Mismatch Repair Research Articles

Excellent concordance of the molecular classification between preoperative biopsy and final hysterectomy in endometrial carcinoma

ObjectiveThe 2023 International Federation of Gynecology and Obstetrics classification with molecular classification shows superior discriminatory ability compared to staging systems lacking molecular data. However, the accuracy of endometrial biopsy data in molecular classification remains uncertain. This study aimed to assess the concordance of molecular classifications between preoperative biopsy and hysterectomy to predict prognosis before surgical staging. MethodsEndometrial biopsies and corresponding hysterectomy specimens were collected at the National Cancer Center Hospital between 2012 and 2023. Immunohistochemistry for p53 and mismatch repair (MMR) proteins and next-generation sequencing of all exons of polymerase epsilon (POLE) were performed. Given the limited number of POLE mut cases in prior studies, we prepared a POLE mut-enriched cohort. Cohen's kappa estimates were used to determine concordance for molecular and clinicopathological subgroup assignments. ResultsAmong 70 patients classified into four molecular subtype groups, 33 exhibited POLE mutations, 15 showed loss of MMR protein expression, 13 had p53-abnormality, and 9 had no specific molecular profile. Concordance between biopsy and hysterectomy specimens was 100% (κ = 1.000). In contrast, histological types and grades between biopsy and surgical specimens showed moderate and substantial agreement (κ = 0.420 and κ = 0.780, respectively). ConclusionsMolecular subtypes were completely consistent with those derived from surgical specimens, demonstrating high concordance between preoperative and postoperative molecular classifications. This suggests that endometrial biopsies could reliably predict prognosis. Future studies should investigate how biopsy-based molecular profiling influences treatment planning and patient outcomes.

Durvalumab plus carboplatin/paclitaxel followed by durvalumab with or without olaparib as first-line treatment for endometrial cancer (DUO-E/GOG-3041/ENGOT-EN10): Objective response rate and duration of response by mismatch repair status

Durvalumab plus carboplatin/paclitaxel followed by durvalumab with or without olaparib as first-line treatment for endometrial cancer (DUO-E/GOG-3041/ENGOT-EN10): Objective response rate and duration of response by mismatch repair status

Concurrent POLE hotspot mutations and mismatch repair deficiency in endometrial cancer: Defining cancer drivers

Concurrent POLE hotspot mutations and mismatch repair deficiency in endometrial cancer: Defining cancer drivers

High-risk histology endometrial cancer and mismatch repair status: The impact of histologic subtype and MLH1 hypermethylation on outcomes

High-risk histology endometrial cancer and mismatch repair status: The impact of histologic subtype and MLH1 hypermethylation on outcomes

A phase II, two-stage study of avelumab and axitinib among patients with mismatch repair proficient recurrent or persistent endometrial cancer: Final efficacy analysis and correlative studies

A phase II, two-stage study of avelumab and axitinib among patients with mismatch repair proficient recurrent or persistent endometrial cancer: Final efficacy analysis and correlative studies

Immune checkpoint inhibition for mismatch repair deficient endometrial cancer: MLH1 hypermethylation does not impact outcome in a multi-institutional retrospective database

Immune checkpoint inhibition for mismatch repair deficient endometrial cancer: MLH1 hypermethylation does not impact outcome in a multi-institutional retrospective database

Spatial profiling of mismatch repair deficient endometrial tumors identifies patterns associated with recurrence and response to immune checkpoint therapy

Spatial profiling of mismatch repair deficient endometrial tumors identifies patterns associated with recurrence and response to immune checkpoint therapy

ASO Author Reflections: Stage II/III Colorectal Cancer Patients with Mismatch Repair Deficiency Need More Personalized Adjuvant Chemotherapy.

ASO Author Reflections: Stage II/III Colorectal Cancer Patients with Mismatch Repair Deficiency Need More Personalized Adjuvant Chemotherapy.

The impact of environmental factors and social determinants of health on mismatch repair status in a single-center endometrial cancer cohort

The impact of environmental factors and social determinants of health on mismatch repair status in a single-center endometrial cancer cohort

A randomized, double-blind, phase II study of MK-4280A (coformulation of favezelimab and pembrolizumab) plus lenvatinib versus pembrolizumab plus lenvatinib among patients with previously-treated mismatch repair proficient advanced endometrial cancer

A randomized, double-blind, phase II study of MK-4280A (coformulation of favezelimab and pembrolizumab) plus lenvatinib versus pembrolizumab plus lenvatinib among patients with previously-treated mismatch repair proficient advanced endometrial cancer

Mismatch repair deficiency and tumor mutational burden are associated with higher microbiome diversity in the reproductive tract

Mismatch repair deficiency and tumor mutational burden are associated with higher microbiome diversity in the reproductive tract

Characteristics of mismatch repair deficient endometrial cancer in a diverse cohort

Characteristics of mismatch repair deficient endometrial cancer in a diverse cohort

Defects in mismatch repair promote disease character likeness amongst Black and White women with endometrial cancer

Defects in mismatch repair promote disease character likeness amongst Black and White women with endometrial cancer

Durvalumab plus carboplatin/paclitaxel followed by durvalumab with or without olaparib as a firstline treatment for endometrial cancer: Overall survival and additional secondary efficacy en‑dpoints by mismatch repair status in the DUO-E/GOG-3041/ENGOT-EN10 Trial

Durvalumab plus carboplatin/paclitaxel followed by durvalumab with or without olaparib as a firstline treatment for endometrial cancer: Overall survival and additional secondary efficacy en‑dpoints by mismatch repair status in the DUO-E/GOG-3041/ENGOT-EN10 Trial

Intronic Variants in the MSH2 (rs2303426 and rs10179950) and PMS2 (rs2286681 and rs62456178) Genes Are Not Associated with Colorectal Cancer in Mexican Patients

Background/Objectives: In the origin and development of colorectal cancer (CRC), a global public health problem, a dysfunction mismatch repair system appears to be a key factor. The objective was to determine the association of intronic variants in the MSH2 and PMS2 genes with CRC in Mexican patients. Methods: Blood samples of 143 CRC patients and 146 reference individuals were genotyped through TaqMan® Genotyping Assays. Genotypic and allelic frequencies were determined by direct counting. To compare genotypic and allelic distributions, the chi-square test was used. For the association analysis, the risks of alleles and genotypes were estimated by odds ratio with 95% confidence intervals. Haplogroups were inferred with a Bayesian algorithm. Linkage disequilibrium was measured using D’ and r2 with Arlequin v3.5.2. The in silico analysis was carried out using the SpliceAI, UCSC, JASPAR and TRRUST platforms. All statistical analyses were performed with SPSS v29.0.2.0. Results: In the CRC group, the mean age was 58.2 ± 14.7 years and 60.8% were men. No variant was associated with CRC or implicated in gene post-replicative processing. Linkage disequilibrium was observed for loci rs2303426 and rs10179950 in MSH2 and for loci rs2286681 and rs62456178 in PMS2. Conclusions: The genotypic and allelic frequencies of the four variants are reported for the first time in Mexican patients with CRC. No association was found between gene variants and risk for CRC but there was a strong linkage disequilibrium between the loci of both MSH2 and PMS2 genes. None of the variants showed a possible repercussion on splicing.

Validation and clinical performance of a single test, DNA based endometrial cancer molecular classifier

ObjectivesWe have previously shown that DNA based, single test molecular classification by next generation sequencing (NGS) (Proactive Molecular risk classifier for Endometrial cancer (ProMisE) NGS) is highly concordant with the...

Treatment Strategies for Advanced Endometrial Cancer According to Molecular Classification

The management of advanced endometrial cancer (EC) has changed in the last few years due to the introduction of a new molecular classification and the approval of immunotherapy. For a long time, carboplatin plus paclitaxel was considered the standard treatment for first-line advanced EC, since the approval of the combination of chemotherapy plus immunotherapy. For patients with recurrent EC, with previous platinum-based chemotherapy, single-agent immunotherapy or in combination with tyrosine-kinase inhibitor (TKI) has been approved according to mismatch repair status. Ongoing trials are exploring the possibility of a chemo-free future for mismatch repair-deficient (dMMR) EC and new molecular targets are under investigation. The treatment paradigm for advanced EC has shifted from standard chemotherapy for all to a more personalized approach. The aim of this review is to provide an updated therapeutic landscape for the management of patients with advanced/metastatic EC according to their disease history and molecular biology.

Germline variants of homology-directed repair or mismatch repair genes in cervical cancer.

While cervical cancer is associated with a persistent human papillomavirus (HPV) infection, the progression to cancer is influenced by genomic risk factors that have remained largely obscure. Pathogenic variants in genes of the homology-directed repair (HDR) or mismatch repair (MMR) are known to predispose to diverse tumour entities including breast and ovarian cancer (HDR) or colon and endometrial cancer (MMR). We here investigate the spectrum of HDR and MMR germline variants in cervical cancer, with particular focus on the HPV status and histological subgroups. We performed targeted next-generation sequencing for 5 MMR genes and 12 HDR genes on 728 German patients with cervical dysplasia or invasive cancer. In total, 4% of our patients carried a pathogenic germline variant, based on ClinVar classifications and additional ESM1b and AlphaMissense predictions. These included 15 patients with truncating variants in HDR genes (BARD1, BRCA1, BRCA2, BRIP1, FANCM, RAD51D and SLX4). MMR-related gene variants were less prevalent and mainly of the missense type. While MMR-related gene variants tended to associate with adenocarcinomas, HDR gene variants were commonly observed in squamous cancers. While one patient with HPV-negative cancer carried a pathogenic MMR gene variant (in MSH6), the HDR germline variants were found in patients with HPV-positive cancers and tended to associate with HPV18. Taken together, our study supports a potentially risk-modifying role of MMR and HDR germline variants in cervical cancer but no association with HPV-negative status. These variants may be exploitable in future therapeutic managements.

Olaparib: A Chemosensitizer for the Treatment of Glioblastoma.

Glioblastoma (GBM) is the most prevalent and deadly primary brain tumor. The current treatment for GBM includes adjuvant chemotherapy with temozolomide (TMZ), radiation therapy, and surgical tumor excision. There is still an issue because 50% of patients with GBM who get TMZ have low survival rates due to TMZ resistance. The activation of several DNA repair mechanisms, such as Base Excision Repair (BER), DNA Mismatch Repair (MMR), and O-6- Methylguanine-DNA Methyltransferase (MGMT), is the main mechanism via which TMZ resistance develops. The zinc-finger DNA-binding enzyme poly (ADP-ribose) polymerase-1 (PARP1), which is activated by binding to DNA breaks, affects the activation of the MGMT, BER, and MMR pathway deficiency, which results in TMZ resistance in GBM. PARP inhibitors have been studied recently as sensitizing medications to increase TMZ potency. The first member of the PARP inhibitor family to be identified was Olaparib. It inhibits PARP1 and PARP2, which causes apoptosis in cancer cells and DNA strand break. Olaparib is currently investigated as a radio- and/or chemo-sensitizer in addition to being used as a single agent because it may increase the cytotoxic effects of other treatments. This review addresses Olaparib and its significance in treating TMZ resistance in GBM.

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

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