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Kooi EJ, Marcelis L, Wesseling P. Pathological diagnosis of central nervous system tumours in adults: what's new? Pathology 2025; 57:144-156. [PMID: 39818455 DOI: 10.1016/j.pathol.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 01/18/2025]
Abstract
In the course of the last decade, the pathological diagnosis of many tumours of the central nervous system (CNS) has transitioned from a purely histological to a combined histological and molecular approach, resulting in a more precise 'histomolecular diagnosis'. Unfortunately, translation of this refinement in CNS tumour diagnostics into more effective treatment strategies is lagging behind. There is hope though that incorporating the assessment of predictive markers in the pathological evaluation of CNS tumours will help to improve this situation. The present review discusses some novel aspects with regard to the pathological diagnosis of the most common CNS tumours in adults. After a brief update on recognition of clinically meaningful subgroups in adult-type diffuse gliomas and the value of assessing predictive markers in these tumours, more detailed information is provided on predictive markers of (potential) relevance for immunotherapy especially for glioblastomas, IDH-wildtype. Furthermore, recommendations for improved grading of meningiomas by using molecular markers are briefly summarised, and an overview is given on (predictive) markers of interest in metastatic CNS tumours. In the last part of this review, some 'emerging new CNS tumour types' that may occur especially in adults are presented in a table. Hopefully, this review provides useful information on 'what's new' for practising pathologists diagnosing CNS tumours in adults.
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Affiliation(s)
- Evert-Jan Kooi
- Department of Pathology, Amsterdam University Medical Centers/VUmc, Amsterdam, The Netherlands.
| | - Lukas Marcelis
- Department of Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Pieter Wesseling
- Department of Pathology, Amsterdam University Medical Centers/VUmc, Amsterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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2
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Ree AH, Høye E, Esbensen Y, Beitnes ACR, Negård A, Bernklev L, Tetlie LK, Fretland ÅA, Hamre HM, Kersten C, Hofsli E, Guren MG, Sorbye H, Nilsen HL, Flatmark K, Meltzer S. Complete response of metastatic microsatellite-stable BRAF V600E colorectal cancer to first-line oxaliplatin-based chemotherapy and immune checkpoint blockade. Oncoimmunology 2024; 13:2372886. [PMID: 38952672 PMCID: PMC11216098 DOI: 10.1080/2162402x.2024.2372886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/22/2024] [Indexed: 07/03/2024] Open
Abstract
The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigned to this experimental treatment had metastases from BRAF-mutant MSS-CRC, in general a poor-prognostic subgroup explored here. The ≥70-year-old females presented with ascending colon adenocarcinomas with intermediate tumor mutational burden (6.2-11.8 mutations per megabase). All experienced early disappearance of the primary tumor followed by complete response of all overt metastatic disease, resulting in progression-free survival as long as 20-35 months. However, they encountered recurrence at previously unaffected sites and ultimately sanctuary organs, or as intrahepatic tumor evolution reflected in the terminal loss of initially induced T-cell clonality in liver metastases. Yet, the remarkable first-line responses to short-course oxaliplatin-based chemotherapy alternating with ICB may offer a novel therapeutic option to a particularly hard-to-treat MSS-CRC subgroup.
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Affiliation(s)
- Anne Hansen Ree
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Eirik Høye
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Tumor Biology, Oslo University Hospital, Oslo, Norway
| | - Ying Esbensen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway
| | | | - Anne Negård
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Radiology, Akershus University Hospital, Lørenskog, Norway
| | - Linn Bernklev
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
| | | | - Åsmund A. Fretland
- The Intervention Centre and Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Hanne M. Hamre
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
| | - Christian Kersten
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
- Department of Research, Sørlandet Hospital, Kristiansand, Norway
| | - Eva Hofsli
- Department of Oncology, St. Olav’s Hospital, Trondheim, Norway
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Marianne G. Guren
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Hilde L. Nilsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway
- Department of Microbiology, Oslo University Hospital, Oslo, Norway
| | - Kjersti Flatmark
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Tumor Biology, Oslo University Hospital, Oslo, Norway
- Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
| | - Sebastian Meltzer
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
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3
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Ree AH, Šaltytė Benth J, Hamre HM, Kersten C, Hofsli E, Guren MG, Sorbye H, Johansen C, Negård A, Bjørnetrø T, Nilsen HL, Berg JP, Flatmark K, Meltzer S. First-line oxaliplatin-based chemotherapy and nivolumab for metastatic microsatellite-stable colorectal cancer-the randomised METIMMOX trial. Br J Cancer 2024; 130:1921-1928. [PMID: 38664577 PMCID: PMC11183214 DOI: 10.1038/s41416-024-02696-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 04/12/2024] [Accepted: 04/15/2024] [Indexed: 06/19/2024] Open
Abstract
BACKGROUND We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade. METHODS Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade. RESULTS Eighty patients were randomised and 38 in each group received treatment. PFS was comparable-control group: median 9.2 months (95% confidence interval (CI), 6.3-12.7); experimental group: median 9.2 months (95% CI, 4.5-15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk (p = 0.021) with hazard ratio 0.17 (95% CI, 0.04-0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab (n = 17) reached median PFS 15.8 months (95% CI, 7.8-23.7). One-sixth of experimental-group cases (all KRAS/BRAF-mutant) achieved complete response. CONCLUSIONS The investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer. TRIAL REGISTRATION ClinicalTrials.gov number, NCT03388190 (02/01/2018).
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Affiliation(s)
- Anne Hansen Ree
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Jūratė Šaltytė Benth
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Health Services Research Unit, Akershus University Hospital, Lørenskog, Norway
| | - Hanne M Hamre
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
| | - Christian Kersten
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
- Department of Research, Sørlandet Hospital, Kristiansand, Norway
| | - Eva Hofsli
- Department of Oncology, St Olav's Hospital, Trondheim, Norway
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Marianne G Guren
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Christin Johansen
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
| | - Anne Negård
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Radiology, Akershus University Hospital, Lørenskog, Norway
| | - Tonje Bjørnetrø
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
| | - Hilde L Nilsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway
| | - Jens P Berg
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Kjersti Flatmark
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
- Department of Tumour Biology, Oslo University Hospital, Oslo, Norway
| | - Sebastian Meltzer
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
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Lin D, Zheng T, Huang S, Liu R, Guan S, Zhang Z. Identification of a novel macrophage-related prognostic signature in colorectal cancer. Sci Rep 2024; 14:2767. [PMID: 38307957 PMCID: PMC10837438 DOI: 10.1038/s41598-024-53207-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 01/29/2024] [Indexed: 02/04/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent and deadliest illnesses all around the world. Growing proofs demonstrate that tumor-associated macrophages (TAMs) are of critical importance in CRC pathogenesis, but their mechanisms remain yet unknown. The current research was designed to recognize underlying biomarkers associated with TAMs in CRC. We screened macrophage-related gene modules through WGCNA, selected hub genes utilizing the LASSO algorithm and COX regression, and established a model. External validation was performed by expression analysis using datasets GSE14333, GSE74602, and GSE87211. After validating the bioinformatics results using real-time quantitative reverse transcription PCR, we identified SPP1, C5AR1, MMP3, TIMP1, ADAM8 as potential biomarkers associated with macrophages in CRC.
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Affiliation(s)
- Dongfa Lin
- Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, Jilin University, School of Life Sciences, Changchun, 130012, China
- Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun 130012, China
- School of Life Sciences, Jilin University, Changchun 130012, China
| | - Tingjin Zheng
- Department of Clinical Laboratory, Quanzhou First Hospital Affiliated to Fujian Medical University, No. 248 East Street, Quanzhou, 362000, Fujian, China
| | - Shangyuan Huang
- Laboratory of Molecular Neurobiology, Sheng Yushou center of Cell Biology and Immunology, Department of Genetics and Developmental Biology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Rd., Shanghai, 200240, China
| | - Rui Liu
- School of Life Sciences, Jilin University, Changchun 130012, China
| | - Shuwen Guan
- Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, Jilin University, School of Life Sciences, Changchun, 130012, China.
- Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun 130012, China.
- School of Life Sciences, Jilin University, Changchun 130012, China.
| | - Zhishan Zhang
- Department of Clinical Laboratory, Quanzhou First Hospital Affiliated to Fujian Medical University, No. 248 East Street, Quanzhou, 362000, Fujian, China.
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5
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Heiser CN, Simmons AJ, Revetta F, McKinley ET, Ramirez-Solano MA, Wang J, Kaur H, Shao J, Ayers GD, Wang Y, Glass SE, Tasneem N, Chen Z, Qin Y, Kim W, Rolong A, Chen B, Vega PN, Drewes JL, Markham NO, Saleh N, Nikolos F, Vandekar S, Jones AL, Washington MK, Roland JT, Chan KS, Schürpf T, Sears CL, Liu Q, Shrubsole MJ, Coffey RJ, Lau KS. Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors. Cell 2023; 186:5620-5637.e16. [PMID: 38065082 PMCID: PMC10756562 DOI: 10.1016/j.cell.2023.11.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 08/23/2023] [Accepted: 11/02/2023] [Indexed: 12/18/2023]
Abstract
Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways. Integrated single-cell and spatial transcriptomic data revealed recurring epithelial programs and infiltrating immune states along progression pseudotime. We discovered an immune exclusion signature (IEX), consisting of extracellular matrix regulators DDR1, TGFBI, PAK4, and DPEP1, that charts with CIN+ tumor progression, is associated with reduced cytotoxic cell infiltration, and shows prognostic value in independent cohorts. This spatial multi-omic atlas provides insights into colorectal tumor-microenvironment co-evolution, serving as a resource for stratification and targeted treatments.
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Affiliation(s)
- Cody N Heiser
- Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Alan J Simmons
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Frank Revetta
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Eliot T McKinley
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Marisol A Ramirez-Solano
- Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37235, USA
| | - Jiawei Wang
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Harsimran Kaur
- Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Justin Shao
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Computer Science, Vanderbilt University, Nashville, TN 37235, USA
| | - Gregory D Ayers
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Yu Wang
- Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37235, USA
| | - Sarah E Glass
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Naila Tasneem
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Zhengyi Chen
- Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Yan Qin
- Incendia Therapeutics, Inc., Boston, MA 02135, USA
| | - William Kim
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Andrea Rolong
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Bob Chen
- Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Paige N Vega
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Julia L Drewes
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Nicholas O Markham
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Nabil Saleh
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Fotis Nikolos
- Department of Urology, Neal Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Simon Vandekar
- Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37235, USA
| | - Angela L Jones
- Vanderbilt Technologies for Advanced Genomics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - M Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Joseph T Roland
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Keith S Chan
- Department of Urology, Neal Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA
| | | | - Cynthia L Sears
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Qi Liu
- Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37235, USA
| | - Martha J Shrubsole
- Department of Medicine, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Robert J Coffey
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
| | - Ken S Lau
- Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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6
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Weber CAM, Krönke N, Volk V, Auber B, Förster A, Trost D, Geffers R, Esmaeilzadeh M, Lalk M, Nabavi A, Samii A, Krauss JK, Feuerhake F, Hartmann C, Wiese B, Brand F, Weber RG. Rare germline variants in POLE and POLD1 encoding the catalytic subunits of DNA polymerases ε and δ in glioma families. Acta Neuropathol Commun 2023; 11:184. [PMID: 37990341 PMCID: PMC10664377 DOI: 10.1186/s40478-023-01689-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 11/11/2023] [Indexed: 11/23/2023] Open
Abstract
Pathogenic germline variants in the DNA polymerase genes POLE and POLD1 cause polymerase proofreading-associated polyposis, a dominantly inherited disorder with increased risk of colorectal carcinomas and other tumors. POLE/POLD1 variants may result in high somatic mutation and neoantigen loads that confer susceptibility to immune checkpoint inhibitors (ICIs). To explore the role of POLE/POLD1 germline variants in glioma predisposition, whole-exome sequencing was applied to leukocyte DNA of glioma patients from 61 tumor families with at least one glioma case each. Rare heterozygous POLE/POLD1 missense variants predicted to be deleterious were identified in glioma patients from 10 (16%) families, co-segregating with the tumor phenotype in families with available DNA from several tumor patients. Glioblastoma patients carrying rare POLE variants had a mean overall survival of 21 months. Additionally, germline variants in POLD1, located at 19q13.33, were detected in 2/34 (6%) patients with 1p/19q-codeleted oligodendrogliomas, while POLE variants were identified in 2/4 (50%) glioblastoma patients with a spinal metastasis. In 13/15 (87%) gliomas from patients carrying POLE/POLD1 variants, features of defective polymerase proofreading, e.g. hypermutation, POLE/POLD1-associated mutational signatures, multinucleated cells, and increased intratumoral T cell response, were observed. In a CRISPR/Cas9-derived POLE-deficient LN-229 glioblastoma cell clone, a mutator phenotype and delayed S phase progression were detected compared to wildtype POLE cells. Our data provide evidence that rare POLE/POLD1 germline variants predispose to gliomas that may be susceptible to ICIs. Data compiled here suggest that glioma patients carrying POLE/POLD1 variants may be recognized by cutaneous manifestations, e.g. café-au-lait macules, and benefit from surveillance colonoscopy.
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Affiliation(s)
- Christine A M Weber
- Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Nicole Krönke
- Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Valery Volk
- Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Bernd Auber
- Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Alisa Förster
- Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | | | - Robert Geffers
- Genome Analytics Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | | | - Michael Lalk
- Department of Neurosurgery, KRH Klinikum Nordstadt, Hannover, Germany
| | - Arya Nabavi
- Department of Neurosurgery, KRH Klinikum Nordstadt, Hannover, Germany
| | - Amir Samii
- Department of Neurosurgery, International Neuroscience Institute, Hannover, Germany
| | - Joachim K Krauss
- Department of Neurosurgery, Hannover Medical School, Hannover, Germany
| | - Friedrich Feuerhake
- Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany
- Institute for Neuropathology, University Clinic Freiburg, Freiburg, Germany
| | - Christian Hartmann
- Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Bettina Wiese
- Department of Neurosurgery, Hannover Medical School, Hannover, Germany
- Department of Neurology, Henriettenstift, Diakovere Krankenhaus gGmbH, Hannover, Germany
| | - Frank Brand
- Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Ruthild G Weber
- Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
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7
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Zhu LH, Dong J, Li WL, Kou ZY, Yang J. Genotype-Phenotype Correlations in Autosomal Dominant and Recessive APC Mutation-Negative Colorectal Adenomatous Polyposis. Dig Dis Sci 2023:10.1007/s10620-023-07890-9. [PMID: 36862359 DOI: 10.1007/s10620-023-07890-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/17/2023] [Indexed: 03/03/2023]
Abstract
The most prevalent type of intestinal polyposis, colorectal adenomatous polyposis (CAP), is regarded as a precancerous lesion of colorectal cancer with obvious genetic characteristics. Early screening and intervention can significantly improve patients' survival and prognosis. The adenomatous polyposis coli (APC) mutation is believed to be the primary cause of CAP. There is, however, a subset of CAP with undetectable pathogenic mutations in APC, known as APC (-)/CAP. The genetic predisposition to APC (-)/CAP has largely been associated with germline mutations in some susceptible genes, including the human mutY homologue (MUTYH) gene and the Nth-like DNA glycosylase 1 (NTHL1) gene, and DNA mismatch repair (MMR) can cause autosomal recessive APC (-)/CAP. Furthermore, autosomal dominant APC (-)/CAP could occur as a result of DNA polymerase epsilon (POLE)/DNA polymerase delta 1 (POLD1), axis inhibition protein 2 (AXIN2), and dual oxidase 2 (DUOX2) mutations. The clinical phenotypes of these pathogenic mutations vary greatly depending on their genetic characteristics. Therefore, in this study, we present a comprehensive review of the association between autosomal recessive and dominant APC (-)/CAP genotypes and clinical phenotypes and conclude that APC (-)/CAP is a disease caused by multiple genes with different phenotypes and interaction exists in the pathogenic genes.
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Affiliation(s)
- Li-Hua Zhu
- Department of Oncology, The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Rd, Kunming, 650032, China
| | - Jian Dong
- Department of Internal Medicine-Oncology, Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China
| | - Wen-Liang Li
- Colorectal Cancer Clinical Research Center, Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China
| | - Zhi-Yong Kou
- Department of Oncology, The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Rd, Kunming, 650032, China
| | - Jun Yang
- Department of Oncology, The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Rd, Kunming, 650032, China.
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8
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Wang Q, Shen X, Chen G, Du J. How to overcome resistance to immune checkpoint inhibitors in colorectal cancer: From mechanisms to translation. Int J Cancer 2023. [PMID: 36752642 DOI: 10.1002/ijc.34464] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 01/14/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023]
Abstract
Immunotherapy, especially with immune checkpoint inhibitors (ICIs), has shown advantages in cancer treatment and is a new hope for patients who have failed multiline therapy. However, in colorectal cancer (CRC), the benefit is limited to a small subset of patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic CRC (mCRC). In addition, 45% to 60% of dMMR/MSI-H mCRC patients showed primary or acquired resistance to ICIs. This means that these patients may have potential unknown pathways mediating immune escape. Almost all mismatch repair-proficient (pMMR) or microsatellite-stable (MSS) mCRC patients do not benefit from ICIs. In this review, we discuss the mechanisms of action of ICIs and their current status in CRC. We then discuss the mechanisms of primary and acquired resistance to ICIs in CRC. Finally, we discuss promising therapeutic strategies to overcome resistance to ICIs in the clinic.
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Affiliation(s)
- Qianyu Wang
- Medical Department of General Surgery, The 1st Medical Center, Chinese PLA General Hospital, Beijing, China.,The Second School of Clinical Medicine, Shanxi Medical University, Taiyuan, China
| | - Xiaofei Shen
- Department of General Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Gang Chen
- Medical Department of General Surgery, The 1st Medical Center, Chinese PLA General Hospital, Beijing, China.,Department of General Surgery, The 7th Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Junfeng Du
- Medical Department of General Surgery, The 1st Medical Center, Chinese PLA General Hospital, Beijing, China.,Department of General Surgery, The 7th Medical Center, Chinese PLA General Hospital, Beijing, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
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9
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Zheng Z, Bian C, Wang H, Su J, Meng L, Xin Y, Jiang X. Prediction of immunotherapy efficacy and immunomodulatory role of hypoxia in colorectal cancer. Ther Adv Med Oncol 2022; 14:17588359221138383. [PMID: 36425871 PMCID: PMC9679351 DOI: 10.1177/17588359221138383] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 10/26/2022] [Indexed: 11/26/2023] Open
Abstract
Immunotherapy has been used in the clinical treatment of colorectal cancer (CRC); however, most patients fail to achieve satisfactory survival benefits. Biomarkers with high specificity and sensitivity are being increasingly developed to predict the efficacy of CRC immunotherapy. In addition to DNA alteration markers, such as microsatellite instability/mismatch repair and tumor mutational burden, immune cell infiltration and immune checkpoints (ICs), epigenetic changes and no-coding RNA, and gut microbiomes all show potential predictive ability. Recently, the hypoxic tumor microenvironment (TME) has been identified as a key factor mediating CRC immune evasion and resistance to treatment. Hypoxia-inducible factor-1α is the central transcription factor in the hypoxia response that drives the expression of a vast number of survival genes by binding to the hypoxia response element in cancer and immune cells in the TME. Hypoxia regulates angiogenesis, immune cell infiltration and activation, expression of ICs, and secretion of various immune molecules in the TME and is closely associated with the immunotherapeutic efficacy of CRC. Currently, various agents targeting hypoxia have been found to improve the TME and enhance the efficacy of immunotherapy. We reviewed current markers commonly used in CRC to predict therapeutic efficacy and the mechanisms underlying hypoxia-induced angiogenesis and tumor immune evasion. Exploring the mechanisms by which hypoxia affects the TME will assist the discovery of new immunotherapeutic predictive biomarkers and development of more effective combinations of agents targeting hypoxia and immunotherapy.
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Affiliation(s)
- Zhuangzhuang Zheng
- Department of Radiation Oncology, the First Hospital of Jilin University, Changchun China
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, Changchun, China
- NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, China
| | - Chenbin Bian
- Department of Radiation Oncology, the First Hospital of Jilin University, Changchun China
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, Changchun, China
- NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, China
| | - Huanhuan Wang
- Department of Radiation Oncology, the First Hospital of Jilin University, Changchun China
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, Changchun, China
- NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, China
| | - Jing Su
- Department of Radiation Oncology, the First Hospital of Jilin University, Changchun China
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, Changchun, China
- NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, China
| | - Lingbin Meng
- Department of Hematology and Medical Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Ying Xin
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, 126 Xinmin Street, Changchun 130021, China
| | - Xin Jiang
- Department of Radiation Oncology, the First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China
- Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, Changchun, China
- NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, China
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10
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Favre L, Cohen J, Calderaro J, Pécriaux A, Nguyen C, Bourgoin R, Larnaudie L, Dupuy A, Ollier M, Lechapt E, Sloma I, Tournigand C, Rousseau B, Pujals A. High prevalence of unusual KRAS, NRAS, and BRAF mutations in POLE-hypermutated colorectal cancers. Mol Oncol 2022; 16:3055-3065. [PMID: 35624529 PMCID: PMC9441000 DOI: 10.1002/1878-0261.13257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 04/05/2022] [Accepted: 05/25/2022] [Indexed: 12/04/2022] Open
Abstract
Exonucleasic domain POLE (edPOLE) mutations, which are responsible for a hypermutated tumor phenotype, occur in 1-2% of colorectal cancer (CRC) cases. These alterations represent an emerging biomarker for response to immune checkpoint blockade. This study aimed to assess the molecular characteristics of edPOLE-mutated tumors to facilitate patient screening. Based on opensource data analysis, we compared the prevalence of edPOLE mutations in a control group of unselected CRC patients (n = 222) vs a group enriched for unusual BRAF/RAS mutations (n = 198). Tumor mutational burden (TMB) and immune infiltrate of tumors harboring edPOLE mutations were then analyzed. In total, 420 CRC patients were analyzed: 11 edPOLE-mutated tumors were identified, most frequently in microsatellite (MMR)-proficient young (< 70 years) male patients, with left-sided tumors harboring noncodon 12 KRAS mutation. The prevalence of edPOLE-mutated tumors in the control vs the experimental screening group was, respectively, 0.45% (n = 1) vs 5.0% (n = 10). Among the 11 edPOLE-mutated cases, two had a low TMB, three were hypermutated, and six were ultramutated. EdPOLE-mutated cases had a high CD8+ tumor-infiltrating lymphocyte (TIL) infiltration. These clinicopathological and molecular criteria may help to identify edPOLE mutations associated with a high TMB in CRC, and improve the selection of patients who could benefit from immunotherapy.
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Affiliation(s)
- Loetitia Favre
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
- INSERM, IMRBUniv Paris Est CreteilFrance
| | - Justine Cohen
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | - Julien Calderaro
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
- INSERM, IMRBUniv Paris Est CreteilFrance
| | - Adrien Pécriaux
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | | | - Rémi Bourgoin
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | - Laura Larnaudie
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | | | - Marie Ollier
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | - Emmanuèle Lechapt
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
- INSERM, IMRBUniv Paris Est CreteilFrance
| | - Ivan Sloma
- INSERM, IMRBUniv Paris Est CreteilFrance
- Département d'Hématologie BiologiqueAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | - Christophe Tournigand
- INSERM, IMRBUniv Paris Est CreteilFrance
- Service d'Oncologie MédicaleAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
| | - Benoit Rousseau
- Service d'Oncologie MédicaleAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
- Mortimer B. Zuckerman Research CenterMemorial Sloan Kettering Cancer CenterNew YorkNYUSA
| | - Anaïs Pujals
- Département de PathologieAP‐HP, Centre Hospitalier Universitaire Henri MondorCréteilFrance
- INSERM, IMRBUniv Paris Est CreteilFrance
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11
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Boukouris AE, Theochari M, Stefanou D, Papalambros A, Felekouras E, Gogas H, Ziogas DC. Latest evidence on immune checkpoint inhibitors in metastatic colorectal cancer: A 2022 update. Crit Rev Oncol Hematol 2022; 173:103663. [PMID: 35351582 DOI: 10.1016/j.critrevonc.2022.103663] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 02/07/2023] Open
Abstract
The long-term remissions induced by immune-checkpoint inhibitors (ICIs) in many types of cancers have opened up the possibility of a broader use of immunotherapy in less immunogenic but genetically heterogeneous tumours. Regarding metastatic colorectal cancer (mCRC), in first-line setting, pembrolizumab has been approved as preferred option and nivolumab, alone or in combination with ipilimumab as alternative option for patients with mismatch-repair-deficient and microsatellite instability-high (dMMR/MSI-H) disease, independently of their eligibility for intensive chemotherapy. In subsequent lines, both these immunotherapeutic regimens (e.g., pembrolizumab and nivolumab+/-ipilimumab) as well as dostarlimab-gxly are currently recommended for patients with dMMR/MSI-H chemo-resistant mCRC who have not previously received an ICI. Beginning from the rationale behind the immune-mediated interplay in the dMMR/MSI-H bowel microenvironment, we provide here an update on the evolution status of all available, approved or not, ICIs in mCRC, describing their efficacy and toxicity profile with an emphasis on the pivotal trials supporting current colorectal indications. For each ICI agent, the results from combinations under investigation, particularly for those being upgraded in clinical phasing, the perspectives but also the limitations of main ongoing trials are thoroughly discussed. In the close future, upcoming data are expected to confirm the clinical benefit of ICIs and to further expand their role in mCRC.
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Affiliation(s)
- Aristeidis E Boukouris
- First Department of Internal Medicine, Korgialeneion-Benakeion General Hospital, Athens, Greece.
| | - Maria Theochari
- First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
| | - Dimitra Stefanou
- First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
| | - Alexandros Papalambros
- First Department of Surgery, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, Athens, Greece.
| | - Evangelos Felekouras
- First Department of Surgery, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, Athens, Greece.
| | - Helen Gogas
- First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
| | - Dimitrios C Ziogas
- First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
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12
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Biscaglia G, Latiano A, Castellana S, Fontana R, Gentile A, Latiano T, Corritore G, Panza A, Nardella M, Martino G, Bossa F, Perri F, Mazza T, Andriulli A, Palmieri O. Germline Alterations in Patients With IBD-associated Colorectal Cancer. Inflamm Bowel Dis 2022; 28:447-454. [PMID: 34347074 DOI: 10.1093/ibd/izab195] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Patients with inflammatory bowel diseases (IBD), both ulcerative colitis (UC) and Crohn's disease (CD), are at risk of developing a colorectal cancer (CRC). No information is available on the contribution of patients' genetic background to CRC occurrence. This study investigates germline alterations in patients with IBD-associated CRC. METHODS We profiled a panel of 39 genes potentially involved in cancer predisposition and searched for germline variants in IBD patients with CRC or high-grade dysplasia. RESULTS After clinical exclusion of genetic cancer syndromes, 25 IBD patients (4 CD and 21 UC) with CRC or high-grade dysplasia were studied. After excluding variants with low likelihood of pathogenicity (classes 1 or 2 according the International Agency for Research on Cancer [IARC]), the panel identified pathogenic variants, likely pathogenic, or variants with unknown significance in 18 patients (72%). Six patients (24%) carried pathogenic or likely variants (IARC class 5 or 4). Of the identified variants, 4 encompassed the APC region, 3 the MLH1 gene, and the remaining ones the MSH2, MSH3, monoallelic MUTYH, EPCAM, BRCA1, CHEK2, POLD1, POLE, CDKN2A, and PDGFRA genes. Four patients carried at least 2 variants in different genes. Duration of IBD was significantly shorter in carriers of 4 or 5 IARC variants (7 years; range 0-21; P = .002) and in those with variants with unknown significance (12 years; range 0-22; P = .005) compared with patients without or with only benign variations (23.5 years; range 15-34). CONCLUSIONS In silico analysis and sequence-based testing of germline DNA from IBD patients with CRC or high-grade dysplasia detected 24% of variants positioned in pathogenic classes. In patients with type 3, 4, and 5 variants, the onset of high-grade dysplasia or CRC was significantly earlier than in patients with benign or unidentified variants. The screening for these genes could identify IBD patients requiring a more intensive endoscopic surveillance for earlier detection of dysplastic changes.
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Affiliation(s)
- Giuseppe Biscaglia
- Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Anna Latiano
- Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Stefano Castellana
- Unit of Bioinformatics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Rosanna Fontana
- Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Annamaria Gentile
- Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Tiziana Latiano
- Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Giuseppe Corritore
- Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Anna Panza
- Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Marianna Nardella
- Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Giuseppina Martino
- Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Fabrizio Bossa
- Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Francesco Perri
- Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Tommaso Mazza
- Unit of Bioinformatics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Angelo Andriulli
- Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Orazio Palmieri
- Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
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13
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Li M, Kaili D, Shi L. Biomarkers for response to immune checkpoint inhibitors in gastrointestinal cancers. World J Gastrointest Oncol 2022; 14:19-37. [PMID: 35116101 PMCID: PMC8790411 DOI: 10.4251/wjgo.v14.i1.19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 09/08/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancers account for a large proportion of cancer deaths worldwide and pose a major public health challenge. Immunotherapy is considered to be one of the prominent and successful approaches in cancer treatment in recent years. Among them, immune checkpoint inhibitor (ICI) therapy, has received widespread attention, and many clinical findings support the feasibility of ICIs, with sustained responses and significantly prolonged lifespan observed in a wide range of tumors. However, patients treated with ICIs have not fully benefited, and therefore, the identification and development of biomarkers for predicting ICI treatment response have received further attention and exploration. From tumor genome to molecular interactions in the tumor microenvironment, and further expanding to circulating biomarkers and patient characteristics, the exploration of biomarkers is evolving with high-throughput sequencing as well as bioinformatics. More large-scale prospective and specific studies are needed to explore biomarkers in GI cancers. In this review, we summarize the known biomarkers used in ICI therapy for GI tumors. In addition, some ICI biomarkers applied to other tumors are included to provide insights and further validation for GI tumors. Moreover, we present single-cell analysis and machine learning approaches that have emerged in recent years. Although there are no clear applications yet, it can be expected that these techniques will play an important role in the application of biomarker prediction.
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Affiliation(s)
- Meng Li
- School of Life Sciences, Chongqing University, Chongqing 400044, China
| | - Denis Kaili
- Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, United States
| | - Lei Shi
- School of Life Sciences, Chongqing University, Chongqing 400044, China
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14
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Du F, Liu Y. Predictive molecular markers for the treatment with immune checkpoint inhibitors in colorectal cancer. J Clin Lab Anal 2022; 36:e24141. [PMID: 34817097 PMCID: PMC8761449 DOI: 10.1002/jcla.24141] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/12/2021] [Accepted: 11/13/2021] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer is one of the most common malignant tumors and, hence, has become one of the most important public health issues in the world. Treatment with immune checkpoint inhibitors (ICIs) successfully improves the survival rate of patients with melanoma, non-small-cell lung cancer, and other malignancies, and its application in metastatic colorectal cancer is being actively explored. However, a few patients develop drug resistance. Predictive molecular markers are important tools to precisely screen patient groups that can benefit from treatment with ICIs. The current article focused on certain important predictive molecular markers for ICI treatment in colorectal cancer, including not only some of the mature molecular markers, such as deficient mismatch repair (d-MMR), microsatellite instability-high (MSI-H), tumor mutational burden (TMB), programmed death-ligand-1 (PD-L1), tumor immune microenvironment (TiME), and tumor-infiltrating lymphocytes (TILs), but also some of the novel molecular markers, such as DNA polymerase epsilon (POLE), polymerase delta 1 (POLD1), circulating tumor DNA (ctDNA), and consensus molecular subtypes (CMS). We have reviewed these markers in-depth and presented the results from certain important studies, which suggest their applicability in CRC and indicate their advantages and disadvantages. We hope this article is helpful for clinicians and researchers to systematically understand these markers and can guide the treatment of colorectal cancer.
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Affiliation(s)
- Fenqi Du
- Department of Colorectal SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Yanlong Liu
- Department of Colorectal SurgeryHarbin Medical University Cancer HospitalHarbinChina
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15
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Michaeli O, Ladany H, Erez A, Shachar SB, Izraeli S, Lidzbarsky G, Basel-Salmon L, Biskup S, Maruvka YE, Toledano H, Goldberg Y. Di-genic inheritance of germline POLE and PMS2 pathogenic variants causes a unique condition associated with pediatric cancer predisposition. Clin Genet 2021; 101:442-447. [PMID: 34967012 DOI: 10.1111/cge.14106] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 12/12/2021] [Accepted: 12/25/2021] [Indexed: 11/25/2022]
Abstract
Polymerase proofreading-associated polyposis (PPAP) and Lynch syndrome, caused by mutated POLE and mismatch repair (MMR) genes, respectively, are associated with adult-onset cancer. PPAP and MMR-deficient tumors are both hypermutated, and each has a unique mutational signature. We describe a 4.5-year-old boy with multiple café au lait spots who presented with metastatic Sonic Hedgehog-activated medulloblastoma, with partial response to intensive chemotherapy and immunotherapy. Tumor showed microsatellite stability, loss of PMS2 nuclear expression, and an exceptionally high tumor mutational burden of 276 Mut/Mb. Germline molecular analysis revealed an inherited heterozygous pathogenic POLE variant and a de novo heterozygous PMS2 pathogenic variant. The tumor featured the MMR, POLE, and POLE+MMR mutational signatures. This is the first description of a di-genic condition, which we named "POL-LYNCH syndrome", manifested by an aggressive ultra-mutant pediatric medulloblastoma with a unique genomic signature. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Orli Michaeli
- Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | - Hagay Ladany
- Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Haifa, Israel
| | - Ayelet Erez
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Shay Ben Shachar
- Clalit Research Institute & Department of Genetics, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | - Shai Izraeli
- Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gabriel Lidzbarsky
- Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel
| | - Lina Basel-Salmon
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel
| | - Saskia Biskup
- CeGaT Center for Genomics and Transcriptomics, Tuebingen, Germany
| | - Yosef E Maruvka
- Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Haifa, Israel
| | - Helen Toledano
- Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Goldberg
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel
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16
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POLE, POLD1, and NTHL1: the last but not the least hereditary cancer-predisposing genes. Oncogene 2021; 40:5893-5901. [PMID: 34363023 DOI: 10.1038/s41388-021-01984-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023]
Abstract
POLE, POLD1, and NTHL1 are involved in DNA replication and have recently been recognized as hereditary cancer-predisposing genes, because their alterations are associated with colorectal cancer and other tumors. POLE/POLD1-associated syndrome shows an autosomal dominant inheritance, whereas NTHL1-associated syndrome follows an autosomal recessive pattern. Although the prevalence of germline monoallelic POLE/POLD1 and biallelic NTHL1 pathogenic variants is low, they determine different phenotypes with a broad tumor spectrum overlapping that of other hereditary conditions like Lynch Syndrome or Familial Adenomatous Polyposis. Endometrial and breast cancers, and probably ovarian and brain tumors are also associated with POLE/POLD1 alterations, while breast cancer and other unusual tumors are correlated with NTHL1 pathogenic variants. POLE-mutated colorectal and endometrial cancers are associated with better prognosis and may show favorable responses to immunotherapy. Since POLE/POLD1-mutated tumors show a high tumor mutational burden producing an increase in neoantigens, the identification of POLE/POLD1 alterations could help select patients suitable for immunotherapy treatment. In this review, we will investigate the role of POLE, POLD1, and NTHL1 genetic variants in cancer predisposition, discussing the potential future therapeutic applications and assessing the utility of performing a routine genetic testing for these genes, in order to implement prevention and surveillance strategies in mutation carriers.
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17
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Rochefort P, Desseigne F, Bonadona V, Dussart S, Coutzac C, Sarabi M, la Fouchardiere CD. Immune checkpoint inhibitor sensitivity of DNA repair deficient tumors. Immunotherapy 2021; 13:1205-1213. [PMID: 34494466 DOI: 10.2217/imt-2021-0024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Faithful DNA replication is necessary to maintain genome stability and implicates a complex network with several pathways depending on DNA damage type: homologous repair, nonhomologous end joining, base excision repair, nucleotide excision repair and mismatch repair. Alteration in components of DNA repair machinery led to DNA damage accumulation and potentially carcinogenesis. Preclinical data suggest sensitivity to immune checkpoint inhibitors in tumors with DNA repair deficiency. Here, we review clinical studies that explored the use of immune checkpoint inhibitor in patient harboring tumor with DNA repair deficiency.
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Affiliation(s)
- Pauline Rochefort
- Department of Medical Oncology, Centre Léon Bérard, 69008, Lyon, France
| | | | - Valérie Bonadona
- Unit of Genetic Epidemiology & Prevention, Centre Léon Bérard, 69008, Lyon, France
| | - Sophie Dussart
- Unit of Genetic Epidemiology & Prevention, Centre Léon Bérard, 69008, Lyon, France
| | - Clélia Coutzac
- Department of Medical Oncology, Centre Léon Bérard, 69008, Lyon, France
| | - Matthieu Sarabi
- Department of Medical Oncology, Centre Léon Bérard, 69008, Lyon, France
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18
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Zhou C, Cheng X, Tu S. Current status and future perspective of immune checkpoint inhibitors in colorectal cancer. Cancer Lett 2021; 521:119-129. [PMID: 34464671 DOI: 10.1016/j.canlet.2021.07.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/23/2021] [Accepted: 07/15/2021] [Indexed: 12/16/2022]
Abstract
Immune checkpoint inhibitors (ICIs), as a subverter of immunotherapy in oncology, are changing all aspects of therapy for malignant tumors, especially their remarkable effects on melanoma and non-small cell lung cancer (NSCLC). For colorectal cancer (CRC), only a small number of patients with high immunogenicity (microsatellite instability-high/mismatch-repair deficient (MSI-H/dMMR)) benefit greatly from ICIs treatment, and most CRC patients with low immunogenicity (microsatellite instability-low/mismatch-repair proficient (MSI-L/pMMR)) do not. Currently, numerous clinical trials are ongoing to improve CRC patients' response to ICIs immunotherapy through better patient selection and novel combination strategies. Thus, this review discusses the current status and latest progress of ICIs treatment in CRC. We expect that these studies can change the pattern of CRC immunotherapy in the future.
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Affiliation(s)
- Cong Zhou
- Department of Oncology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Xiaojiao Cheng
- Department of Oncology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China; State Key Laboratory of Oncogenesis and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shuiping Tu
- Department of Oncology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China; State Key Laboratory of Oncogenesis and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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19
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Szmyd B, Mlynarski W, Pastorczak A. Genetic predisposition to lymphomas: Overview of rare syndromes and inherited familial variants. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2021; 788:108386. [PMID: 34893151 DOI: 10.1016/j.mrrev.2021.108386] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 05/14/2021] [Accepted: 06/03/2021] [Indexed: 01/19/2023]
Abstract
Approximately 10 % of malignancies occur in carriers of germline mutations predisposing to cancer. A high risk of developing lymphomas has been noted in many primary immunodeficiencies, including DNA repair disorders. Moreover, implementation of next-generation sequencing has recently enabled to uncover rare genetic variants predisposing patients to lymphoid neoplasms. Some patients harboring inherited predisposition to lymphomas require dedicated clinical management, which will contribute to effective cancer treatment and to the prevention of potential severe toxicities and secondary malignancies. In line with that, our review summarizes the natural history of lymphoid tumors developing on different germline genetic backgrounds and discusses the progress that has been made toward successfully treating these malignancies.
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Affiliation(s)
- Bartosz Szmyd
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland.
| | - Wojciech Mlynarski
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland.
| | - Agata Pastorczak
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland.
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20
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Abstract
Significance: Genomic instability, a hallmark of cancer, renders cancer cells susceptible to genomic stress from both endogenous and exogenous origins, resulting in the increased tendency to accrue DNA damage, chromosomal instability, or aberrant DNA localization. Apart from the cell autonomous tumor-promoting effects, genomic stress in cancer cells could have a profound impact on the tumor microenvironment. Recent Advances: Recently, it is increasingly appreciated that harnessing genomic stress could provide a promising strategy to revive antitumor immunity, and thereby offer new therapeutic opportunities in cancer treatment. Critical Issues: Genomic stress is closely intertwined with antitumor immunity via mechanisms involving the direct crosstalk with DNA damage response components, upregulation of immune-stimulatory/inhibitory ligands, release of damage-associated molecular patterns, increase of neoantigen repertoire, and activation of DNA sensing pathways. A better understanding of these mechanisms will provide molecular basis for exploiting the genomic stress to boost antitumor immunity. Future Directions: Future research should pay attention to the heterogeneity between individual cancers in the genomic instability and the associated immune response, and how to balance the toxicity and benefit by specifying the types, potency, and treatment sequence of genomic stress inducer in therapeutic practice. Antioxid. Redox Signal. 34, 1128-1150.
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Affiliation(s)
- Congying Pu
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Siyao Tao
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jun Xu
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Min Huang
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
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21
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André T, Cohen R. [Is high tumor mutation burden predictive of immune checkpoint blockade efficacy in terms of overall survival across all cancer types?]. Bull Cancer 2021; 108:669-671. [PMID: 33985763 DOI: 10.1016/j.bulcan.2021.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 11/24/2022]
Affiliation(s)
- Thierry André
- AP-HP, Sorbonne université, service d'oncologie médicale, hôpital Saint-Antoine, centre de recherche Saint-Antoine, SIRIC Curamus, unité mixte de recherche scientifique 938, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue nationale contre le cancer, Inserm, 75012 Paris, France.
| | - Romain Cohen
- AP-HP, Sorbonne université, service d'oncologie médicale, hôpital Saint-Antoine, centre de recherche Saint-Antoine, SIRIC Curamus, unité mixte de recherche scientifique 938, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue nationale contre le cancer, Inserm, 75012 Paris, France
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22
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Roufas C, Georgakopoulos-Soares I, Zaravinos A. Molecular correlates of immune cytolytic subgroups in colorectal cancer by integrated genomics analysis. NAR Cancer 2021; 3:zcab005. [PMID: 34316699 PMCID: PMC8210146 DOI: 10.1093/narcan/zcab005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 02/03/2021] [Accepted: 02/09/2021] [Indexed: 12/17/2022] Open
Abstract
Although immune checkpoint inhibition (ICI) has shown promising results in metastatic dMMR/MSI-H colorectal cancer (CRC), the majority of pMMR/MSS patients do not respond to such therapies. To systematically evaluate the determinants of immune response in CRC, we explored whether patients with diverse levels of immune cytolytic activity (CYT) have different patterns of chromothripsis and kataegis. Analysis of CRC genomic data from the TCGA, indicated an excess of chromothriptic clusters among CYT-low colon adenocarcinomas, affecting known cancer drivers (APC, KRAS, BRAF, TP53 and FBXW7), immune checkpoints (CD274, PDCD1LG2, IDO1/2 and LAG3) and immune-related genes (ENTPD1, PRF1, NKG7, FAS, GZMA/B/H/K and CD73). CYT-high tumors were characterized by hypermutation, enrichment in APOBEC-associated mutations and kataegis events, as well as APOBEC activation. We also assessed differences in the most prevalent mutational signatures (SBS15, SBS20, SBS54 and DBS2) across cytolytic subgroups. Regarding the composition of immune cells in the tumor milieu, we found enrichment of M1 macrophages, CD8+ T cells and Tregs, as well as higher CD8+ T-cells/Tregs ratio among CYT-high tumors. CYT-high patients had higher immunophenoscores, which is predictive of their responsiveness if they were to be treated with anti-PD-1 alone or in combination with anti-CTLA-4 drugs. These results could have implications for patient responsiveness to immune checkpoint inhibitors.
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Affiliation(s)
- Constantinos Roufas
- Department of Life Sciences, School of Sciences, European University Cyprus, 1516 Nicosia, Cyprus
| | - Ilias Georgakopoulos-Soares
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA
| | - Apostolos Zaravinos
- Department of Basic Medical Sciences, College of Medicine, Member of QU Health, Qatar University, 2713 Doha, Qatar
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23
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Cohen R, Rousseau B, Vidal J, Colle R, Diaz LA, André T. Immune Checkpoint Inhibition in Colorectal Cancer: Microsatellite Instability and Beyond. Target Oncol 2021; 15:11-24. [PMID: 31786718 DOI: 10.1007/s11523-019-00690-0] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Immune checkpoints inhibitors (ICIs) have been a breakthrough, with unique response and survival patterns compared with chemotherapy for patients with advanced Mismatch Repair-deficient/Microsatellite instable (dMMR/MSI) colorectal cancer, but have shown disappointing results in Mismatch Repair-proficient/Microsatellite stable (pMMR/MSS) colorectal cancer. As up to 50% of patients harboring dMMR/MSI advanced cancers will ultimately progress after PD-1 blockade, biomarkers are needed to predict response/resistance to immunotherapy and to select patients for immunomodulating combination therapies. Patients with pMMR/MSS colorectal cancer present with distinct immune profiles compared to dMMR/MSI tumors, giving evidence of different immune escape mechanisms, which could be overcome through individualized immunotherapeutic strategies. In this review we discuss the latest developments in the field of immunotherapy for dMMR/MSI and pMMR/MSS colorectal cancers, and unresolved questions and considerations concerning the use of ICI therapies in this population. Future immunomodulation strategies based on biomarker selection (tumor mutational burden, Immunoscore®, mutational profile) are discussed.
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Affiliation(s)
- Romain Cohen
- Sorbonne Université, Medical Oncology Department, Hôpital Saint-Antoine, AP-HP, 184 Rue du Faubourg Saint-Antoine, 75012, Paris, France.
| | - Benoît Rousseau
- Department of Medicine-Solid Tumor Division, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Joana Vidal
- Department of Medicine-Solid Tumor Division, Memorial Sloan Kettering Cancer Center, New York, USA
- Medical Oncology Department, Hospital del Mar-IMIM, CIBERONC Instituto de Salud Carlos III, Barcelona, Spain
| | - Raphaël Colle
- Sorbonne Université, Medical Oncology Department, Hôpital Saint-Antoine, AP-HP, 184 Rue du Faubourg Saint-Antoine, 75012, Paris, France
| | - Luis A Diaz
- Department of Medicine-Solid Tumor Division, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Thierry André
- Sorbonne Université, Medical Oncology Department, Hôpital Saint-Antoine, AP-HP, 184 Rue du Faubourg Saint-Antoine, 75012, Paris, France
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24
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Treatments after first progression in metastatic colorectal cancer. A literature review and evidence-based algorithm. Cancer Treat Rev 2020; 92:102135. [PMID: 33307331 DOI: 10.1016/j.ctrv.2020.102135] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 12/23/2022]
Abstract
Prolonging survival, achieving symptoms palliation and preserving quality of life are the primary therapeutic goals of treatments administered after disease progression in mCRC. Even if the impact of these therapies on the prognosis of affected patients is less relevant than the impact of the upfront treatment, tailoring the optimal second-line therapy is increasingly important. Several therapeutic options are available, and different factors including not only patient- and disease-related characteristics, but also the first-line treatment received (i.e., type, timing of disease progression, observed outcome and reported toxicities) may drive this choice. Herein, we describe the current state of the art in the landscape of treatments after progression in mCRC. Based on a critical review of the literature, we built a patient-oriented therapeutic algorithm, aiming to guide clinicians in their daily decision-making.
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25
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Rosa RCA, Yurchenko AA, Chahud F, Ribeiro-Silva A, Brunaldi MO, Silva WA, Kannouche PL, Nikolaev S, Ferraz VEDF. First description of ultramutated endometrial cancer caused by germline loss-of-function and somatic exonuclease domain mutations in POLE gene. Genet Mol Biol 2020; 43:e20200100. [PMID: 33001133 PMCID: PMC7521106 DOI: 10.1590/1678-4685-gmb-2020-0100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 07/08/2020] [Indexed: 11/22/2022] Open
Abstract
Endometrial cancer (EC) harboring heterozygous POLE proofreading inactivating mutations (POLE-exo*) is associated with an increased number of somatic mutations that result in a distinctive anti-tumor immune response. However, the consequences of such POLE mutations in the context of the missing wild-type allele have not yet been described in endometrial tumors. A 72-year-old woman harboring a germline monoallelic frameshift mutation (p.Pro269fsTer26) in POLE was diagnosed with an EC having a somatic heterozygous mutation in the exonuclease domain of POLE (S459F). Targeted gene sequencing revealed an ultramutated phenotype (381 mutations/Mb) in the tumor and a 2-fold excess of mutations on the DNA leading strand. Additionally, we observed a mutational signature similar to the COSMIC signature 10, a higher mutation rate in this tumor than in endometrial tumors with heterozygous POLE-exo*, and an increased number of T lymphocytes. This is the first report of an ultramutated EC harboring a somatic POLE-exo* mutation in association with a germline loss-of-function mutation in this gene. The absence of a wild type POLE allele led to a particularly high mutational burden.
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Affiliation(s)
- Reginaldo Cruz Alves Rosa
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão
Preto, Departamento de Genética, Ribeirão Preto, SP, Brazil
| | - Andrey A. Yurchenko
- Université Paris Saclay, Inserm U981, Gustave Roussy Cancer
Campus, Villejuif, France
| | - Fernando Chahud
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão
Preto, Departamento de Patologia e Medicina Legal, Ribeirão Preto, SP,
Brazil
| | - Alfredo Ribeiro-Silva
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão
Preto, Departamento de Patologia e Medicina Legal, Ribeirão Preto, SP,
Brazil
| | - Mariângela Ottoboni Brunaldi
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão
Preto, Departamento de Patologia e Medicina Legal, Ribeirão Preto, SP,
Brazil
| | - Wilson Araújo Silva
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão
Preto, Departamento de Genética, Ribeirão Preto, SP, Brazil
| | - Patricia L. Kannouche
- Paris-Sud University, CNRS-UMR 8200, Equipe labellisée Ligue
Contre le Cancer, Gustave Roussy Cancer Campus, Villejuif, France
| | - Sergey Nikolaev
- Université Paris Saclay, Inserm U981, Gustave Roussy Cancer
Campus, Villejuif, France
| | - Victor Evangelista de Faria Ferraz
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão
Preto, Departamento de Genética, Ribeirão Preto, SP, Brazil
- Universidade de São Paulo, Centro de Genômica Médica, Hospital
das Clínicas, Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP,
Brazil
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26
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The Macrophages-Microbiota Interplay in Colorectal Cancer (CRC)-Related Inflammation: Prognostic and Therapeutic Significance. Int J Mol Sci 2020; 21:ijms21186866. [PMID: 32962159 PMCID: PMC7558485 DOI: 10.3390/ijms21186866] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/15/2020] [Accepted: 09/16/2020] [Indexed: 02/07/2023] Open
Abstract
Tumor-associated macrophages (TAMs) are the main population of myeloid cells infiltrating solid tumors and the pivotal orchestrators of cancer-promoting inflammation. However, due to their exceptional plasticity, macrophages can be also key effector cells and powerful activators of adaptive anti-tumor immunity. This functional heterogeneity is emerging in human tumors, colorectal cancer (CRC) in particular, where the dynamic co-existence of different macrophage subtypes influences tumor development, outcome, and response to therapies. Intestinal macrophages are in close interaction with enteric microbiota, which contributes to carcinogenesis and affects treatment outcomes. This interplay may be particularly relevant in CRC, one of the most prevalent and lethal cancer types in the world. Therefore, both macrophages and intestinal microbiota are considered promising prognostic indicators and valuable targets for new therapeutic approaches. Here, we discuss the current understanding of the molecular circuits underlying the interplay between macrophages and microbiota in CRC development, progression, and response to both conventional therapies and immunotherapies.
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27
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Mo S, Ma X, Li Y, Zhang L, Hou T, Han-Zhang H, Qian J, Cai S, Huang D, Peng J. Somatic POLE exonuclease domain mutations elicit enhanced intratumoral immune responses in stage II colorectal cancer. J Immunother Cancer 2020; 8:jitc-2020-000881. [PMID: 32859741 PMCID: PMC7454238 DOI: 10.1136/jitc-2020-000881] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2020] [Indexed: 12/12/2022] Open
Abstract
Previous studies found patients with POLE exonuclease domain mutations (EDMs) in targeted exons were related to significant better outcomes in stage II-III colorectal cancer (CRC). The detailed mutational profile of the entire POLE exonuclease domain, tumor mutation burden (TMB) and immune cell infiltration in POLE EDMs tumors, and the prognostic value of such mutations in stage II CRCs were largely unknown to us. This study was to clarify the characteristics, immune response and prognostic value of somatic POLE EDMs in stage II CRC. A total of 295 patients with stage II CRC were sequenced by next-generation sequencing with a targeted genetic panel. Simultaneous detection of the immune cells was conducted using a five-color immunohistochemical multiplex technique. The detailed molecular characteristics, tumor-infiltrating lymphocyte (TIL) and prognostic effect of POLE EDMs in stage II CRC were analyzed. For stage II CRCs, the POLE EDMs were detected in 3.1% of patients. Patients with POLE EDMs were more prone to be microsatellite instability-high (MSI-H) (33.3% vs 11.2%, p=0.043), younger at diagnosis (median 46 years vs 62 years, p<0.001) and more common at right-sided location (66.7% vs 23.1%; p=0.003). All patients with POLE EMDs were assessed as extremely high TMB, with a mean TMB of 200.8. Compared with other stage II CRCs, POLE EDMs displayed an enhanced intratumoral cytotoxic T cell response, evidenced by increased numbers of CD8+TILs and CD8A expression. Patients with stage II CRCs could be classified into three risk subsets, with significant different 5 years disease-free survival rates of 100% for POLE EDMs, 82.0% for MSI-H and 63.0% for MSS, p=0.013. In conclusion, characterized by a robust intratumoral T cell response, ultramutated POLE EDMs could be detected in a small subset of stage II CRCs with extremely high TMB. Patients with POLE EDMs had excellent outcomes in stage II CRCs, regardless of MSI status. Sequencing of all the exonuclease domain of POLE gene is recommended in clinical practice.
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Affiliation(s)
- Shaobo Mo
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, Shanghai, China
| | - Xiaoji Ma
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, Shanghai, China
| | - Yaqi Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, Shanghai, China
| | - Long Zhang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, Shanghai, China.,Department of Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
| | - Ting Hou
- Burning Rock Biotech, Guangdong, China
| | | | - Juanjuan Qian
- Genecast Precision Medicine Technology Institute, Beijing, China
| | - Sanjun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, Shanghai, China.,Department of Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
| | - Dan Huang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, Shanghai, China .,Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
| | - Junjie Peng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, Shanghai, China
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28
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Role of POLE and POLD1 in familial cancer. Genet Med 2020; 22:2089-2100. [PMID: 32792570 PMCID: PMC7708298 DOI: 10.1038/s41436-020-0922-2] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/20/2020] [Accepted: 07/21/2020] [Indexed: 02/06/2023] Open
Abstract
Purpose Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study. Methods POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case–control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation. Results Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies <1%, were identified. One ED variant (POLE p.Met294Arg) was classified as likely pathogenic, four as likely benign, and seven as variants of unknown significance. The most commonly associated tumor types were colorectal, endometrial and ovarian cancers. Loss-of-function and outside-ED variants are likely not pathogenic for this syndrome. Conclusions Polymerase proofreading–associated syndrome constitutes 0.1–0.4% of familial cancer cases, reaching 0.3–0.7% when only CRC and polyposis are considered. ED variant interpretation is challenging and should include multiple pieces of evidence.
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29
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Cohen R, Shi Q, André T. Immunotherapy for Early Stage Colorectal Cancer: A Glance into the Future. Cancers (Basel) 2020; 12:E1990. [PMID: 32708216 PMCID: PMC7409300 DOI: 10.3390/cancers12071990] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/10/2020] [Accepted: 07/17/2020] [Indexed: 12/16/2022] Open
Abstract
Immune checkpoint inhibitors (ICI) have reshaped therapeutic strategies for cancer patients. The development of ICI for early stage colorectal cancer is accompanied by specific challenges: (i) the selection of patients who are likely to benefit from these treatments, i.e., patients with tumors harboring predictive factors of efficacy of ICI, such as microsatellite instability and/or mismatch repair deficiency (MSI/dMMR), or other potential parameters (increased T cell infiltration using Immunoscore® or others, high tumor mutational burden, POLE mutation), (ii) the selection of patients at risk of disease recurrence (poor prognostic features), and (iii) the choice of an accurate clinical trial methodological framework. In this review, we will discuss the ins and outs of clinical research of ICI for early stage MSI/dMMR CC patients in adjuvant and neoadjuvant settings. We will then summarize data that might support the development of ICI in localized colorectal cancer beyond MSI/dMMR.
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Affiliation(s)
- Romain Cohen
- Department of Medical Oncology, Hôpital Saint-Antoine, Sorbonne Université, Assistance Publique-Hôpitaux de Paris (AP-HP), F-75012 Paris, France;
- Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA;
| | - Qian Shi
- Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA;
| | - Thierry André
- Department of Medical Oncology, Hôpital Saint-Antoine, Sorbonne Université, Assistance Publique-Hôpitaux de Paris (AP-HP), F-75012 Paris, France;
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30
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Silvestri R, Landi S. DNA polymerases in the risk and prognosis of colorectal and pancreatic cancers. Mutagenesis 2020; 34:363-374. [PMID: 31647559 DOI: 10.1093/mutage/gez031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 09/17/2019] [Indexed: 12/30/2022] Open
Abstract
Human cancers arise from the alteration of genes involved in important pathways that mainly affect cell growth and proliferation. DNA replication and DNA damages recognition and repair are among these pathways and DNA polymerases that take part in these processes are frequently involved in cancer onset and progression. For example, damaging alterations within the proofreading domain of replicative polymerases, often reported in patients affected by colorectal cancer (CRC), are considered risk factors and drivers of carcinogenesis as they can lead to the accumulation of several mutations throughout the genome. Thus, replicative polymerases can be involved in cancer when losses of their physiological functions occur. On the contrary, reparative polymerases are often involved in cancer precisely because of their physiological role. In fact, their ability to repair and bypass DNA damages, which confers genome stability, can also counteract the effect of most anticancer drugs. In addition, the altered expression can characterise some type of cancers, which exacerbates this aspect. For example, all of the DNA polymerases involved a damage bypass mechanism, known as translesion synthesis, with the only exception of polymerase theta, are downregulated in CRC. Conversely, in pancreatic ductal adenocarcinoma (PDAC), most of these polymerase result upregulated. This suggests that different types of cancer can rely on different reparative polymerases to acquire drug resistance. Here we will examine all of the aspects that link DNA polymerases with CRC and PDAC.
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Affiliation(s)
| | - Stefano Landi
- Department of Biology, University of Pisa, Pisa, Italy
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31
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Siraj AK, Bu R, Iqbal K, Parvathareddy SK, Masoodi T, Siraj N, Al-Rasheed M, Kong Y, Ahmed SO, Al-Obaisi KAS, Victoria IG, Arshad M, Al-Dayel F, Abduljabbar A, Ashari LH, Al-Kuraya KS. POLE and POLD1 germline exonuclease domain pathogenic variants, a rare event in colorectal cancer from the Middle East. Mol Genet Genomic Med 2020; 8:e1368. [PMID: 32567205 PMCID: PMC7434734 DOI: 10.1002/mgg3.1368] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 12/11/2022] Open
Abstract
Background Colorectal cancer (CRC) is a major contributor to morbidity and mortality related to cancer. Only ~5% of all CRCs occur as a result of pathogenic variants in well‐defined CRC predisposing genes. The frequency and effect of exonuclease domain pathogenic variants of POLE and POLD1 genes in Middle Eastern CRCs is still unknown. Methods Targeted capture sequencing and Sanger sequencing technologies were employed to investigate the germline exonuclease domain pathogenic variants of POLE and POLD1 in Middle Eastern CRCs. Immunohistochemical analysis of POLE and POLD1 was performed to look for associations between protein expression and clinico‐pathological characteristics. Results Five damaging or possibly damaging variants (0.44%) were detected in 1,135 CRC cases, four in POLE gene (0.35%, 4/1,135) and one (0.1%, 1/1,135) in POLD1 gene. Furthermore, low POLE protein expression was identified in 38.9% (417/1071) cases and a significant association with lymph node involvement (p = .0184) and grade 3 tumors (p = .0139) was observed. Whereas, low POLD1 expression was observed in 51.9% (555/1069) of cases and was significantly associated with adenocarcinoma histology (p = .0164), larger tumor size (T3 and T4 tumors; p = .0012), and stage III tumors (p = .0341). Conclusion POLE and POLD1 exonuclease domain pathogenic variants frequency in CRC cases was very low and these exonuclease domain pathogenic variants might be rare causative events of CRC in the Middle East. POLE and POLD1 can be included in multi‐gene panels to screen CRC patients.
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Affiliation(s)
- Abdul K Siraj
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia
| | - Rong Bu
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia
| | - Kaleem Iqbal
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia
| | - Sandeep K Parvathareddy
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia
| | - Tariq Masoodi
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia
| | - Nabil Siraj
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia
| | - Maha Al-Rasheed
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia
| | - Yan Kong
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia
| | - Saeeda O Ahmed
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia
| | - Khadija A S Al-Obaisi
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia
| | - Ingrid G Victoria
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia
| | - Maham Arshad
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia
| | - Fouad Al-Dayel
- Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Alaa Abduljabbar
- Colorectal Section, Department of Surgery, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Luai H Ashari
- Colorectal Section, Department of Surgery, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Khawla S Al-Kuraya
- Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia
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Jian M, Ren L, He G, Lin Q, Tang W, Chen Y, Chen J, Liu T, Ji M, Wei Y, Chang W, Xu J. A novel patient-derived organoids-based xenografts model for preclinical drug response testing in patients with colorectal liver metastases. J Transl Med 2020; 18:234. [PMID: 32532289 PMCID: PMC7291745 DOI: 10.1186/s12967-020-02407-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 06/05/2020] [Indexed: 12/11/2022] Open
Abstract
Backgrounds Cancer-related mortality in patients with colorectal cancer (CRC) is predominantly caused by development of colorectal liver metastases (CLMs). How to screen the sensitive chemotherapy and targeted therapy is the key element to improve the prognosis of CLMs patients. The study aims to develop patient-derived organoids-based xenografted liver metastases (PDOX-LM) model of CRC, to recapitulate the clinical drug response. Methods We transplanted human CRC primary tumor derived organoids in murine spleen to obtain xenografted liver metastases in murine liver. Immunohistochemistry (IHC) staining, whole-exome and RNA sequencing, and drug response testing were utilized to identify the homogeneity in biological and genetic characteristics, and drug response between the PDOX-LM models and donor liver metastases. Results We successfully established PDOX-LM models from patients with CLMs. IHC staining showed that positive expression of CEA, Ki67, VEGF, FGFR2 in donor liver metastases were also well preserved in matched xenografted liver metastases. Whole-exon sequencing and transcriptome analysis showed that both xenografted and donor liver metastases were highly concordant in somatic variants (≥ 0.90 frequency of concordance) and co-expression of driver genes (Pearson’s correlation coefficient reach up to 0.99, P = 0.001). Furthermore, drug response testing showed that the PDOX-LM models can closely recapitulated the clinical response to mFOLFOX6 regiments. Conclusions This PDOX-LM model provides a more convenient and informative platform for preclinical testing of individual tumors by retaining the histologic and genetic features of donor liver metastases. This technology holds great promise to predict treatment sensitivity for patients with CLMs undergoing chemotherapy.
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Affiliation(s)
- Mi Jian
- Department of General Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200030, China
| | - Li Ren
- Department of General Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200030, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, 200030, China
| | - Guodong He
- Department of General Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200030, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, 200030, China
| | - Qi Lin
- Department of General Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200030, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, 200030, China
| | - Wentao Tang
- Department of General Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200030, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, 200030, China
| | - Yijiao Chen
- Department of General Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200030, China
| | - Jingwen Chen
- Department of General Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200030, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, 200030, China
| | - Tianyu Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200030, China
| | - Meiling Ji
- Department of General Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200030, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, 200030, China
| | - Ye Wei
- Department of General Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200030, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, 200030, China
| | - Wenju Chang
- Department of General Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200030, China. .,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, 200030, China.
| | - Jianmin Xu
- Department of General Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200030, China. .,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, 200030, China.
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He M, Abro B, Kaushal M, Chen L, Chen T, Gondim M, Yan W, Neidich J, Dehner LP, Pfeifer JD. Tumor mutation burden and checkpoint immunotherapy markers in primary and metastatic synovial sarcoma. Hum Pathol 2020; 100:15-23. [PMID: 32387103 DOI: 10.1016/j.humpath.2020.04.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 04/16/2020] [Accepted: 04/18/2020] [Indexed: 12/29/2022]
Abstract
Synovial sarcoma (SS) is a soft-tissue malignancy that most often affects patients aged between 15 and 40 years, and the prognosis for patients with metastatic disease is generally poor. This study was performed to evaluate checkpoint blockade immunotherapy markers in SS, including tumor mutational burden (TMB), DNA mismatch repair (MMR) status, and PDL-1 (programmed cell death ligand 1), PD1 (programmed cell death 1), and CD8 expression by normal-tumor paired whole-exome sequencing (WES) and immunohistochemistry (IHC). Outcomes evaluated included event-free and overall survival. Twenty one (21) FISH (Fluorescence In Situ Hybridization)-confirmed SS cases (11 F, 10 M) were studied, with age ranging from 8 to 89 years at diagnosis and follow-up ranging from 1 to 16 years. TMB (n = 16) ranged from 0.83 to 212/Mb (median, 1.7). Only one case showed a high TMB of 212/Mb and missense variants of MMR genes in the primary tumor, while the other 15 cases had a low TMB of less than 5/Mb. IHC was performed on all 21 tumor samples for PD-L1, PD1, CD8, and MMR proteins. PD-L1 membranous staining was detected in 3 of 21 cases (14.3%), ranging from 1 to 5% for tumor proportion score and 1-10 for combined positive score. PD1 was detected in 15 of 21 cases (71.4%), ranging from 1 to 25/HPF (high power field) (median, 2). CD8 stain was seen in all cases, ranging from 2 to 60/HPF (median, 5). PD1 staining results correlated with CD8 staining results (P < 0.0001). No correlation of TMB or IHC markers was found with survival. No fixed pattern of TMB or IHCs between primary and metastatic tumors was observed; there was no correlation between TMB or IHCs and age, location, or diagnosis subtype. All of the cases tested showed retained expression of MMR proteins. The results show that for SS, a tumor with strong driver translocation, most cases have a low TMB, but occasionally a high TMB may be present, as observed in 1 of the 16 (6.25%) cases. The demonstration of a subgroup of SS cases with high TMB might explain the 10% response rate to checkpoint immunotherapy observed in clinical trials in patients with SS.
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Affiliation(s)
- Mai He
- Department of Pathology & Immunology, Washington University at St. Louis School of Medicine, St. Louis, MO, 63110, USA.
| | - Brooj Abro
- Department of Pathology & Immunology, Washington University at St. Louis School of Medicine, St. Louis, MO, 63110, USA
| | - Madhurima Kaushal
- Institute of Bioinformatics, Washington University at St. Louis School of Medicine, St. Louis, MO, 63110, USA
| | - Ling Chen
- Division of Statistics, Washington University at St. Louis School of Medicine, St. Louis, MO, 63110, USA
| | - Tiffany Chen
- Department of Pathology & Immunology, Washington University at St. Louis School of Medicine, St. Louis, MO, 63110, USA
| | - Mercia Gondim
- Department of Pathology & Immunology, Washington University at St. Louis School of Medicine, St. Louis, MO, 63110, USA
| | - Weisi Yan
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Julie Neidich
- Department of Pathology & Immunology, Washington University at St. Louis School of Medicine, St. Louis, MO, 63110, USA
| | - Louis P Dehner
- Department of Pathology & Immunology, Washington University at St. Louis School of Medicine, St. Louis, MO, 63110, USA
| | - John D Pfeifer
- Department of Pathology & Immunology, Washington University at St. Louis School of Medicine, St. Louis, MO, 63110, USA
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Picard E, Verschoor CP, Ma GW, Pawelec G. Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer. Front Immunol 2020; 11:369. [PMID: 32210966 PMCID: PMC7068608 DOI: 10.3389/fimmu.2020.00369] [Citation(s) in RCA: 334] [Impact Index Per Article: 66.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 02/17/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.
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Affiliation(s)
- Emilie Picard
- Health Sciences North Research Institute, Sudbury, ON, Canada
| | | | - Grace W Ma
- Department of Surgery, Health Sciences North, Sudbury, ON, Canada
| | - Graham Pawelec
- Health Sciences North Research Institute, Sudbury, ON, Canada.,Department of Immunology, University of Tübingen, Tübingen, Germany
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Coupez D, Hulo P, Touchefeu Y, Bossard C, Bennouna J. Pembrolizumab for the treatment of colorectal cancer. Expert Opin Biol Ther 2020; 20:219-226. [PMID: 31952453 DOI: 10.1080/14712598.2020.1718095] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction: Colorectal cancer (CRC) is one of the most frequent and lethal cancers in the world, and therapies are still insufficient. Immune checkpoint inhibitors (ICI) in metastatic CRC (mCRC) have not revolutionized treatment to the extent that they have in melanoma or renal carcinoma. Their use is limited to a molecular niche of mCRC with microsatellite instability (MSI). This review summarizes clinical data published with pembrolizumab in mCRC and also tries to identify potential new strategies.Areas covered: This paper focuses on pembrolizumab in mCRC. We screened all trials on PubMed and ClinicalTrials.gov and describe the most significant ones in our opinion.Expert opinion: Pembrolizumab seems to be effective in tumors with MSI-high status. It defines a new horizon for therapeutic strategy called 'agnostic' medicine. For microsatellite stable (MSS) colorectal cancers, the future challenge will be to successfully redraw the immune microenvironment to make it immunogenic with new therapeutic combinations, including ICI.
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Affiliation(s)
- Dahna Coupez
- Digestive Oncology, Institut Des Maladies De l'Appareil Digestif, Centre Hospitalier Universitaire De Nantes, Nantes, France
| | - Pauline Hulo
- Digestive Oncology, Institut Des Maladies De l'Appareil Digestif, Centre Hospitalier Universitaire De Nantes, Nantes, France.,Centre De Recherche En Cancérologie Et Immunologie Nantes-Angers (CRCINA), INSERM, Université d'Angers, Université De Nantes, Nantes, France
| | - Yann Touchefeu
- Digestive Oncology, Institut Des Maladies De l'Appareil Digestif, Centre Hospitalier Universitaire De Nantes, Nantes, France
| | - Céline Bossard
- Service d'Anatomie Et Cytologie Pathologiques, Centre Hospitalier Universitaire, Nantes, France
| | - Jaafar Bennouna
- Digestive Oncology, Institut Des Maladies De l'Appareil Digestif, Centre Hospitalier Universitaire De Nantes, Nantes, France.,Centre De Recherche En Cancérologie Et Immunologie Nantes-Angers (CRCINA), INSERM, Université d'Angers, Université De Nantes, Nantes, France
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Matsuoka T, Yashiro M. Precision medicine for gastrointestinal cancer: Recent progress and future perspective. World J Gastrointest Oncol 2020; 12:1-20. [PMID: 31966910 PMCID: PMC6960076 DOI: 10.4251/wjgo.v12.i1.1] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 10/12/2019] [Accepted: 11/04/2019] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal (GI) cancer has a high tumor incidence and mortality rate worldwide. Despite significant improvements in radiotherapy, chemotherapy, and targeted therapy for GI cancer over the last decade, GI cancer is characterized by high recurrence rates and a dismal prognosis. There is an urgent need for new diagnostic and therapeutic approaches. Recent technological advances and the accumulation of clinical data are moving toward the use of precision medicine in GI cancer. Here we review the application and status of precision medicine in GI cancer. Analyses of liquid biopsy specimens provide comprehensive real-time data of the tumor-associated changes in an individual GI cancer patient with malignancy. With the introduction of gene panels including next-generation sequencing, it has become possible to identify a variety of mutations and genetic biomarkers in GI cancer. Although the genomic aberration of GI cancer is apparently less actionable compared to other solid tumors, novel informative analyses derived from comprehensive gene profiling may lead to the discovery of precise molecular targeted drugs. These progressions will make it feasible to incorporate clinical, genome-based, and phenotype-based diagnostic and therapeutic approaches and apply them to individual GI cancer patients for precision medicine.
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Affiliation(s)
- Tasuku Matsuoka
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
| | - Masakazu Yashiro
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
- Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
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37
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Nguyen LH, Goel A, Chung DC. Pathways of Colorectal Carcinogenesis. Gastroenterology 2020; 158:291-302. [PMID: 31622622 PMCID: PMC6981255 DOI: 10.1053/j.gastro.2019.08.059] [Citation(s) in RCA: 297] [Impact Index Per Article: 59.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 08/13/2019] [Accepted: 08/15/2019] [Indexed: 12/15/2022]
Abstract
Colorectal cancer is a heterogeneous disease that develops via stepwise accumulation of well-characterized genetic and epigenetic alterations. We review the genetic changes associated with the development of precancerous colorectal adenomas and their progression to tumors, as well as the effects of defective DNA repair, chromosome instability, microsatellite instability, and alterations in the serrated pathway and DNA methylation. We provide insights into the different molecular subgroups of colorectal tumors that develop via each of these different mechanisms and their associations with patient outcomes.
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Affiliation(s)
- Long H Nguyen
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Dallas, Texas; Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas; Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
| | - Daniel C Chung
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Center for Cancer Risk Assessment, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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38
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Non-small cell lung cancer with loss of expression of the SWI/SNF complex is associated with aggressive clinicopathological features, PD-L1-positive status, and high tumor mutation burden. Lung Cancer 2019; 138:35-42. [DOI: 10.1016/j.lungcan.2019.10.009] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 10/06/2019] [Accepted: 10/08/2019] [Indexed: 02/08/2023]
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39
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Walk EE, Yohe SL, Beckman A, Schade A, Zutter MM, Pfeifer J, Berry AB. The Cancer Immunotherapy Biomarker Testing Landscape. Arch Pathol Lab Med 2019; 144:706-724. [PMID: 31714809 DOI: 10.5858/arpa.2018-0584-cp] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Cancer immunotherapy provides unprecedented rates of durable clinical benefit to late-stage cancer patients across many tumor types, but there remains a critical need for biomarkers to accurately predict clinical response. Although some cancer immunotherapy tests are associated with approved therapies and considered validated, other biomarkers are still emerging and at various states of clinical and translational exploration. OBJECTIVE.— To provide pathologists with a current and practical update on the evolving field of cancer immunotherapy testing. The scientific background, clinical data, and testing methodology for the following cancer immunotherapy biomarkers are reviewed: programmed death ligand-1 (PD-L1), mismatch repair, microsatellite instability, tumor mutational burden, polymerase δ and ε mutations, cancer neoantigens, tumor-infiltrating lymphocytes, transcriptional signatures of immune responsiveness, cancer immunotherapy resistance biomarkers, and the microbiome. DATA SOURCES.— Selected scientific publications and clinical trial data representing the current field of cancer immunotherapy. CONCLUSIONS.— The cancer immunotherapy field, including the use of biomarker testing to predict patient response, is still in evolution. PD-L1, mismatch repair, and microsatellite instability testing are helping to guide the use of US Food and Drug Administration-approved therapies, but there remains a need for better predictors of response and resistance. Several categories of tumor and patient characteristics underlying immune responsiveness are emerging and may represent the next generation of cancer immunotherapy predictive biomarkers. Pathologists have important roles and responsibilities as the field of cancer immunotherapy continues to develop, including leadership of translational studies, exploration of novel biomarkers, and the accurate and timely implementation of newly approved and validated companion diagnostics.
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Affiliation(s)
- Eric E Walk
- From the Department of Medical & Scientific Affairs, Roche Tissue Diagnostics, Tucson, Arizona (Dr Walk); the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis (Drs Yohe and Beckman); Diagnostic and Experimental Pathology, Eli Lilly and Company, Indianapolis, Indiana (Dr Schade); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee (Dr Zutter); the Department of Molecular Pathology and Genomics, Swedish Cancer Institute, Seattle, Washington (Dr Berry); and the Department of Pathology, Washington University School of Medicine, St Louis, Missouri (Dr Pfeifer)
| | - Sophia L Yohe
- From the Department of Medical & Scientific Affairs, Roche Tissue Diagnostics, Tucson, Arizona (Dr Walk); the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis (Drs Yohe and Beckman); Diagnostic and Experimental Pathology, Eli Lilly and Company, Indianapolis, Indiana (Dr Schade); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee (Dr Zutter); the Department of Molecular Pathology and Genomics, Swedish Cancer Institute, Seattle, Washington (Dr Berry); and the Department of Pathology, Washington University School of Medicine, St Louis, Missouri (Dr Pfeifer)
| | - Amy Beckman
- From the Department of Medical & Scientific Affairs, Roche Tissue Diagnostics, Tucson, Arizona (Dr Walk); the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis (Drs Yohe and Beckman); Diagnostic and Experimental Pathology, Eli Lilly and Company, Indianapolis, Indiana (Dr Schade); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee (Dr Zutter); the Department of Molecular Pathology and Genomics, Swedish Cancer Institute, Seattle, Washington (Dr Berry); and the Department of Pathology, Washington University School of Medicine, St Louis, Missouri (Dr Pfeifer)
| | - Andrew Schade
- From the Department of Medical & Scientific Affairs, Roche Tissue Diagnostics, Tucson, Arizona (Dr Walk); the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis (Drs Yohe and Beckman); Diagnostic and Experimental Pathology, Eli Lilly and Company, Indianapolis, Indiana (Dr Schade); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee (Dr Zutter); the Department of Molecular Pathology and Genomics, Swedish Cancer Institute, Seattle, Washington (Dr Berry); and the Department of Pathology, Washington University School of Medicine, St Louis, Missouri (Dr Pfeifer)
| | - Mary M Zutter
- From the Department of Medical & Scientific Affairs, Roche Tissue Diagnostics, Tucson, Arizona (Dr Walk); the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis (Drs Yohe and Beckman); Diagnostic and Experimental Pathology, Eli Lilly and Company, Indianapolis, Indiana (Dr Schade); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee (Dr Zutter); the Department of Molecular Pathology and Genomics, Swedish Cancer Institute, Seattle, Washington (Dr Berry); and the Department of Pathology, Washington University School of Medicine, St Louis, Missouri (Dr Pfeifer)
| | - John Pfeifer
- From the Department of Medical & Scientific Affairs, Roche Tissue Diagnostics, Tucson, Arizona (Dr Walk); the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis (Drs Yohe and Beckman); Diagnostic and Experimental Pathology, Eli Lilly and Company, Indianapolis, Indiana (Dr Schade); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee (Dr Zutter); the Department of Molecular Pathology and Genomics, Swedish Cancer Institute, Seattle, Washington (Dr Berry); and the Department of Pathology, Washington University School of Medicine, St Louis, Missouri (Dr Pfeifer)
| | - Anna B Berry
- From the Department of Medical & Scientific Affairs, Roche Tissue Diagnostics, Tucson, Arizona (Dr Walk); the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis (Drs Yohe and Beckman); Diagnostic and Experimental Pathology, Eli Lilly and Company, Indianapolis, Indiana (Dr Schade); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee (Dr Zutter); the Department of Molecular Pathology and Genomics, Swedish Cancer Institute, Seattle, Washington (Dr Berry); and the Department of Pathology, Washington University School of Medicine, St Louis, Missouri (Dr Pfeifer)
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Germline POLE mutation in a child with hypermutated medulloblastoma and features of constitutional mismatch repair deficiency. Cold Spring Harb Mol Case Stud 2019; 5:mcs.a004499. [PMID: 31624068 PMCID: PMC6824253 DOI: 10.1101/mcs.a004499] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 08/15/2019] [Indexed: 01/02/2023] Open
Abstract
Ultra-hypermutation (>100 mutations/Mb) is rare in childhood cancer genomes and has been primarily reported in patients with constitutional mismatch repair deficiency (CMMRD) caused by biallelic germline mismatch repair (MMR) gene mutations. We report a 5-yr-old child with classic clinical features of CMMRD and an ultra-hypermutated medulloblastoma with retained MMR protein expression and absence of germline MMR mutations. Mutational signature analysis of tumor panel sequencing data revealed a canonical DNA polymerase-deficiency-associated signature, prompting further genetic testing that uncovered a germline POLE p.A456P missense variant, which has previously been reported as a recurrent somatic driver mutation in cancers. This represents the earliest known onset of malignancy in a patient with a germline mutation in the POLE proofreading polymerase. The clinical features in this child, virtually indistinguishable from those of CMMRD, suggest that polymerase-proofreading deficiency should be considered in the differential diagnosis of CMMRD patients with retained MMR function.
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41
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Tintelnot J, Stein A. Immunotherapy in colorectal cancer: Available clinical evidence, challenges and novel approaches. World J Gastroenterol 2019; 25:3920-3928. [PMID: 31413527 PMCID: PMC6689806 DOI: 10.3748/wjg.v25.i29.3920] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Revised: 05/21/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023] Open
Abstract
In contrast to other tumor types, immunotherapy has not yet become a relevant part of the treatment landscape of unselected colorectal cancer. Beside the small subgroup of deficient mismatch repair or microsatellite instable tumors (about 5%) as a surrogate for high mutational burden and subsequently high neoantigen load and immunogenicity, inhibitors of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1) and/or cytotoxic T lymphocyte-associated antigen-4 were not or only modestly effective in metastatic colorectal cancer. Thus, a variety of combination approaches with chemotherapy, targeted therapy, toll-like receptor agonists, local ablation or oncolytic viruses is currently being evaluated in different disease settings. Despite several encouraging single arm data already presented or published, available randomized data are unimpressive. Adding PD-1/PD-L1 inhibitors to fluoropyrimidines and bevacizumab maintenance showed no beneficial impact on delaying progression. In refractory disease, the combination of PD-1/PD-L1 and MEK inhibitor was not different from regorafenib, whereas a PD-1/PD-L1 and cytotoxic T lymphocyte-associated antigen-4 inhibitor combination demonstrated better overall survival compared to supportive care alone. Clinical trials in all disease settings applying different combination approaches are ongoing and may define the role of immunotherapy in colorectal cancer.
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Affiliation(s)
- Joseph Tintelnot
- Department of Internal Medicine II (Oncology Center), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Alexander Stein
- Department of Internal Medicine II (Oncology Center), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
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42
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Park R, Winnicki M, Liu E, Chu WM. Immune checkpoints and cancer in the immunogenomics era. Brief Funct Genomics 2019; 18:133-139. [PMID: 30137232 DOI: 10.1093/bfgp/ely027] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 03/22/2018] [Accepted: 07/09/2018] [Indexed: 12/16/2022] Open
Abstract
Immune checkpoints have been the subject of a wave of new studies. Among these checkpoints are tytotoxic T-lymphocyte-associated antigen 4, checkpoints programmed death-1 and programmed death-ligand 1; their blockades have been approved by the Food and Drug Administration for therapy of melanoma and other types of cancers. Immunogenomics, which combines the latest nucleic acid sequencing strategy with immunotherapy, provides precise information about genomic alterations (e.g. mutations) and enables a paradigm shift of immune checkpoint therapy from tumor types to molecular signatures. Studying these critical checkpoints in relation to genomic mutations and neoantigens has produced groundbreaking results. This article examines these studies and delves into the relationships between immune checkpoint blockade and tumors harboring certain genomic mutations. Moreover, this article reviews recent studies on resistance to immune checkpoint therapy.
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Affiliation(s)
- Ryan Park
- University of Hawaii Cancer Center. He is an expert in the innate immunity and chronic inflammation-associated cancer fields
| | - Mary Winnicki
- University of Hawaii Cancer Center and studies the mechanisms of chronic inflammation-associated cancer
| | - Evan Liu
- University of Hawaii Cancer Center and studies the mechanisms of chronic inflammation-associated cancer
| | - Wen-Ming Chu
- University of Hawaii Cancer Center and studies the mechanisms of chronic inflammation-associated cancer
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43
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Pellat A, Netter J, Perkins G, Cohen R, Coulet F, Parc Y, Svrcek M, Duval A, André T. [Lynch syndrome: What is new?]. Bull Cancer 2019; 106:647-655. [PMID: 30527816 DOI: 10.1016/j.bulcan.2018.10.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 10/02/2018] [Indexed: 12/17/2022]
Abstract
Lynch syndrome is a genetic condition defined by a germline mutation of an MMR (MisMatch Repair) gene leading to a defective DNA MMR system. Therefore, it is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer (CRC) and endometrial cancer (EC). Lynch syndrome-related CRC accounts for 3% of all CRC. Lynch syndrome also accounts for 2% of all EC. In case of Lynch syndrome, there is usually a familial history of cancer defined by the Amsterdam and Bethesda criteria. Diagnosis is made by tumor testing with (i) MMR immunohistochemistry and (ii) PCR for MSI (microsatellite instability), a genetic phenotype that characterizes these tumors. MSI can also be detected in sporadic tumors, through epigenetic events inactivating the MMR system. Progress in diagnosis and molecular biology has allowed for better identification of Lynch patients but also other rare genetic syndromes. MSI tumors can now benefit from new treatments such as immunotherapy which underlines the importance of their diagnosis. Finally, patients with Lynch syndrome as well as their relatives, undergo specific surveillance in order to prevent development of other cancers. This review will summarize the different aspects of Lynch syndrome and also focus on recent progress on the topic.
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Affiliation(s)
- Anna Pellat
- AP-HP, Sorbonne université, hôpital Saint-Antoine, et service d'oncologie médicale, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France.
| | - Jeanne Netter
- AP-HP, hôpital Tenon, service de gastro entérologie, 4, rue de la Chine, 75020 Paris, France
| | - Géraldine Perkins
- AP-HP, hôpital européen Georges Pompidou, unité d'oncogénétique, 20, rue Leblanc, 75015 Paris, France
| | - Romain Cohen
- AP-HP, Sorbonne université, hôpital Saint-Antoine, et service d'oncologie médicale, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Sorbonne université, unité Mixte de Recherche Scientifique 938 et SIRIC CURAMUS, Centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, Inserm, 75012 Paris, France
| | - Florence Coulet
- AP-HP, hôpitaux universitaire Pitié Salpêtrière-Charles, département de génétique, 47-83, boulevard de l'Hôpital, 75013 Paris, France
| | - Yann Parc
- AP-HP, Sorbonne université, hôpital Saint-Antoine, service de chirurgie générale et digestive, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France
| | - Magali Svrcek
- Sorbonne université, unité Mixte de Recherche Scientifique 938 et SIRIC CURAMUS, Centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, Inserm, 75012 Paris, France; AP-HP, hôpital Saint-Antoine, Sorbonne université et service d'anatomopathologie, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France
| | - Alex Duval
- Sorbonne université, unité Mixte de Recherche Scientifique 938 et SIRIC CURAMUS, Centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, Inserm, 75012 Paris, France
| | - Thierry André
- AP-HP, Sorbonne université, hôpital Saint-Antoine, et service d'oncologie médicale, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Sorbonne université, unité Mixte de Recherche Scientifique 938 et SIRIC CURAMUS, Centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, Inserm, 75012 Paris, France
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Hino H, Shiomi A, Kusuhara M, Kagawa H, Yamakawa Y, Hatakeyama K, Kawabata T, Oishi T, Urakami K, Nagashima T, Kinugasa Y, Yamaguchi K. Clinicopathological and mutational analyses of colorectal cancer with mutations in the POLE gene. Cancer Med 2019; 8:4587-4597. [PMID: 31240875 PMCID: PMC6712448 DOI: 10.1002/cam4.2344] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 05/28/2019] [Accepted: 05/31/2019] [Indexed: 01/03/2023] Open
Abstract
Here, we investigated the clinicopathological and mutation profiles of colorectal cancer (CRC) with POLE mutations. Whole‐exome sequencing was performed in 910 surgically resected primary CRCs. Tumors exceeding 500 counts of nonsynonymous single nucleotide variants (SNVs) were classified as hypermutators, whereas the remaining were classified as nonhypermutators. The hypermutators were subdivided into 2 groups. CRCs harboring more than 20% C‐to‐A and less than 3% C‐to‐G transversions were classified as POLE category tumors, whereas the remaining were classified as common‐hypermutators. Gene expression profiling (GEP) analysis was performed in 892 (98.0%) tumors. Fifty‐seven (6.3%) and 10 (1.1%) tumors were classified common‐hypermutators and POLE category tumors, respectively. POLE category tumors harbored a significantly higher SNV count than common‐hypermutators, and all POLE category tumors were associated with exonuclease domain mutations, such as P286R, F367C, V411L, and S297Y, in the POLE gene. Patients with POLE category tumors were significantly younger than those with nonhypermutators and common‐hypermutators. All POLE mutations in the early‐onset (age of onset ≤50 years old) POLE category (7 tumors) were P286R mutations. GEP analysis revealed that PD‐L1 and PD‐1 gene expression levels were significantly increased in both common‐hypermutators and POLE category tumors compared with those in nonhypermutators. CD8A expression was significantly upregulated in POLE category tumors compared with that in nonhypermutators. Thus, we concluded that CRCs with POLE proofreading deficiency had characteristics distinct from those of other CRCs. Analysis of POLE proofreading deficiency may be clinically significant for personalized management of CRCs.
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Affiliation(s)
- Hitoshi Hino
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Akio Shiomi
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Masatoshi Kusuhara
- Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Hiroyasu Kagawa
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Yushi Yamakawa
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Keiichi Hatakeyama
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Takanori Kawabata
- Clinical Research Promotion Unit, Clinical Research Center, Shizuoka Cancer Center, Shizuoka, Japan
| | - Takuma Oishi
- Division of Pathology, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Kenichi Urakami
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | | | - Yusuke Kinugasa
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan.,Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ken Yamaguchi
- Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, Japan
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45
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Jaeger AM, Stopfer L, Lee S, Gaglia G, Sandel D, Santagata S, Lin NU, Trepel JB, White F, Jacks T, Lindquist S, Whitesell L. Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation. Clin Cancer Res 2019; 25:6392-6405. [PMID: 31213460 DOI: 10.1158/1078-0432.ccr-19-0596] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 04/18/2019] [Accepted: 06/14/2019] [Indexed: 12/30/2022]
Abstract
PURPOSE Despite the accumulation of extensive genomic alterations, many cancers fail to be recognized as "foreign" and escape destruction by the host immune system. Immunotherapies designed to address this problem by directly stimulating immune effector cells have led to some remarkable clinical outcomes, but unfortunately, most cancers fail to respond, prompting the need to identify additional immunomodulatory treatment options.Experimental Design: We elucidated the effect of a novel treatment paradigm using sustained, low-dose HSP90 inhibition in vitro and in syngeneic mouse models using genetic and pharmacologic tools. Profiling of treatment-associated tumor cell antigens was performed using immunoprecipitation followed by peptide mass spectrometry. RESULTS We show that sustained, low-level inhibition of HSP90 both amplifies and diversifies the antigenic repertoire presented by tumor cells on MHC-I molecules through an IFNγ-independent mechanism. In stark contrast, we find that acute, high-dose exposure to HSP90 inhibitors, the only approach studied in the clinic to date, is broadly immunosuppressive in cell culture and in patients with cancer. In mice, chronic non-heat shock-inducing HSP90 inhibition slowed progression of colon cancer implants, but only in syngeneic animals with intact immune function. Addition of a single dose of nonspecific immune adjuvant to the regimen dramatically increased efficacy, curing a subset of mice receiving combination therapy. CONCLUSIONS These highly translatable observations support reconsideration of the most effective strategy for targeting HSP90 to treat cancers and suggest a practical approach to repurposing current orally bioavailable HSP90 inhibitors as a new immunotherapeutic strategy.See related commentary by Srivastava and Callahan, p. 6277.
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Affiliation(s)
- Alex M Jaeger
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology Cambridge, Massachusetts.,Whitehead Institute for Biomedical Research, Cambridge, Massachusetts
| | - Lauren Stopfer
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology Cambridge, Massachusetts.,Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Sunmin Lee
- Developmental Therapeutics Branch, National Cancer Institute, Bethesda, Maryland
| | - Giorgio Gaglia
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.,Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Demi Sandel
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology Cambridge, Massachusetts
| | - Sandro Santagata
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.,Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.,Laboratory for Systems Pharmacology, Harvard Medical School, Boston, Massachusetts
| | - Nancy U Lin
- Department of Oncologic Pathology, Harvard Medical School, Massachusetts.,Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts
| | - Jane B Trepel
- Developmental Therapeutics Branch, National Cancer Institute, Bethesda, Maryland
| | - Forest White
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology Cambridge, Massachusetts.,Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Tyler Jacks
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology Cambridge, Massachusetts.,Howard Hughes Medical Institute, Chevy Chase, Maryland
| | - Susan Lindquist
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.,Howard Hughes Medical Institute, Chevy Chase, Maryland
| | - Luke Whitesell
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
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46
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Abro B, Kaushal M, Chen L, Wu R, Dehner LP, Pfeifer JD, He M. Tumor mutation burden, DNA mismatch repair status and checkpoint immunotherapy markers in primary and relapsed malignant rhabdoid tumors. Pathol Res Pract 2019; 215:152395. [DOI: 10.1016/j.prp.2019.03.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 03/01/2019] [Accepted: 03/18/2019] [Indexed: 12/27/2022]
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47
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Yamamoto H, Imai K. An updated review of microsatellite instability in the era of next-generation sequencing and precision medicine. Semin Oncol 2019; 46:261-270. [DOI: 10.1053/j.seminoncol.2019.08.003] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 03/27/2019] [Accepted: 08/14/2019] [Indexed: 12/23/2022]
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48
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Gegen Qinlian decoction enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by remodelling the gut microbiota and the tumour microenvironment. Cell Death Dis 2019; 10:415. [PMID: 31138779 PMCID: PMC6538740 DOI: 10.1038/s41419-019-1638-6] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 05/07/2019] [Accepted: 05/08/2019] [Indexed: 12/16/2022]
Abstract
Therapeutic antibodies targeting PD-1 have made major breakthroughs in cancer treatment. However, the majority of colorectal cancer (CRC) cases are microsatellite stable (MSS) and do not respond to anti-PD-1-based immunotherapy. Combination therapy will be an ideal strategy to overcome this limitation. Gegen Qinlian decoction (GQD), a classical traditional Chinese medicine (TCM) formula, has been clinically proven to be effective in the treatment of ulcerative colitis (UC) and type 2 diabetes mellitus. Here, a systemic pharmacological study revealed that GQD acts through multiple targets and pathways in the human body. Combination therapy with GQD and anti-mouse PD-1 potently inhibited the growth of CT26 tumours in a xenograft model. Gut microbiota analysis revealed that combination therapy with GQD and anti-mouse PD-1 significantly enriched for s__Bacteroides_acidifaciens and s__uncultured_organism_g__norank_f__Bacteroidales_S24-7_group. Based on metabolomic analyses, profoundly altered metabolites were identified in the combination therapy group. Two metabolic signalling pathways, namely, glycerophospholipid metabolism and sphingolipid metabolism, were explored. In particular, we found that combination therapy with GQD and anti-mouse PD-1 significantly increased the proportion of CD8+ T cells in peripheral blood and tumour tissues. Direct treatment with GQD and anti-mouse PD-1 increased the expression of IFN-γ, which is a critical factor in antitumour immunotherapy. In addition, combination therapy with GQD and anti-mouse PD-1 downregulated PD-1 and increased IL-2 levels, suggesting that the combination therapy could effectively restore T-cell functions by suppressing inhibitory checkpoints. The application of the Chinese medicinal formula GQD with PD-1 blockade-based immunotherapy can be a novel therapeutic strategy for CRC patients with MSS tumours.
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49
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Oliveira AF, Bretes L, Furtado I. Review of PD-1/PD-L1 Inhibitors in Metastatic dMMR/MSI-H Colorectal Cancer. Front Oncol 2019; 9:396. [PMID: 31139574 PMCID: PMC6527887 DOI: 10.3389/fonc.2019.00396] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Accepted: 04/26/2019] [Indexed: 12/15/2022] Open
Abstract
There are a wide range of therapies for metastatic colorectal cancer (CRC) available, but outcomes remain suboptimal. Learning the role of the immune system in cancer development and progression led to advances in the treatment over the last decade. While the field is rapidly evolving, PD-1, and PD-L1 inhibitors have a leading role amongst immunomodulatory agents. They act against pathways involved in adaptive immune suppression resulting in immune checkpoint blockade. Immunotherapy has been slow to impact the management of this patient population due to disappointing results, mainly when used broadly. Nevertheless, some patients with microsatellite-instability-high (MSI-H) or mismatch repair-deficient (dMMR) CRC appear to be susceptible to checkpoint inhibitors with objective and sustained clinical responses, providing a new therapeutic option for patients with advanced disease. This article provides a comprehensive review of the early and late phase trials with the updated data of PD-1/PD-L1 inhibitors alone or in combination with other therapies (immunotherapy, targeted therapy and chemotherapy). While data is still limited, many ongoing trials are underway, testing the efficacy of these agents in CRC. Current and future challenges of PD-1 and PD-L1 inhibitors are also discussed.
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Affiliation(s)
- André F. Oliveira
- Serviço de Oncologia Médica, Centro Hospitalar Universitário Algarve, Faro, Portugal
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50
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Abstract
The stability and function of many oncogenic mutant proteins depend on heat shock protein 90 (HSP90). This unique activity has inspired the exploration of HSP90 as an anticancer target for over two decades. Unfortunately, while clinical trials of highly optimized HSP90 inhibitors have demonstrated modest benefit for patients with advanced cancers, most commonly stabilization of disease, no HSP90 inhibitor has demonstrated sufficient efficacy to achieve FDA approval to date. This review discusses potential reasons for the limited success of these agents and how our increasingly sophisticated understanding of HSP90 suggests alternative, potentially more effective strategies for targeting it to treat cancers. First, we focus on insights gained from model organisms that suggest a fundamental role for HSP90 in supporting the adaptability and heterogeneity of cancers, key factors underlying their ability to evolve and acquire drug resistance. Second, we examine how HSP90’s role in promoting the stability of mutant proteins might be targeted in genetically unstable tumor cells to reveal their aberrant, foreign proteome to the immune system. Both of these emerging aspects of HSP90 biology suggest that the most effective use of HSP90 inhibitors may not be at high doses with the intent to kill cancer cells, but rather in combination with other molecularly targeted therapies at modest, non-heat shock-inducing exposures that limit the adaptive capacity of cancers.
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Affiliation(s)
- Alex M. Jaeger
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
| | - Luke Whitesell
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
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