Mismatch Repair Research Articles

CD24 affects the immunosuppressive effect of tumor-infiltrating cells and tumor resistance in a variety of cancers

BackgroundCluster of differentiation 24 (CD24) is a highly glycosylated glycosylphosphatidylinositol (GPI)-anchored surface protein, expressed in various tumor cells, as a "don't eat me" signaling molecule in tumor immune. This study aimed to investigate the potential features of CD24 in pan-cancer.MethodsThe correlations between 22 immune cells and CD24 expression were using TIMER analysis. R package “ESTIMATE” was used to predict the proportion of immune and stromal cells in pan-cancer. Spearman's correlation analysis was performed to evaluate the relationships between CD24 expression and immune checkpoints, chemokines, mismatch repair, tumor mutation burden and microsatellite instability, and qPCR and western blot were conducted to assess CD24 expression levels in liver hepatocellular carcinoma (LIHC). In addition, loss of function was performed for the biological evaluation of CD24 in LIHC.ResultsCD24 expression was positively correlated with myeloid cells, including neutrophils and myeloid-derived suppressor cells, in various tumors, such as BLCA, HNSC-HPV, HNSC, KICH, KIRC, KIRP, TGCT, THCA, THYM, and UCEC. In contrast, anti-tumor NK cells and NKT cells showed a negative association with CD24 expression in BRCA-Her2, ESCA, HNSC-HPV, KIRC, THCA, and THYM. The top three tumors with the highest correlation between CD24 and ImmuneScore were TGCT, THCA, and SKCM. Functional enrichment analysis revealed CD24 expression was negatively associated with various immune-related pathways. Immune checkpoints and chemokines also exhibited inverse correlations with CD24 in CESC, CHOL, COAD, ESCA, READ, TGCT, and THCA. Additionally, CD24 was overexpressed in most tumors, with high CD24 expression in BRCA, LIHC, and CESC correlating with poor prognosis. The TIDE database indicated tumors with high CD24 expression, particularly melanoma, were less responsive to PD1/PD-L1 immunotherapy. Finally, CD24 knockdown resulted in impaired proliferation and cell cycle progression in LIHC.ConclusionCD24 participates in regulation of immune infiltration, influences patient prognosis and serves as a potential tumor marker.

Investigation of the Relationship Between DNA Mismatch Repair Genes and Microsatellite Instability in Solid Tumors

Aim: In this study, we aimed to detect the MSI status and somatic mutations in MMR genes (MSH2, MSH6, MLH1, PMS2) of a total of 55 solid tumors diagnosed with colorectal, endometrium and ovarian cancer by NGS method and to reveal the relationship between them. Material and Method: DNA isolation was performed by taking 10-micron sections from paraffin-embedded tissue samples of 55 patients diagnosed with kolorektal, endometrium ve ovarian solid tümörlerinin and Kapa NGS DNA extraction kit was used for sequence analysis. The purity and concentration of the DNA obtained was measured by Qubit fluoremeter, and NadPrep DNA Universal Library Preparation Kit was used for high quality library preparation. Bioinformatics analyses were performed on the Genomize Seq platform. The MSI value was analysed by Roche Navify Mutation Caller software and percentage MSI values were determined using the MSIsensor2 pipeline for secondary analysis of NGS. Results: All ovarian tumors were in the MSI-Stable category. The average MSI value was 2.01. One sample had an MSI of zero. In addition, no mutations in the MSH2 and MLH1 genes were detected in any of the ovarian tumors. 3 of 4 endometrial tumors were in the MSI-Stable category, and 1 tumor was in the MSI-low (MSI value: 13.2) category. No variants were detected in the MSH2 and PMS2 genes in endometrial tumors. 2 of the 41 colorectal tumors (Case4, Case16) were in the MSI-High category. No variants were detected in the MMR genes in 19 tumors. Conclusion: Although frame-shift and stop-gain mutations were detected in 23 tumors that would cause protein deficiency in MMR genes, MSI-H was not detected, as expected, except for two colorectal tumors. Therefore, the results of our study emphasise the need to define new predictive biomarkers clinically within the framework of algorithms to predict response to immunotherapy and determine prognosis.

Single-cell AI-based detection and prognostic and predictive value of DNA mismatch repair deficiency in colorectal cancer

Testing for DNA mismatch repair deficiency (MMRd) is recommended for all colorectal cancers (CRCs). Automating this would enable precision medicine, particularly if providing information on etiology not captured by deep learning (DL) methods. We present AIMMeR, an AI-based method for determination of mismatch repair (MMR) protein expression at a single-cell level in routine pathology samples. AIMMeR shows an area under the receiver-operator curve (AUROC) of 0.98, and specificity of ≥75% at 98% sensitivity against pathologist ground truth in stage II/III in two trial cohorts, with positive predictive value of ≥98% for the commonest pattern of somatic MMRd. Lower agreement with microsatellite instability (MSI) testing (AUROC 0.86) reflects discordance between MMR and MSI PCR rather than AIMMeR misclassification. Analysis of the SCOT trial confirms MMRd prognostic value in oxaliplatin-treated patients; while MMRd does not predict differential benefit of chemotherapy duration, it correlates with difference in relapse by regimen (PInteraction= 0.04). AIMMeR may help reduce pathologist workload and streamline diagnostics in CRC.

779P Testing unselected women with newly diagnosed high-grade serous ovarian cancer (HGSOC) for germline pathogenic variants (PVs) in mismatch repair (MMR) genes is unnecessary

779P Testing unselected women with newly diagnosed high-grade serous ovarian cancer (HGSOC) for germline pathogenic variants (PVs) in mismatch repair (MMR) genes is unnecessary

Rarely Observed Histopathological Subtypes of Endometrial Malignant Tumors in a Tertiary Care Center: A Case Series.

Introduction Endometrial cancer, one of the most prevalent gynecological malignancies, represents a significant contributor to global mortality and morbidity. The histological subtype of this cancer is pivotal in treatment planning and patient risk stratification. This case series, comprising seven cases, underscores the significance of rare endometrial cancer variants and the importance of ancillary studies, specifically immunohistochemistry, in comprehending and diagnosing the condition. Materials and methods The data of all the rare histological subtypes of malignant endometrial tumors encountered from April 2021 to April 2024 were collected. The data collected included age; risk factor; histological type; tumor, node, metastasis (TNM) stage; the International Federation of Gynecology and Obstetrics (FIGO)grade; P53; and mismatch repair (MMR) status. The histopathology specimens were reviewed using a Labomed microscope (LX500) manufactured in India. Images were taken and added wherever necessary, and the results were studied, analyzed, clinically correlated, and are shown in tables. Results Seven rare histopathological subtypes of malignant endometrial tumors were encountered in this period in this tertiary care center. This included mesonephric like adenocarcinoma, high-grade carcinosarcoma, carcinosarcoma with the serous and chondrosarcomatous components, clear cell carcinoma of endometrium, endometrial stromal sarcoma with smooth muscle differentiation, endometrial stromal sarcoma, and undifferentiated sarcoma with focal myxoid degeneration. Conclusion Diagnosis of uncommon endometrial carcinomas proves to be challenging due to their various histological subtypes, most often with overlapping features. The cornerstone of effective care lies in collaboration with clinicians, radiologists, and pathologists to identify these lesions as early as possible using a multidisciplinary approach for optimal patient outcome management.

The type of DNA damage response after decitabine treatment depends on the level of DNMT activity.

Decitabine and azacytidine are considered as epigenetic drugs that induce DNA methyltransferase (DNMT)-DNA crosslinks, resulting in DNA hypomethylation and damage. Although they are already applied against myeloid cancers, important aspects of their mode of action remain unknown, highly limiting their clinical potential. Using a combinatorial approach, we reveal that the efficacy profile of both compounds primarily depends on the level of induced DNA damage. Under low DNMT activity, only decitabine has a substantial impact. Conversely, when DNMT activity is high, toxicity and cellular response to both compounds are dramatically increased, but do not primarily depend on DNA hypomethylation or RNA-associated processes. By investigating proteome dynamics on chromatin, we show that decitabine induces a strictly DNMT-dependent multifaceted DNA damage response based on chromatin recruitment, but not expression-level changes of repair-associated proteins. The choice of DNA repair pathway hereby depends on the severity of decitabine-induced DNA lesions. Although under moderate DNMT activity, mismatch (MMR), base excision (BER), and Fanconi anaemia-dependent DNA repair combined with homologous recombination are activated in response to decitabine, high DNMT activity and therefore immense replication stress induce activation of MMR and BER followed by non-homologous end joining.

580P Impact of RAS and BRAFV600E mutations on tumor immune microenvironment and associated genomic alterations in patients with microsatellite instability (MSI) or DNA mismatch repair deficient (dMMR) colorectal cancers

580P Impact of RAS and BRAFV600E mutations on tumor immune microenvironment and associated genomic alterations in patients with microsatellite instability (MSI) or DNA mismatch repair deficient (dMMR) colorectal cancers

The Proteogenomics of Prostate Cancer Radioresistance.

Radiation is standard of care in prostate cancer. Yet, we have little understanding of its failure. We demonstrate a new paradigm that radioresistance is fractionation specific and identified POLQ as a radioresistance modulator.

Circ_0025373 inhibits carbon black nanoparticles-induced malignant transformation of human bronchial epithelial cells by affecting DNA damage through binding to MSH2

Carbon black nanoparticles (CBNPs) have been demonstrated to induce DNA damage in epithelial cells. However, the potential of the damage to initiate carcinogenesis and the underlying mechanism remain poorly understood. Therefore, we constructed an in vitro model of malignant transformation of human bronchial epithelial cells (16HBE-T) by treating 40 μg/mL CBNPs for 120 passages. We observed tumor-like transformation and sustained DNA damage. Using transcriptome sequencing and RIP-seq, we identified the overexpression of the critical DNA mismatch repair genes MutS homolog 2 (MSH2) and its related circular RNA, circ_0025373, in the 16HBE-T cells. Mechanistically, circ_0025373 was found to inhibit DNA damage by binding to MSH2, thereby modifying its expression and influencing its nuclear and cytoplasmic distribution, which lead to inhibition of CBNP-induced malignant transformation of human bronchial epithelial cells. Our findings provide novel evidence on the carcinogenicity of CBNPs, and offer biological insights into the potential epigenetic regulation and potential therapeutic targets for lung carcinogenesis.

564P Short-course radiotherapy combined with chemotherapy and PD-1 inhibitor in proficient mismatch repair or microsatellite stable (pMMR/MSS) low-lying early rectal cancer: Preliminary findings from a prospective, multi-center, phase II trial (TORCH-E)

564P Short-course radiotherapy combined with chemotherapy and PD-1 inhibitor in proficient mismatch repair or microsatellite stable (pMMR/MSS) low-lying early rectal cancer: Preliminary findings from a prospective, multi-center, phase II trial (TORCH-E)

Clinical status and future prospects of neoadjuvant immunotherapy for localized mismatch repair-deficient cancers: a review.

Frameshift mutations accumulate in cancers related to mismatch repair deficiency (dMMR), which has the potential to produce various neoantigens, representing a distinct subset of cancers that respond considerably to immunotherapy. In recent years, robust evidence has supported the first-line application of immunotherapy for patients with metastatic dMMR cancers, which provoked extensive investigations of the feasibility and efficacy of immunotherapy in up-front settings, including neoadjuvant therapy. Several completed trials with small sample sizes suggested that neoadjuvant immunotherapy can achieve an impressively high complete response rate, for the first time offering the potential of systemic therapy to cure cancer without the need for surgical resection. However, a difficult dilemma emerges: clinicians are now facing a selection between the standard of care with good evidence for proficient MMR but suboptimal for dMMR cancers and the emerging immunotherapy with promising results but only based on a limited number of patients with shorter duration of follow-up. This review aims to provide a comprehensive summary of the biological rationale and clinical status of neoadjuvant immunotherapy in patients with dMMR cancers. Furthermore, I elaborate on particular issues that must be taken into consideration for further advancement in the field.

741P Comparison of the Idylla microsatellite instability (MSI) test with a gold standard MSI test and mismatch repair immunohistochemistry in endometrial cancer

741P Comparison of the Idylla microsatellite instability (MSI) test with a gold standard MSI test and mismatch repair immunohistochemistry in endometrial cancer

Spatial Cancer-Immune Phenotypes Predict Shorter Recurrence-Free Survival in the No Specific Molecular Profile Molecular Subtype of Endometrial Carcinoma

Compartmentation of the immune response into 3 main spatial cancer-immune phenotypes (SCIs) – inflamed, excluded, and desert – has been proposed as the main predictor of response to immune checkpoint inhibitors in solid tumors. The objective of the study was to define and characterize the SCI in a consecutive series of 213 endometrial carcinomas (ECs) by correlating it with molecular subtypes, clinicopathologic features, and prognosis. Immunohistochemistry (IHC) and next-generation sequencing were used to assign surrogate molecular EC subtypes: POLE mutant (POLE), mismatch repair deficient (MMRd), TP53 mutant (p53abn), and no specific molecular profile (NSMP). Immune cell markers (CD20, CD3, CD8, CD68, PD-L1) were assessed by IHC on whole sections and quantified by digital image analysis to define the 3 SCIs. ECs were stratified into 4 molecular subtypes: 17 (8.0%) POLE, 68 (31.9%) MMRd, 42 (19.7%) p53abn, and 86 (40.4%) NSMP. SCI determination showed 105 (49.3%) inflamed, 62 (29.1%) desert, and 46 (25.6%) excluded tumors. The inflamed phenotype was more prevalent in MMRd (64.7%) and POLE (76.5%) subtypes compared with NSMP (45.3%) and p53abn (21.4%). SCI revealed a strong correlation with disease-free survival in NSMP tumors: inflamed 96.2%, desert 83.2%, and excluded 40.5%. The SCI prognostic impact was also maintained in NSMP cases treated with adjuvant therapy resulting in a significant difference in recurrence between the inflamed and excluded phenotypes. To simplify SCI determination, a subset of immune cell markers was selected as appropriate to define the 3 SCI patterns: high intraepithelial CD8 for the inflamed phenotype; CD68, CD20, and PD-L1 to discriminate between desert and excluded tumors. The integration of SCI into molecular classification could be a promising opportunity to improve the prognostic risk stratification of patients and may guide the therapeutic approach, particularly in the NSMP subtype. Thus, the different patterns of immune response are a new prognostic parameter in the NSMP subtype.

550P The impact of mismatch repair status on accuracy of clinical staging in upfront resected stage II/III rectal cancer in the Netherlands

550P The impact of mismatch repair status on accuracy of clinical staging in upfront resected stage II/III rectal cancer in the Netherlands

Impact of molecular and histopathological findings on FIGO 2009 stage I endometrial cancer: Transition to FIGO 2023 staging system.

This study aims to investigate the impact of integrating molecular and histopathological findings into the revised International Federation of Gynecology and Obstetrics (FIGO) 2023 staging system on patients initially diagnosed with stage I endometrial cancer (EC) according to the FIGO 2009 criteria. A cohort of 197 EC patients, initially classified as stage I under FIGO 2009, underwent restaging based on the updated FIGO 2023 criteria. The patients' molecular and histopathological characteristics were documented, and their impact on upstaging was analyzed. Molecular profiling was conducted for 81.2% (160/197) of the patients, revealing that 55.3% (109/197) were classified as non-specific molecular profile, 14.7% (29/197) as mismatch repair deficiency, 11.2% (22/197) as p53 abnormality (p53abn), and 18.8% (37/197) as unknown. Upstaging was identified in 26.9% (43/160) of the 160 patients with known molecular profiles. Among the upstaged patients, 51.2% experienced upstaging due to p53 abnormality, 20.9% due to substantial lymphovascular space invasion (LVSI), 20.9% due to aggressive histological types, and 6.9% due to high grade. The introduction of the molecular profile into the revised FIGO 2023 staging system for stage I EC has led to notable changes in the staging of approximately one-fifth of patients. While p53 abnormalities have emerged as the most influential factor contributing to the upstaging, LVSI and aggressive histological types also represent significant contributing factors.

569P Mismatch repair deficient, stage II/III rectal cancer: Real-world patient, tumour, and treatment characteristics in the Netherlands

569P Mismatch repair deficient, stage II/III rectal cancer: Real-world patient, tumour, and treatment characteristics in the Netherlands

509O Total neoadjuvant treatment (TNT) with non-operative management (NOM) for proficient mismatch repair locally advanced rectal cancer (pMMR LARC): First results of NO-CUT trial

509O Total neoadjuvant treatment (TNT) with non-operative management (NOM) for proficient mismatch repair locally advanced rectal cancer (pMMR LARC): First results of NO-CUT trial

143P Efficacy of immunotherapy in gastro-intestinal (GI) tumors with mismatch repair deficient (MMRd) unusual phenotype

143P Efficacy of immunotherapy in gastro-intestinal (GI) tumors with mismatch repair deficient (MMRd) unusual phenotype

Assessing Disease Control in Mismatch Repair-Proficient Colorectal Cancer With Peritoneal Metastases Treated With Immune Checkpoint Blockade-Based Combination Therapies

PURPOSE Metastatic colorectal adenocarcinoma (mCRC) with proficient mismatch repair (pMMR) is associated with poor response to cytotoxic chemotherapy in the refractory setting. Immunotherapy regimens using a combination of immune checkpoint blockade (ICB)–based combination therapies have shown promise, although few studies include patients with peritoneal metastases (PMs). This study sought to examine the disease control rate (DCR) and overall survival (OS) of patients treated with PM who were treated with ICB-containing regimens. METHODS Patients with pMMR metastatic colorectal cancer treated with ICB-based combination regimens after progression on first- and second-line therapy at The University of Texas MD Anderson Cancer Center from 2015 to 2022 were identified. Disease response within each metastatic site was determined. OS and DCR were calculated. RESULTS A total of 30 patients with PM, with or without other metastases, had a median follow-up on an ICB containing regimen of 8.5 months and a median follow-up until death or censoring of 13.3 months. The median OS was 16.7 (10.0-Not reported) months, and 18-month survival was 47%. Among patients treated for ≥6 months, DCR at 6 months at each metastatic site was 20% (2/10) for liver, 68% for peritoneum (13/19, P = .02 v liver), 50% for lung (5/10, P = .35 v liver), and 0% for retroperitoneal adenopathy (0/2, P = 1.00 v liver). CONCLUSIONS Among patients with mCRC, ICB-based combination regimens can provide disease control in the peritoneum in the majority of patients, and median OS compares favorably to standard-of-care therapy in the refractory setting. Patients with peritoneal disease should be included in future ICB trials since treatment options are otherwise limited.

FREQUENCY OF LOSS OF MISMATCH REPAIR PROTEINS’ IMMUNOHISTOCHEMICAL EXPRESSION IN SEBACEOUS NEOPLASMS, POTENTIAL MARKERS/TOOLS INDICATING THE POSSIBILITY OF MUIR-TORRE SYNDROME

Screening for Muir-Torre Syndrome (MTS) using Mismatch Repair (MMR) gene immunohistochemistry (IHC) on sebaceous neoplasms (SNs) is technically feasible. Research for this indication is limited, especially in Asia. To address this knowledge gap, we examined the frequency of loss of IHC staining of MMR proteins in SNs. Methods: We conducted a cross-sectional study including 98 patients (120 SNs). Eleven out of 98 patients had concurrent or subsequent SNs. Results: The size and type of tumor showed a significant association with MMR loss. Fifteen (12.5%) sebaceous adenomas, 12 (10.0%) sebaceous, and 93 (77.5%) sebaceous carcinomas were included in the study—sixty-one (50.83 %) SNs presented with loss of one or more MMR proteins. Isolated loss of MSH2 was the most common IHC pattern (27.8%). Fifty cases (29.58%) showed a combined loss of MSH2 and MSH6, and 40 (23.66%) showed a combined loss of MLH1 and PMS2. Most SAs showed isolated loss of MLH1 and PMS2 (7, 26.9% each). Sebaceomas showed isolated loss of MSH2 and MSH6 as the most common (4, 33.3%) pattern. Isolated loss of MSH2 only (37, 28.2%) was the predominant pattern of IHC loss in SCs. Weak to fragile associations between MMR protein status and histopathological findings were observed, with the most notable association being between MLH1 and ulceration on the surface. The models have an accuracy of around 50%, indicating moderate prediction capability. In our cohort, personal and family history was available in 33 cases (25 out of 98 patients). Conclusion: We recommend that MMR IHC be performed routinely on all SNs, considering clinicopathological factors of the lesions, mainly the anatomic site and tumor type. The panel should include antibodies against all four MMR proteins.