microenvironment in metastatic NSCLC. EXPERIMENTAL DESIGN: We retrospectively analyzed real-world data from patients with metastatic NSCLC using the Tempus AI database. Tumors were sequenced with Tempus xT DNA and xR RNA assays and classified based on the presence (DDRmt) or absence (DDRwt) of a pathogenic somatic alteration or copy number deletion in a DDR pathway gene. Associations between DDR alterations and immune cell infiltration, PD-L1 immunohistochemistry, tumor mutational burden (TMB), and microsatellite instability (MSI-H) were examined. RESULTS: Among 14,127 patients (median age = 67, 49% female), 5,276 (37%) were DDRmt. There was a higher prevalence of current/former smokers in the DDRmt group (86% vs. 82%; p<0.001). DDRmt tumors were more likely to have higher levels of TMB (median: 5.4 vs. 4.6; p<0.001), MSI-H (1.1 % vs. <0.1 %; p<0.001), and infiltrating CD8+ T cells (p=0.003) compared to DDRwt tumors. A lower frequency of macrophages (p<0.001) were observed among DDRmt compared with DDRwt tumors with no difference in PDL1 positivity. CONCLUSIONS: Among patients with metastatic NSCLC, 37% present with DDRmt tumors characterized by higher TMB, frequency of MSI-H, and changes in immune cell infiltrates. These findings provide insight into the immunogenic landscape of DDR-altered NSCLC and may inform biomarker selection and therapeutic strategies.

Humans↗

PubMed2026

Integrating germline and tumor sequencing to improve hereditary cancer diagnosis and care.

A subset of cancers arises due to inherited germline pathogenic variants in specific genes, known as hereditary cancers. These genes typically include tumor suppressors, DNA repair and replication fidelity genes, and occasionally oncogenes. In most hereditary cancer syndromes, Knudson's two-hit hypothesis applies, where a second somatic event inactivates the remaining allele of a tumor suppressor or DNA repair gene, leading to tumorigenesis. Advancements in genome-wide sequencing have significantly enhanced our understanding of the mutational processes involved in hereditary cancers. In particular, the assessment of microsatellite instability (MSI), tumor mutational burden (TMB), and mutational signatures has emerged as a powerful tool for the identification of hereditary tumors. Tumors with high or ultra-high TMB often reflect underlying DNA repair deficiencies, while specific mutational signatures can pinpoint the defective pathway. These tumor mutational features are especially informative in syndromes involving mismatch repair (MMR), homologous recombination (HR), base excision repair (BER), nucleotide excision repair (NER), and polymerase proofreading. Moreover, tumor sequencing aids in the interpretation of germline variants, identifies somatic mosaicism, and helps differentiate hereditary from sporadic cancers. Additionally, tumor molecular features associated with DNA repair deficiencies offer insights into personalized therapies, such as the use of PARP inhibitors for BRCA1/2-deficient tumors and immune checkpoint inhibitors for MMR- and polymerase proofreading-deficient cancers. Tumor profiling also uncovers actionable mutations in oncogenes like RET and VHL, which can be targeted with specific therapies. This review explores the integration of tumor molecular features with germline genetic data to refine diagnosis, risk assessment, and therapeutic strategies in hereditary cancer.

Humans↗

PubMed2026

Targeting DNA mismatch repair in Huntington's disease.

Somatic expansion of the HTT CAG repeat is a key feature of Huntington's disease (HD) pathogenesis. Mismatch repair (MMR) enzymes drive this process through erroneous DNA repair, with variants in MMR genes modifying the onset and progression of disease features. Cell-type-specific CAG repeat sizing recently confirmed that elevated somatic expansion underlies the selective vulnerability of HD medium spiny neurons, with expansion beyond certain CAG thresholds associated with distinct stages of cellular pathogenesis. In this review, we synthesise insights from post-mortem brain tissue, cell systems, and mouse models, detailing key CAG repeat-length-dependent changes. In addition, we critically evaluate the MMR proteins MSH3, MLH3, and PMS1 as therapeutic targets for slowing somatic expansion and outline key safety considerations for emerging MMR-modulating approaches.

Huntington Disease↗

PubMed2026

Bayesian Integration of Tumor Mutational Signatures and Somatic Features Refines Pathogenicity Assessment of Germline Mismatch Repair Variants.

Variants of uncertain significance (VUS) in mismatch repair (MMR) genes represent a persistent bottleneck in germline interpretation for Lynch syndrome, creating a critical opportunity to leverage tumor biology to refine pathogenicity assessment. Although tumor features such as microsatellite instability (MSI) and immunohistochemistry (IHC) are routinely evaluated, they are typically interpreted separately from germline classification, and their quantitative contribution within ACMG/AMP frameworks remains poorly defined. We therefore analyzed paired germline and tumor sequencing data from 1110 tumors across 1073 patients with colorectal or endometrial cancer to determine whether mismatch repair-deficient (MMR-d) mutational signatures can be quantitatively integrated into Bayesian germline variant interpretation. Using COSMIC single-base substitution signatures, tumors were classified as MMR-d or MMR proficient, and an empirically derived likelihood ratio (LR) quantified the association between MMR-d signatures and pathogenic germline MMR variants. The presence of an MMR-d signature increased the likelihood of an underlying pathogenic germline MMR variant approximately eightfold (LR ≈ 8; log10 LR ≈ 0.90), whereas its absence provided moderate-to-strong benign evidence (LR ≈ 0.156; log10 LR ≈ -0.81). Applying this integrative framework to 45 germline MMR VUS, joint modeling of tumor mutational signatures with additional somatic and variant-level evidence resulted in clinically significant reclassification of 38 (84.4%) variants, including three reclassified as pathogenic or likely pathogenic and 35 as likely benign. A total of 16 downgraded variants were independently downgraded by Invitae. These findings demonstrate that tumor mutational signatures can be formally incorporated into Bayesian germline interpretation, transforming tumor data into quantitative pathogenicity evidence and offering a principled strategy to reduce VUS burden in hereditary cancer genetics.

Humans↗

PubMed2026

Pan-Cancer Quantification of Driver Alteration Transmission Across Molecular Layers Reveals Limited Propagation to Protein Abundance.

Precision oncology relies primarily on DNA-level alterations for therapeutic decisions, but the extent to which driver mutations propagate to protein abundance has not been systematically evaluated. Here, I developed a regression-based transmission score (TS_R 2) to quantify driver alteration signal propagation across DNA, mRNA, and protein layers. Applying this framework to matched genomic, transcriptomic, proteomic, and phosphoproteomic data from 754 Clinical Proteomic Tumor Analysis Consortium (CPTAC) tumors across seven cancer types, I analyzed 86 driver gene-cancer type pairs, of which 83 were evaluable for the full two-layer transmission score. I employed covariate-adjusted regression for each molecular transition, assessing significance via permutation testing (n = 1000). Mixed-effects modeling then partitioned gene-intrinsic from cancer-type-dependent effects. Only 5 of 83 evaluable pairs (6%) demonstrated high transmission (TS_R 2 > 0.05), with receptor tyrosine kinases (EGFR, FGFR2) exemplifying this class. The primary bottleneck occurred at the mutation-mRNA transition, not mRNA-protein translation. Gene identity accounted for 49% of transmission efficiency variance, nearly double the contribution of cancer type (29%). Copy number alterations transmitted signals 13.8-fold more efficiently than point mutations, and truncating mutations showed higher transmission than missense variants (Wilcoxon p = 0.005). Microsatellite instability attenuated mRNA-protein transmission in UCEC and COAD. These findings demonstrate that many driver alterations show limited propagation to protein abundance. This challenges DNA-only interpretations in precision oncology and provides a framework for integrated functional driver prioritization.

Humans↗

PubMed2026

Engineering bubble structures as Cas12a activators for highly sensitive monitoring of WRN helicase function.

The Werner syndrome helicase (WRN) is a critical synthetic lethal target in microsatellite instability cancers, essential for resolving complex genomic structures like replication bubbles and R-loops. However, strategies to simultaneously discriminate WRN activity on DNA versus DNA-RNA substrates in living cells are lacking. Here, we developed a structure-specific CRISPR/Cas12a biosensing strategy to visualize WRN functional activity by engineering bubble-structure probes. These probes were rationally designed to structurally mimic DNA replication bubbles and R-loop associated DNA-RNA hybrids. Upon specific unwinding by WRN, the probes release a sequestered activator strand that triggers Cas12a trans-cleavage, effectively converting the unwinding event into an amplified fluorescent signal. This assay achieves low picomolar sensitivity (LODs: 5.6-6.0 pM) and exceptional selectivity against homologous RecQ helicases. Uniquely, this strategy enables the parallel quantification of WRN activity on both substrate types, providing insights into distinct WRN-mediated pathways for resolving genomic stress. We further demonstrated the strategy's utility by visualizing endogenous WRN dynamics in living cells and profiling the efficacy of small-molecule inhibitors. This work offers a powerful molecular toolkit for dissecting WRN biology and facilitating high-throughput drug screening in targeted cancer therapy.

Werner Syndrome Helicase↗

PubMed2026

RNF43 Mutations Are Associated With the Classical Molecular Subtype, Vigorous Antitumor Immune Responses, and Prolonged Survival in Pancreatic Adenocarcinoma.

RNF43 mutations were correlated with microsatellite status in colorectal cancer and with fewer and later recurrences in pancreatic ductal adenocarcinoma (PDAC). Here, we undertake a detailed assessment of RNF43 mutations in PDAC. A total of 313 PDACs (308 microsatellite stable [MSS] and 5 microsatellite-instable [MSI] cases) underwent next-generation sequencing (Oncomine Tumor Mutation Load assay; Thermo Fisher). Spatial analyses (NanoString) classified PDACs according to their transcriptomic and proteomic immune signaling. Fluorescent imaging was used to define spatial compartments (tumor: pancytokeratin+/CD45- and leukocytes: pancytokeratin-/CD45+). Each of 20 PDACs with RNF43 mutations (RNF43mut) and without RNF43 mutations (RNF43wt) underwent multiplex immunofluorescence analysis to determine immune status. A total of 153 PDACs (22 RNF43mut and 131 RNF43wt cases) underwent bulk RNA sequencing to assign into molecular subtypes. Overall, 24 RNF43 mutations were identified (22 MSS PDACs and 2 MSI PDACs). The incidence of RNF43 mutations in MSS PDACs (7.1%) was consistent with The Cancer Genome Atlas (6.7%). However, RNF43 mutations were more frequent among MSI PDACs (40%). Additionally, RNF43mut had differential frequencies of other mutations (including Wnt pathway genes), higher tumor mutational burden values (5.5 mut/mb vs 1.67 mut/mb; P < .01), and significantly longer overall survival (47 vs 18 months; P < .0001) than RNF43wt. Moreover, RNF43mut exhibited significantly higher densities of CD8+ T lymphocytes, dendritic cells, and B lymphocytes (P < .001) and an upregulation of ITGAX, CD11c, CD8, and HLA-DR compared with RNF43wt. Patients with RNF43mut PDACs were more often of the classical molecular subtype (20/22, 90.9%). RNF43mut PDACs showed high tumor mutational burden values, suggesting increased neoantigen load coupled with an abundance of antigen-presenting immune cells and an upregulation of immune determinants promoting antigen presentation. All this contributes to stronger antitumor immune responses and improved clinical outcomes.

Humans↗

PubMed2025

Polygenic variants in DNA repair genes are associated with neurodevelopmental disorders, regression and increased burdens of somatic variants and short tandem repeat expansions.

PURPOSE: Developmental regression, characterized by the loss of acquired milestones, occurs in some individuals with neurodevelopmental disorders (NDDs); yet, its molecular basis remains unclear. Studies suggest that DNA damage repair (DDR) genes, such as FAN1, may protect against neurological dysfunction by modulating the somatic stability of short tandem repeats (STRs). This study explores the contribution of DDR gene variants in NDD cases presenting with regression. METHODS: We analyzed 1087 NDD patients, focusing on those carrying variants in DDR genes and presenting regression. We assessed the sensitivity to DNA damage using mitomycin C on lymphoblastoid cells. Somatic variants and STR expansions were evaluated through high-depth short-read genome sequencing. To further investigate the pathogenetic role of STR expansions, we performed long-read genome sequencing on the most severely affected proband. RESULTS: Probands with regression carried multiple DDR gene variants, several within the Fanconi anemia pathway. Their lymphoblastoid cells showed increased sensitivity to mitomycin C-induced cytotoxicity compared with parental and control samples. Probands with severe phenotypes and regression exhibited an accumulation of somatic variants and STR instability, enriched in neurodevelopmental genes. CONCLUSION: Our findings suggest that polygenic DDR gene variants may contribute to developmental regression in NDDs by promoting the accumulation of somatic variants and STR expansions.

Humans↗

PubMed2026

Comprehensive genomic profiling and tumor mutational burden in parathyroid carcinoma: a nationwide real-world study from Japan.

PURPOSE: Parathyroid carcinoma (PC) is an extremely rare endocrine malignancy with limited treatment options for unresectable or recurrent cases. With the increasing use of comprehensive genomic profiling (CGP), treatment based on genomic findings is becoming more common. However, the frequency and clinical significance of elevated tumor mutational burden (TMB) in PC remain unclear because previous studies have been limited by small sample sizes. METHODS: We retrospectively analyzed genomic and clinical data of patients with PC registered in the Center for Cancer Genomics and Advanced Therapeutics database in Japan between June 2019 and March 2025. TMB values were obtained as reported by each CGP assay. TMB-H was defined as TMB ≥ 10 mut/Mb for descriptive analyses. We also assessed genomic alterations, microsatellite instability (MSI) status, and clinicogenomic characteristics. RESULTS: Twenty-five patients with PC were included. The median assay-reported TMB was 4.0 mut/Mb (range, 0-35). Seven tumors (28.0%) had assay-reported TMB values of ≥ 10 mut/Mb, including three (12.0%) with TMB ≥ 20 mut/Mb. The most frequently altered genes were CDC73 (40%), TP53 (32%), and MEN1 (24%). No co-alterations were observed between CDC73 and MEN1 or between CDC73 and TP53. One tumor was MSI-high and was included in the TMB-H group. POLE alterations were detected in three cases, including two tumors in the TMB-H group. CONCLUSION: This nationwide, real-world study demonstrated that a subset of PCs showed elevated assay-reported TMB values and genomic features potentially related to abnormalities in DNA replication or repair pathways. These findings support the clinical relevance of comprehensive genomic profiling in identifying the molecular heterogeneity and potential therapeutic opportunities for this rare malignancy.

Humans↗

PubMed1992

Duplication within chromosome 17p11.2 in 12 families of French ancestry with Charcot-Marie-Tooth disease type 1a. The French CMT Research Group.

Hereditary motor and sensory neuropathy type I (HMSN I), also designated Charcot-Marie-Tooth disease type 1 (CMT1), is a peripheral neuropathy frequently inherited as an autosomal dominant trait, characterised by progressive distal muscular atrophy and sensory loss with markedly decreased nerve conduction velocity. A duplication within chromosome 17p11.2, cosegregating with the disease, has recently been reported in several CMT1a families. In order to estimate the frequency of this anomaly and determine the location of a duplication in this region, 12 CMT1 families were analysed with polymorphic DNA markers located within 17p11.2-12. Duplications were found in all families including loci D17S61 (EW401), D17S122 (VAW409R3a and RM11-GT), and D17S125 (VAW412R3). The duplications were completely linked and associated with the disease (lod score of 20.77 at zero recombination). Screening for the RM11-GT microsatellite showed that most of the duplicated haplotypes were heterozygous, supporting the hypothesis that the duplication resulted from an unequal crossing over. There was no significant haplotype association within the duplicated region suggesting that the duplication resulted de novo as an independent event in each family. In one family, recombination within the duplicated region was observed, indicating that genetic instability in 17p11.2 might be related to a high recombination rate. Since most cases of CMT1a seem to result from this segmental trisomy, it can be used as a basis for DNA diagnosis of the disease.

Base Sequence↗