Repair Deficiency Research Articles

Relation of Mismatch Repair Deficiency in Endometrial Carcinoma and Its Clinical Implication

Relation of Mismatch Repair Deficiency in Endometrial Carcinoma and Its Clinical Implication

PMS2CL interference leading to erroneous identification of a pathogenic PMS2 variant in Black patients

This study investigates the frequency of a clinically reported variant in PMS2, NM_000535.7:c.2523G>A p.(W841∗), from next-generation sequencing studies in 2 racially diverse cohorts. We identified clinical reports of the PMS2 c.2523G>A p.(W841∗) variant in the National Precision Oncology Program’s somatic testing database (n = 25,168). We determined frequency of the variant in germline exome sequencing from the Penn Medicine BioBank (n = 44,256) and in gnomAD. The PMS2 c.2523G>A p.(W841∗) was identified as a homozygous variant on tumor testing in an adult patient of self-identified Black race/ethnicity with no evidence of constitutional mismatch repair deficiency. The variant was clinically reported on 35 total tumor and liquid biopsy tests (0.1%), and all individuals with the variant were of self-identified Black race/ethnicity (0.6% of n = 5787). In individuals of African genetic ancestry (AFR), the variant's germline frequency was reported to be 0.2% and 1.3% in the Penn Medicine BioBank (PMBB) and gnomAD, respectively. The variant cannot be found in any individuals of European genetic ancestry (EUR) from either of the databases. The variant is found in a region of PMS2 with 100% homology to the PMS2CL pseudogene. PMS2 c.2523G>A p.(W841∗), when identified, is typically an African-ancestry-specific PMS2CL pseudogene variant, which should be recognized to prevent misdiagnosis of Lynch syndrome in Blacks.

Unravelling the molecular basis of PARP inhibitor resistance in prostate cancer with homologous recombination repair deficiency.

Prostate cancer is a disease with heterogeneous characteristics, making its treatability and curability dependent on the cancer's stage. While prostate cancer is often indolent, some cases can be aggressive and evolve into metastatic castration-resistant prostate cancer (mCRPC), which is lethal. A significant subset of individuals with mCRPC exhibit germline and somatic variants in components of the DNA damage repair (DDR) pathway. Recently, PARP inhibitors (PARPi) have shown promise in treating mCRPC patients who carry deleterious alterations in BRCA2 and 13 other DDR genes that are important for the homologous recombination repair (HRR) pathway. These inhibitors function by trapping PARP, resulting in impaired PARP activity and increased DNA damage, ultimately leading to cell death through synthetic lethality. However, the response to these inhibitors only lasts for 3-4 months, after which the cancer becomesPARPi resistant. Cancer cells can develop resistance to PARPi through numerous mechanisms, such as secondary reversion mutations in DNA repair pathway genes, heightened drug efflux, loss of PARP expression, HRR reactivation, replication fork stability, and upregulation of Wnt/Catenin and ABCB1 pathways. OvercomingPARPi resistance is a critical and complex process, and there are two possible ways to sensitize the resistance. The first approach is to potentiate thePARPi agents through chemo/radiotherapy and combination therapy, while the second approach entails targeting different signaling pathways. This review article highlights the latest evidence on the resistance mechanism ofPARPi in lethal prostate cancer and discusses additional therapeutic opportunities available for prostate cancer patients with DDR gene alterations who do not respond toPARPi.

Constitutional mismatch repair deficiency syndrome as a cause of numerous malignancies in a teenage patient - a case report

Constitutional mismatch repair deficiency syndrome as a cause of numerous malignancies in a teenage patient - a case report

An update on central nervous system tumors in germline replication-repair deficiency syndromes.

DNA replication-repair deficiency (RRD) arises from pathogenic variants in the mismatch repair and/or polymerase-proofreading genes. Multiple germline cancer predisposition syndromes in children and young adults, including constitutional mismatch repair deficiency (CMMRD), Lynch, polymerase-proofreading deficiency, and rare digenic syndromes can lead to RRD cancers. The most frequent brain tumors in these children are high-grade gliomas. Embryonal tumors like medulloblastoma have also been described. Lower-grade tumors are reported from cancer surveillance initiatives. The latter has an extremely high rate of malignant transformation. Novel functional assays quantifying the genomic microsatellite indel load have been demonstrated to be highly sensitive and specific for the diagnosis of RRD cancers and children with germline CMMRD. Importantly, RRD brain tumors uniformly harbor high mutation and microsatellite burden. High T-cell infiltration makes these aggressive cancers amenable to immune checkpoint inhibition, irrespective of their germline genetic background. Synergistic combinations are reported to be successful in patients failing checkpoint inhibitor monotherapy. Future directions include the development of innovative approaches to improve immune surveillance for RRD brain cancers. Additionally, the use of novel tools including circulating tumor DNA and quantifying microsatellite indel load over time can be useful to monitor disease burden and treatment responses in patients.

Combined strategies with PARP inhibitors for the treatment of BRCA wide type cancer.

Genomic instability stands out as a pivotal hallmark of cancer, and PARP inhibitors (PARPi) emerging as a groundbreaking class of targeted therapy drugs meticulously crafted to inhibit the repair of DNA single-strand breaks(SSB) in tumor cells. Currently, PARPi have been approved for the treatment of ovarian cancer, pancreatic cancer, breast cancer, and prostate cancer characterized by homologous recombination(HR) repair deficiencies due to mutations in BRCA1/2 or other DNA repair associated genes and acquiring the designation of breakthrough therapy. Nonetheless, PARPi exhibit limited efficacy in the majority of HR-proficient BRCA1/2 wild-type cancers. At present, the synergistic approach of combining PARPi with agents that induce HR defects, or with chemotherapy and radiotherapy to induce substantial DNA damage, significantly enhances the efficacy of PARPi in BRCA wild-type or HR-proficient patients, supporting extension the use of PARPi in HR proficient patients. Therefore, we have summarized the effects and mechanisms of the combined use of drugs with PARPi, including the combination of PARPi with HR defect-inducing drugs such as ATRi, CHKi, HR indirectly inducing drugs like VEGFRi, CDKi, immune checkpoint inhibitors and drugs instigating DNA damage such as chemotherapy or radiotherapy. In addition, this review discusses several ongoing clinical trials aimed at analyzing the clinical application potential of these combined treatment strategies.

Response to immune checkpoint inhibition in a meningioma with DNA mismatch repair deficiency.

Response to immune checkpoint inhibition in a meningioma with DNA mismatch repair deficiency.

Transcriptomic Meta-Analysis Identifies Upregulated Clotting and Fibrinolysis Pathways in Colorectal Cancer Tumors Containing Hereditary PMS2 Mismatch Repair Deficiency.

Lynch Syndrome is characterized by deficient mismatch repair (dMMR) components. We performed a meta-analysis of multiple RNA-sequencing datasets from patients with different dMMR variants (PMS2, MLH1, and MSH2) to better characterize the unique transcriptional profiles. Our results reveal enriched signaling pathways from tumor samples with germline mutations in the PMS2 gene including upregulation in pathways related to intrinsic and extrinsic prothrombin activation, fibrinolysis, and uPA/uPAR-mediated signaling. These pathways have been associated with tumor growth, invasiveness, and metastasis. This work provides support for further exploration into the role of PMS2 in tumor development, and as a potential therapeutic mechanism.

Clinicopathological characteristics of endometrial carcinoma with different molecular subtypes and their correlation with lymph node metastasis.

Endometrial carcinoma (EC) is one of the three major malignancies of the female reproductive organs. With intense research of tumor molecular mechanisms and development of precision medicine in recent years, the traditional pathomorphological classification fails to meet the needs of clinical diagnosis and treatment for EC. This study aims to analyze the correlation of different Proactive Molecular Risk Classifier for Endometrial Cancer molecular subtypes with lymph node metastasis (LNM) and other clinical features in EC. 120 treatment-naive EC patients with surgery were enrolled in this study. The molecular subtypes of these patients were classified as follows by Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) molecular subtyping: mismatch repair deficiency (MMRd) in 22 cases (18.33%), polymerase epsilon exonuclease domain mutation (POLE EDM) in 2 cases (1.67%), p53 wild-type (p53-wt) in 64 cases (53.33%), and p53 abnormal (p53-abn) in 32 cases (26.67%). The clinicopathological features of 120 patients were retrospectively analyzed. Statistical significance was identified among the four molecular subtypes in terms of histological classification, International Federation of Gynecology and Obstetrics (FIGO) staging, pathological grading, and LNM. Among the enrolled cases, 26 had LNM and 94 had no lymph node involvement. According to the multivariate Logistic regression analysis, p53 wt (P=0.008, OR=0.078, 95% CI: 0.012-0.510) was a protective factor for LNM in EC patients, while poorly differentiated histology (P=0.001, OR=15.137, 95% CI: 3.013-76.044) was a risk factor. ProMisE classification system, being more objective and reproducible, can provide an important reference for preoperative decision-making. The patients with p53 wt by ProMisE had a low risk of LNM in preoperative diagnostic curettage specimens, while there was a higher risk of LNM among the patients with poorly differentiated EC.

DPP4 valorphin activate NR4As pathway and OPA1 that protect from CoQ10 deficiency from OPA1 dysfunctions and from WMH

Valorphin (known as VV-hemorphin-5 ) is nine essential amino acids : Leu_Val_Val_Tyr, _Pro _Pro _Thr_ Gln_& Arg are having important role in activating mitochondrial functions and in activating both serotonin and NR4As pathway that promote oxytocin and Nrf2 synthesis. Deficiency in Thr, Tph (TGG), Glu, Gln (cycle) and Leucine due to increasing in the polarizability in mTORC1 and in S6K genes and subunits can cause disorders or deficiency in OPA1 repair that can be the result of Primary coenzyme Q10 (CoQ10) deficiency disease that characterized by damage in the inner mitochondrial membrane which is necessary for activating glucocorticoids receptor GCR Synthesis. Mitochondrial damage or disorder can lead to accumulation in pro-inflammation which can cause mutations in subunit and protein. The reduction in tryptophan, in Gly (which considered as the mirror of tryptophan triplets), and in Arg will cause reductions in Proline synthesis and consequently reductions in tRNAs, followed by reduction in mitochondrial OPA1 repairs and functions (that reduction in Gly can cause reduction in GTPase), followed by reduction in IL17 synthesis and accumulation of proinflammatory molecules, and followed by reduction in serotonin synthesis and in all of GC-beta, oxitocin, and Nrf2 production, that will be followed by decreasing in megakaryocytes proliferation and followed by reduction in hematopoiesis which associated to white matter hyperintensity

Mismatch repair deficiency in adult granulosa cell tumours

NA

Artificial Intelligence in Predicting Microsatellite Instability and KRAS, BRAF Mutations from Whole-Slide Images in Colorectal Cancer: A Systematic Review.

Mismatch repair deficiency (d-MMR)/microsatellite instability (MSI), KRAS, and BRAF mutational status are crucial for treating advanced colorectal cancer patients. Traditional methods like immunohistochemistry or polymerase chain reaction (PCR) can be challenged by artificial intelligence (AI) based on whole slide images (WSI) to predict tumor status. In this systematic review, we evaluated the role of AI in predicting MSI status, KRAS, and BRAF mutations in colorectal cancer. Studies published in PubMed up to June 2023 were included (n = 17), and we reported the risk of bias and the performance for each study. Some studies were impacted by the reduced number of slides included in the data set and the lack of external validation cohorts. Deep learning models for the d-MMR/MSI status showed a good performance in training cohorts (mean AUC = 0.89, [0.74-0.97]) but slightly less than expected in the validation cohort when available (mean AUC = 0.82, [0.63-0.98]). Contrary to the MSI status, the prediction of KRAS and BRAF mutations was less explored with a less robust methodology. The performance was lower, with a maximum of 0.77 in the training cohort, 0.58 in the validation cohort for KRAS, and 0.82 AUC in the training cohort for BRAF.

DNA repair-deficient premature aging models display accelerated epigenetic age.

Several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (Ercc1, LAKI, Polg, and Xpg). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in Ercc1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. Similarly, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight that mouse models with deficiencies in DNA repair, unlike other premature aging models, display accelerated epigenetic age, suggesting a strong connection between DNA damage and epigenetic dysregulation during aging.

Molecular and Immune Landscape of Fumarate Hydratase-mutated Renal Cell Carcinoma

Fumarate hydratase-deficient renal cell carcinomas are an aggressive form of kidney cancer that often results in poor prognosis and high fatality rates. The implications of somatic mutations are not well described, and standard treatment has not been established for this renal cell carcinoma subtype. Further molecular characterization of fumarate hydratase-deficient renal cell carcinomas could potentially help to identify biomarkers that can be exploited with future targeted therapies. 2199 renal cell carcinomas were analyzed by DNA sequencing (592-gene panel) and whole- transcriptome sequencing and 40 tumors were identified with pathogenic FH mutations. Co-occurrence of mutation with other cancer-related genes were assessed along with immune profiles and immunotherapy biomarkers. Fumarate hydratase-deficient renal cell carcinomas had a lower prevalence of co-mutation with common renal cell carcinoma driver mutations such as VHL and chromatin remodeling genes when compared to wild type renal cell carcinoma. Conversely, prevalence of several cancer-related genes (MAX, BRCA1, PMS2, BRAF, NF2, and AKT1) was higher in fumarate hydratase-deficient renal cell carcinomas. Immunotherapy biomarkers (mismatch repair deficiency and tumor mutational burden) were detected at low frequency in mutant and wild type renal cell carcinomas, while PDL1 expression occurred at higher frequency in fumarate hydratase-deficient renal cell carcinomas. Fumarate hydratase-mutated kidney tumors may have a different mutational and immune landscape than wild type tumors. The absence of VHL mutations in a significant number of fumarate hydratase deficient renal cell carcinomas suggest that FH mutations may drive tumorigenesis using distinct angiogenic pathways. Our study highlights potential therapeutic implications that will require further study.

Liquid biopsy in ovarian cancer in China and the world: current status and future perspectives.

Ovarian cancer (OC) is the eighth most common cancer in women, but the mild, non-specific clinical presentation in early stages often prevents diagnosis until progression to advanced-stage disease, contributing to the high mortality associated with OC. While serum cancer antigen 125 (CA-125) has been successfully used as a blood-borne marker and is routinely monitored in patients with OC, CA-125 testing has limitations in sensitivity and specificity and does not provide direct information on important molecular characteristics that can guide treatment decisions, such as homologous recombination repair deficiency. We comprehensively review the literature surrounding methods based on liquid biopsies, which may provide improvements in sensitivity, specificity, and provide valuable additional information to enable early diagnosis, monitoring of recurrence/progression/therapeutic response, and accurate prognostication for patients with OC, highlighting applications of this research in China.

Concomitant Immunotherapy and Metastasis-Directed Radiotherapy in Upper Tract Urothelial Carcinoma: A Biomarker-Driven, Original, Case-Based Proof-of-Concept Study.

Metastatic upper tract urothelial carcinoma (mUTUC) has a poor prognosis. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in patients with metastatic urothelial carcinoma. However, data supporting the use of ICIs in patients with mUTUC are limited. A promising synergy between ICI and concomitant radiotherapy (RT) has been reported in patients with mUTUC. Our research involved a case-based investigation and emphasized the successful integration of different specialists' skills. Observed after partial urethrectomy procedures for muscle-invasive upper tract urothelial carcinoma (UTUC), the radiological detection of lung metastases prompted us to implement cisplatin-based first-line chemotherapy and molecular characterization in the treatment process. We uncovered alterations in the ERBB2 and FGFR3 genes and mismatch repair deficiency at a molecular level. First-line chemotherapy treatment led to a stable disease, and the patient was started on maintenance immunotherapy with Avelumab. Subsequently, an increase in the size of the lung nodules was described, and the patient received radiotherapy for three lung lesions in combination with immunotherapy. After 3 months, a restaging CT scan reported a complete response, which is still ongoing. We discuss the mechanisms driving RT/ICI synergy and the molecular profile of mUTUC as factors that should be considered in therapeutic strategy planning. Molecular insight enhances the originality of our study, providing a nuanced understanding of the genetic landscape of mUTUC and paving the way for targeted therapeutic strategies. The therapeutic armamentarium expansion encourages the design of a multimodal and personalized approach for each mUTUC patient, taking into account tumor heterogeneity and molecular profiling.

“De novo replication repair deficient glioblastoma, IDH-wildtype” is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant “ultrahypermutation”. The median age at diagnosis was 50 years (range 27–78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as “Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A”. Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that “De novo replication repair deficient glioblastoma, IDH-wildtype” represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

Diabetes-associated breast cancer is molecularly distinct and shows a DNA damage repair deficiency.

Diabetes commonly affects patients with cancer. We investigated the influence of diabetes on breast cancer biology using a 3-pronged approach that included analysis of orthotopic human tumor xenografts, patient tumors, and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. We aimed to identify shared phenotypes and molecular signatures by investigating the metabolome, transcriptome, and tumor mutational burden. Diabetes and hyperglycemia did not enhance cell proliferation but induced mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. They also promoted oxyradical formation and both a transcriptome and mutational signatures of DNA repair deficiency. Moreover, food- and microbiome-derived metabolites tended to accumulate in breast tumors in the presence of diabetes, potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, we conclude that diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors.

Stromal localization of inactive CD8+ T cells in metastatic mismatch repair deficient colorectal cancer.

The determinants of metastasis in mismatch repair deficiency with high levels of microsatellite instability (MSI-H) in colorectal cancer (CRC) are poorly understood. Here, we hypothesized that distinct immune and stromal microenvironments in primary tumors may discriminate between non-metastatic MSI-H CRC and metastatic MSI-H CRC. We profiled 46,727 single cells using high-plex imaging mass cytometry and analyzed both differential cell type abundance, and spatial distribution of fibroblasts and immune cells in primary CRC tumors with or without metastatic capacity. We validated our findings in a second independent cohort using immunohistochemistry. High-plex imaging mass cytometry and hierarchical clustering based on microenvironmental markers separated primary MSI-H CRC tumors with and without metastatic capacity. Primary tumors with metastatic capacity displayed a high stromal content and low influx of CD8+ T cells, which expressed significantly lower levels of markers reflecting proliferation (Ki67) and antigen-experience (CD45RO) compared to CD8+ T cells in non-metastatic tumors. CD8+ T cells showed intra-epithelial localization in non-metastatic tumors, but stromal localization in metastatic tumors, which was validated in a second cohort. We conclude that localization of phenotypically distinct CD8+ T cells within stroma may predict metastasis formation in MSI-H CRC.

Increased Lipogenesis Is Important for Hexavalent Chromium-Transformed Lung Cells and Xenograft Tumor Growth

Hexavalent chromium, Cr(VI), is a known carcinogen and environmental health concern. It has been established that reactive oxygen species, genomic instability, and DNA damage repair deficiency are important contributors to the Cr(VI)-induced carcinogenesis mechanism. However, some hallmarks of cancer remain under-researched regarding the mechanism behind Cr(VI)-induced carcinogenesis. Increased lipogenesis is important to carcinogenesis and tumorigenesis in multiple types of cancers, yet the role increased lipogenesis has in Cr(VI) carcinogenesis is unclear. We report here that Cr(VI)-induced transformation of three human lung cell lines (BEAS-2B, BEP2D, and WTHBF-6) resulted in increased lipogenesis (palmitic acid levels), and Cr(VI)-transformed cells had an increased expression of key lipogenesis proteins (ATP citrate lyase [ACLY], acetyl-CoA carboxylase [ACC1], and fatty acid synthase [FASN]). We also determined that the Cr(VI)-transformed cells did not exhibit an increase in fatty acid oxidation or lipid droplets compared to their passage-matched control cells. Additionally, we observed increases in ACLY, ACC1, and FASN in lung tumor tissue compared with normal-adjacent lung tissue (in chromate workers that died of chromate-induced tumors). Next, using a known FASN inhibitor (C75), we treated Cr(VI)-transformed BEAS-2B with this inhibitor and measured cell growth, FASN protein expression, and growth in soft agar. We observed that FASN inhibition results in a decreased protein expression, decreased cell growth, and the inhibition of colony growth in soft agar. Next, using shRNA to knock down the FASN protein in Cr(VI)-transformed BEAS-2B cells, we saw a decrease in FASN protein expression and a loss of the xenograft tumor development of Cr(VI)-transformed BEAS-2B cells. These results demonstrate that FASN is important for Cr(VI)-transformed cell growth and cancer properties. In conclusion, these data show that Cr(VI)-transformation in vitro caused an increase in lipogenesis, and that this increase is vital for Cr(VI)-transformed cells.