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Surgical Pathology Clinics Dec 2022Prostate cancer (PCa) is characterized by profound genomic heterogeneity. Recent advances in personalized treatment entail an increasing need of genomic profiling. For... (Review)
Review
Prostate cancer (PCa) is characterized by profound genomic heterogeneity. Recent advances in personalized treatment entail an increasing need of genomic profiling. For localized PCa, gene expression assays can support clinical decisions regarding active surveillance and adjuvant treatment. In metastatic PCa, homologous recombination deficiency, microsatellite instability-high (MSI-H), and CDK12 deficiency constitute main actionable alterations. Alterations in DNA repair genes confer variable sensitivities to poly(ADP-ribose)polymerase inhibitors, and the use of genomic instability assays as predictive biomarker is still incipient. MSI can be assessed by immunohistochemistry To date there is a lack of consensus as to testing standards.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Microsatellite Instability; Prostatic Neoplasms; Genetic Testing; Molecular Biology
PubMed: 36344179
DOI: 10.1016/j.path.2022.08.002 -
Cancer Cell Sep 2023Deep learning (DL) can accelerate the prediction of prognostic biomarkers from routine pathology slides in colorectal cancer (CRC). However, current approaches rely on...
Deep learning (DL) can accelerate the prediction of prognostic biomarkers from routine pathology slides in colorectal cancer (CRC). However, current approaches rely on convolutional neural networks (CNNs) and have mostly been validated on small patient cohorts. Here, we develop a new transformer-based pipeline for end-to-end biomarker prediction from pathology slides by combining a pre-trained transformer encoder with a transformer network for patch aggregation. Our transformer-based approach substantially improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. After training and evaluating on a large multicenter cohort of over 13,000 patients from 16 colorectal cancer cohorts, we achieve a sensitivity of 0.99 with a negative predictive value of over 0.99 for prediction of microsatellite instability (MSI) on surgical resection specimens. We demonstrate that resection specimen-only training reaches clinical-grade performance on endoscopic biopsy tissue, solving a long-standing diagnostic problem.
Topics: Humans; Algorithms; Biomarkers; Biopsy; Microsatellite Instability; Colorectal Neoplasms
PubMed: 37652006
DOI: 10.1016/j.ccell.2023.08.002 -
Nature Medicine Jul 2019Microsatellite instability determines whether patients with gastrointestinal cancer respond exceptionally well to immunotherapy. However, in clinical practice, not every...
Microsatellite instability determines whether patients with gastrointestinal cancer respond exceptionally well to immunotherapy. However, in clinical practice, not every patient is tested for MSI, because this requires additional genetic or immunohistochemical tests. Here we show that deep residual learning can predict MSI directly from H&E histology, which is ubiquitously available. This approach has the potential to provide immunotherapy to a much broader subset of patients with gastrointestinal cancer.
Topics: Deep Learning; Gastrointestinal Neoplasms; Humans; Immunotherapy; Microsatellite Instability
PubMed: 31160815
DOI: 10.1038/s41591-019-0462-y -
Cell Nov 2017Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from...
Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection almost absent outside homozygous loss of essential genes. This allows exome-wide enumeration of all driver coding mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We systematically catalog cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.
Topics: Humans; INDEL Mutation; Microsatellite Instability; Models, Genetic; Mutation Rate; Neoplasms; Point Mutation; Polymorphism, Single Nucleotide; Selection, Genetic
PubMed: 29056346
DOI: 10.1016/j.cell.2017.09.042 -
Low neoantigen expression and poor T-cell priming underlie early immune escape in colorectal cancer.Nature Cancer Oct 2021Immune evasion is a hallmark of cancer, and therapies that restore immune surveillance have proven highly effective in cancers with high tumor mutation burden (TMB)...
Immune evasion is a hallmark of cancer, and therapies that restore immune surveillance have proven highly effective in cancers with high tumor mutation burden (TMB) (e.g., those with microsatellite instability (MSI)). Whether low TMB cancers, which are largely refractory to immunotherapy, harbor potentially immunogenic neoantigens remains unclear. Here, we show that tumors from all patients with microsatellite stable (MSS) colorectal cancer (CRC) express clonal predicted neoantigens despite low TMB. Unexpectedly, these neoantigens are broadly expressed at lower levels compared to those in MSI CRC. Using a versatile platform for modulating neoantigen expression in CRC organoids and transplantation into the distal colon of mice, we show that low expression precludes productive cross priming and drives immediate T cell dysfunction. Strikingly, experimental or therapeutic rescue of priming rendered T cells capable of controlling tumors with low neoantigen expression. These findings underscore a critical role of neoantigen expression level in immune evasion and therapy response.
Topics: Animals; Antigens, Neoplasm; Colorectal Neoplasms; Humans; Immunotherapy; Mice; Microsatellite Instability; T-Lymphocytes
PubMed: 34738089
DOI: 10.1038/s43018-021-00247-z -
ESMO Open Feb 2022Microsatellite instability (MSI) testing and tumor mutational burden (TMB) are genomic biomarkers used to identify patients who are likely to benefit from immune...
INTRODUCTION
Microsatellite instability (MSI) testing and tumor mutational burden (TMB) are genomic biomarkers used to identify patients who are likely to benefit from immune checkpoint inhibitors. Pembrolizumab was recently approved by the Food and Drug Administration for use in TMB-high (TMB-H) tumors, regardless of histology, based on KEYNOTE-158. The primary objective of this retrospective study was real-world applicability and use of immunotherapy in TMB/MSI-high patients to lend credence to and refine this biomarker.
METHODS
Charts of patients with advanced solid tumors who had MSI/TMB status determined by next generation sequencing (NGS) (FoundationOne CDx) were reviewed. Demographics, diagnosis, treatment history, and overall response rate (ORR) were abstracted. Progression-free survival (PFS) was determined from Kaplan-Meier curves. PFS1 (chemotherapy PFS) and PFS2 (immunotherapy PFS) were determined for patients who received immunotherapy after progressing on chemotherapy. The median PFS2/PFS1 ratio was recorded.
RESULTS
MSI-high or TMB-H [≥20 mutations per megabase (mut/MB)] was detected in 157 adults with a total of 27 distinct tumor histologies. Median turnaround time for NGS was 73 days. ORR for most recent chemotherapy was 34.4%. ORR for immunotherapy was 55.9%. Median PFS for patients who received chemotherapy versus immunotherapy was 6.75 months (95% confidence interval, 3.9-10.9 months) and 24.2 months (95% confidence interval, 9.6 months to not reached), respectively (P = 0.042). Median PFS2/PFS1 ratio was 4.7 in favor of immunotherapy.
CONCLUSION
This real-world study reinforces the use of TMB as a predictive biomarker. Barriers exist to the timely implementation of NGS-based biomarkers and more data are needed to raise awareness about the clinical utility of TMB. Clinicians should consider treating TMB-H patients with immunotherapy regardless of their histology.
Topics: Adult; Biomarkers, Tumor; Humans; Immunotherapy; Microsatellite Instability; Neoplasms; Retrospective Studies
PubMed: 34953399
DOI: 10.1016/j.esmoop.2021.100336 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... May 2021Lymphoma is one of the most common malignant tumor of the hematologic system. The genome instability is not only an important molecular basis for the development of...
Lymphoma is one of the most common malignant tumor of the hematologic system. The genome instability is not only an important molecular basis for the development of lymphoma, but also has important value in the diagnosis and prognosis of lymphoma. There are 2 types of genome instability: Microsatellite instability (MSI/MIN) at gene level and chromosomal instability at chromosome level. Through the study on genes associated with lymphoma, the unstable genes associated with lymphoma could be found, meanwhile the mechanism of its occurrence and development of lymphoma could be explored, and the important basis of molecular biology could also be provided in the field of current hot lymphoma precision medical research.
Topics: Genomic Instability; Humans; Lymphoma; Microsatellite Instability; Microsatellite Repeats; Neoplasms
PubMed: 34148893
DOI: 10.11817/j.issn.1672-7347.2021.190427 -
Genomics, Proteomics & Bioinformatics Feb 2020Microsatellite instability (MSI) is a key biomarker for cancer therapy and prognosis. Traditional experimental assays are laborious and time-consuming, and...
Microsatellite instability (MSI) is a key biomarker for cancer therapy and prognosis. Traditional experimental assays are laborious and time-consuming, and next-generation sequencing-based computational methods do not work on leukemia samples, paraffin-embedded samples, or patient-derived xenografts/organoids, due to the requirement of matched normal samples. Herein, we developed MSIsensor-pro, an open-source single sample MSI scoring method for research and clinical applications. MSIsensor-pro introduces a multinomial distribution model to quantify polymerase slippages for each tumor sample and a discriminative site selection method to enable MSI detection without matched normal samples. We demonstrate that MSIsensor-pro is an ultrafast, accurate, and robust MSI calling method. Using samples with various sequencing depths and tumor purities, MSIsensor-pro significantly outperformed the current leading methods in both accuracy and computational cost. MSIsensor-pro is available at https://github.com/xjtu-omics/msisensor-pro and free for non-commercial use, while a commercial license is provided upon request.
Topics: Humans; Microsatellite Instability; Microsatellite Repeats; Neoplasms; Software
PubMed: 32171661
DOI: 10.1016/j.gpb.2020.02.001 -
Biophysical Chemistry Jun 2017Microsatellites are short, tandemly repeated DNA motifs of 1-6 nucleotides, also termed simple sequence repeats (SRSs) or short tandem repeats (STRs). Collectively,... (Review)
Review
Microsatellites are short, tandemly repeated DNA motifs of 1-6 nucleotides, also termed simple sequence repeats (SRSs) or short tandem repeats (STRs). Collectively, these repeats comprise approximately 3% of the human genome Subramanian et al. (2003), Lander and Lander (2001) [1,2], and represent a large reservoir of loci highly prone to mutations Sun et al. (2012), Ellegren (2004) [3,4] that contribute to human evolution and disease. Microsatellites are known to stall and reverse replication forks in model systems Pelletier et al. (2003), Samadashwily et al. (1997), Kerrest et al. (2009) [5-7], and are hotspots of chromosomal double strand breaks (DSBs). We briefly review the relationship of these repeated sequences to replication stalling and genome instability, and present recent data on the impact of replication stress on DNA fragility at microsatellites in vivo.
Topics: DNA Breaks, Double-Stranded; DNA Replication; Humans; Microsatellite Instability; Microsatellite Repeats
PubMed: 27914716
DOI: 10.1016/j.bpc.2016.11.007 -
Current Oncology Reports Jun 2021Patients with Lynch syndrome have a high probability of developing colorectal and other carcinomas. This review provides a comprehensive assessment of the immunologic... (Review)
Review
PURPOSE OF REVIEW
Patients with Lynch syndrome have a high probability of developing colorectal and other carcinomas. This review provides a comprehensive assessment of the immunologic aspects of Lynch syndrome pathogenesis and provides an overview of potential immune interventions for patients with Lynch syndrome polyps and Lynch syndrome-associated carcinomas.
RECENT FINDINGS
Immunogenic properties of the majority of Lynch syndrome polyps and associated cancers include microsatellite instability leading to a high mutational burden and the development of novel frameshift peptides, i.e., neoantigens. In addition, patients with Lynch syndrome develop T cell responses in the periphery and in the tumor microenvironment (TME) to tumor-associated antigens, and a proinflammatory cytokine TME has also been identified. However, Lynch syndrome lesions also possess immunosuppressive entities such as alterations in MHC class I antigen presentation, TGFβ receptor mutations, regulatory T cells, and upregulation of PD-L1 on tumor-associated lymphocytes. The rich immune microenvironment of Lynch syndrome polyps and associated carcinomas provides an opportunity to employ the spectrum of immune-mediating agents now available to induce and enhance host immune responses and/or to also reduce immunosuppressive entities. These agents can be employed in the so-called prevention trials for the treatment of patients with Lynch syndrome polyps and for trials in patients with Lynch syndrome-associated cancers.
Topics: Antibodies; Colorectal Neoplasms, Hereditary Nonpolyposis; Humans; Microsatellite Instability; Microsatellite Repeats; Tumor Microenvironment
PubMed: 34125344
DOI: 10.1007/s11912-021-01085-z