DNA polymerase and mismatch repair deficient cancers exert distinct genome-wide microsatellite signatures 2
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ABSTRACT:
PROVIDER: EGAS00001004816 | EGA |
REPOSITORIES: EGA
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Project description:DNA mismatch repair-deficient colorectal tumors (CRC) frequently show coding microsatellite frameshift mutations in the MSI tumor driver Transforming Growth Factor Beta Receptor Type 2 (TGFBR2) leading to cellular alteration of MSI tumor cells [Lee, J., Warnken, U., Schnölzer, M., Gebert, J. & Kopitz, J. (2015) Protein Sci. 24, 1686-94; Lee, J., Ballikaya, S., Schonig, K., Ball, C. R., Glimm, H., Kopitz, J. & Gebert, J. (2013) PloS one. 8, e57074]. Whether this receptor expression in MSI tumor cells also impacts the exosomal proteomic cargo of these cells is still unknown.
2017-04-07 | PXD005620 | Pride
Project description:Colorectal cancer (CRC) remains the third most common cancer in the US, with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1. DNA methylation and transcriptome analysis was performed to evaluate the rhesus macaque as a model organism to study carcinogenesis, develop immunotherapies and vaccines, and implement chemoprevention approaches pertinent to sporadic MSI-H and LS CRC in humans. NIH grant(s): Grant ID: 5 P30 CA016672-44 Grant title: Cancer Center Support Grant Affiliation: The University of Texas MD Anderson Cancer Center Grantor: NCI
2022-03-31 | GSE178377 | GEO
Project description:Colorectal cancer (CRC) remains the third most common cancer in the US, with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1. DNA methylation and transcriptome analysis was used to evaluate the rhesus macaque as a model organism to study carcinogenesis, develop immunotherapies and vaccines, and implement chemoprevention approaches pertinent to sporadic MSI-H and LS CRC in humans. NIH grant(s): Grant ID: 5 P30 CA016672-44 Grant title: Cancer Center Support Grant Affiliation: The University of Texas MD Anderson Cancer Center Grantor: NCI
2022-03-31 | GSE178381 | GEO
Project description:Whole genome sequencing data used in the manuscript: DNA polymerase and mismatch repair exert distinct microsatellite instability signatures in normal and malignant human cells.
| EGAD00001006593 | EGA
Project description:Lynch syndrome (LS) patients develop DNA mismatch repair deficient tumors which generate high loads of neoantigens (neoAgs), thus constituting a well-defined population that can benefit from cancer immune-interception strategies, including neoantigen-based vaccines. Using paired whole-exome sequencing and mRNAseq of colorectal cancers (CRC) (n=13) and pre-cancers (n=61) from our LS patient cohort (N=46), we performed in-silico prediction and immunogenicity ranking of highly recurrent frameshift-neoags, followed by their in-vitro validation. We described the somatic mutation landscape in all cancers and pre-cancers, and showed that mutation burden is positively correlated with neoAgs load. Furthermore, our in-vitro validation showed a 65% validation rate of our top 100 predicted neoags. Consistent with neoAgs burden, our transcriptomic results revealed increased infiltration of CD8+ and CD4+ T-cells in microsatellite unstable samples. Overall, our neoAgs catalog and all other findings, improve our understanding of cancer development in LS and guide us towards the advancement of immunoprevention vaccine strategies.
2024-03-25 | GSE224707 | GEO
Project description:The main purpose of this study is to assess the efficacy and safety of IBI310 in combination with sintilimab in patients with Microsatellite Instability High (MSI-H) or Mismatch Repair Deficient (dMMR) locally advance or metastatic colorectal cancer.
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Project description:Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.This article is highlighted in the In This Issue feature, p. 995.
| S-EPMC8223607 | biostudies-literature
Project description:Mutations in mismatch repair genes leading to mismatch repair (MMR) deficiency (dMMR) and microsatellite instability (MSI) have been implicated in multiple types of gynecologic malignancies. Endometrial carcinoma represents the largest group, with approximately 30% of these cancers caused by dMMR/MSI. Thus, testing for dMMR is now routine for endometrial cancer. Somatic mutations leading to dMMR account for approximately 90% of these cancers. However, in 5-10% of cases, MMR protein deficiency is due to a germline mutation in the mismatch repair genes MLH1, MSH2, MSH6, PMS2, or EPCAM. These germline mutations, known as Lynch syndrome, are associated with an increased risk of both endometrial and ovarian cancer, in addition to colorectal, gastric, urinary tract, and brain malignancies. So far, gynecological cancers with dMMR/MSI are not well characterized and markers for detection of MSI in gynecological cancers are not well defined. In addition, currently advanced endometrial cancers have a poor prognosis and are treated without regard to MSI status. Elucidation of the mechanism causing dMMR/MSI gynecological cancers would aid in diagnosis and therapeutic intervention. Recently, a new immunotherapy was approved for the treatment of solid tumors with MSI that have recurred or progressed after failing traditional treatment strategies. In this review, we summarize the MMR defects and MSI observed in gynecological cancers, their prognostic value, and advances in therapeutic strategies to treat these cancers.
| S-EPMC7697596 | biostudies-literature
Project description:Using in vitro directed evolution, we show that mismatch repair-deficient Pseudomonas aeruginosa can engage novel resistance mechanisms to ceftazidime-avibactam.
2021-08-30 | GSE180086 | GEO
Project description:This clinical trial evaluates the effect of tislelizumab in treating patients with mismatch repair deficient endometrial cancer that has come back (recurrent). Deoxyribonucleic acid (DNA) mismatch repair (MMR) is a system for recognizing and repairing DNA errors and damage. Mismatch repair deficient tumors (dMMR) may have difficulty repairing DNA mutations during replication that may affect tumor’s response to therapy. Immunotherapy with monoclonal antibodies, such as tislelizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving tislelizumab may help treat patients with mismatch repair deficient endometrial cancer.
| 2379033 | ecrin-mdr-crc