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Article ; Online: Y-Chromosome-Linked Genes Are Associated With Sex-Related Head-Neck Squamous Cell Carcinoma Survival.

Feng, Xin / Zhang, Tan / Chou, Jeff / Patwa, Hafiz S / Sullivan, Christopher A / Browne, J Dale

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery

2023 Volume 169, Issue 6, Page(s) 1533–1541

Abstract: Objective: To define novel gene biomarkers for prognosis of head and neck squamous cell carcinoma (HNSCC) patients' survival.: Study design: Retrospective study.: Setting: The Cancer Genome Atlas (TCGA) HNSCC RNA-Seq dataset.: Methods: ... ...

Abstract	Objective: To define novel gene biomarkers for prognosis of head and neck squamous cell carcinoma (HNSCC) patients' survival. Study design: Retrospective study. Setting: The Cancer Genome Atlas (TCGA) HNSCC RNA-Seq dataset. Methods: Coexpressed gene clusters were extracted from TCGA RNA-seq data using our previously published method (EPIG). Kaplan-Meier estimator was then used for overall survival-relevant analysis, with patients partitioned into 3 groups based on gene expression levels: female, male_low, and male_high. Results: Male had better overall survival than female and male with higher expression level of Y-chromosome-linked (Y-linked) genes had significantly better survival than those with lower expression levels. In addition, male with a higher expression level of Y-linked genes showed even better survival when they have a higher level of coexpressed cluster of genes related to B or T cell immune response. Other clinical conditions related to immune responses also consistently showed favorable effects on the Y-linked genes for survival estimation. Male patients with higher expression level of Y-linked genes also have significantly higher tumor/normal tissue (T/N) ratio of those genes and higher level of several immune responses related clinical measurements (eg, lymphocyte and TCR related). Male patients with lower expression level of Y-linked genes benefited from radiation-only treatment. Conclusions: The favorable role of a cluster of coexpressed Y-linked genes in HNSCC patients' survival is potentially associated with elevated level of immune responses. These Y-linked genes could serve as useful prognostic biomarkers for HNSCC patients' survival estimation and treatment.
MeSH term(s)	Humans ; Male ; Female ; Squamous Cell Carcinoma of Head and Neck/genetics ; Head and Neck Neoplasms/genetics ; Genes, Y-Linked ; Retrospective Studies ; Prognosis ; Chromosomes ; Biomarkers ; Biomarkers, Tumor/genetics ; Gene Expression Regulation, Neoplastic
Chemical Substances	Biomarkers ; Biomarkers, Tumor
Language	English
Publishing date	2023-07-07
Publishing country	England
Document type	Journal Article
ZDB-ID	392085-9
ISSN	1097-6817 ; 0161-6439 ; 0194-5998
ISSN (online)	1097-6817
ISSN	0161-6439 ; 0194-5998
DOI	10.1002/ohn.421
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Article ; Online: Prognostic attributes of immune signatures in soft tissue sarcomas show differential dependencies on tumor mutational burden.

Raj, Shailaja K S / Routh, Eric D / Chou, Jeff W / Votanopoulos, Konstantinos I / Triozzi, Pierre L / Miller, Lance D

Cancer

2022 Volume 128, Issue 17, Page(s) 3254–3264

Abstract: Background: Cellular and intrinsic markers of sarcoma immunogenicity are poorly understood. To gain insight into whether tumor-immune interactions correlate with clinical aggressiveness, the authors examined the prognostic significance of immune gene ... ...

Abstract	Background: Cellular and intrinsic markers of sarcoma immunogenicity are poorly understood. To gain insight into whether tumor-immune interactions correlate with clinical aggressiveness, the authors examined the prognostic significance of immune gene signatures in combination with tumor mutational burden (TMB) and cancer-testis antigen (CTA) expression. Methods: RNA sequencing and clinical data of 259 soft tissue sarcomas from The Cancer Genome Atlas project were used to investigate associations between published immune gene signatures and patient overall survival (OS) in the contexts of TMB, as computed from whole-exome sequencing data, and CTA gene expression. Multivariate Cox proportional hazards regression models and log-rank tests were used to assess survival associations. Results: Immune signature scores that reflected in part the intratumoral abundance of cytotoxic T cells showed significant positive associations with OS. However, the prognostic power of the T-cell signatures was highly dependent on TMB-high status, consistent with protective effects of tumor-infiltrating T cells in tumors with elevated antigenicity. In TMB-low tumors, a signature of infiltrating plasma B cells was significantly and positively associated with OS, independent of T-cell signature status. Although tumor subtypes based on differential expression patterns of CTA genes showed different survival associations within leiomyosarcoma and myxofibrosarcoma histologies, neither CTA nor histologic subtype interacted with the T-cell-survival association. Conclusions: Signatures of T-cell and plasma B-cell infiltrates were associated with a survival benefit in soft tissue sarcomas. TMB, but not CTA expression, influenced the prognostic power of T-cell-associated, but not plasma B-cell-associated, survival. Lay summary: Clinical data and RNA analysis of 259 soft tissue sarcomas from The Cancer Genome Atlas project were used to investigate associations between five published gene immune cell expression signatures and survival in the context of tumor mutations. Activated T cells had a significant positive association with patient survival. Although high tumor mutation burden was associated with good survival, the prognostic power of T-cell signatures was highly dependent on tumor mutational status, consistent with protective effects of tumor-infiltrating T cells in tumors with high levels of antigens. In low tumor mutation-bearing tumors, plasma B cells were positively associated with survival.
MeSH term(s)	Adult ; Biomarkers, Tumor/genetics ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Mutation ; Prognosis ; Sarcoma/genetics ; Soft Tissue Neoplasms/genetics ; Whole Exome Sequencing
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2022-06-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1429-1
ISSN	1097-0142 ; 0008-543X ; 1934-662X
ISSN (online)	1097-0142
ISSN	0008-543X ; 1934-662X
DOI	10.1002/cncr.34333
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Article ; Online: Visceral adipose microbial and inflammatory signatures in metabolically healthy and unhealthy nonhuman primates.

Ruggiero, Alistaire D / Vemuri, Ravichandra / DeStephanis, Darla / Brock, Ashlynn / Block, Masha R / Chou, Jeff / Das, Swapan K / Williams, Abigail G / Kavanagh, Kylie

Obesity (Silver Spring, Md.)

2023 Volume 31, Issue 10, Page(s) 2543–2556

Abstract: Objective: Obesity is a key risk factor for metabolic syndrome (MetS); however, >10% of lean individuals meet MetS criteria. Visceral adipose tissue (VAT) disproportionately contributes to inflammation and insulin resistance compared with subcutaneous ... ...

Abstract	Objective: Obesity is a key risk factor for metabolic syndrome (MetS); however, >10% of lean individuals meet MetS criteria. Visceral adipose tissue (VAT) disproportionately contributes to inflammation and insulin resistance compared with subcutaneous fat depots. The primary aim of this study was to profile tissue microbiome components in VAT over a wide range of metabolic statuses in a highly clinically relevant model. Methods: VAT was profiled from nonhuman primates that naturally demonstrate four distinct health phenotypes despite consuming a healthy diet, namely metabolically healthy lean and obese and metabolically unhealthy lean and obese. Results: VAT biopsied from unhealthy lean and obese nonhuman primates demonstrated upregulation of immune signaling pathways, a tissue microbiome enriched in gram-negative bacteria including Pseudomonas, and deficiencies in anti-inflammatory adipose tissue M2 macrophages. VAT microbiomes were distinct from fecal microbiomes, and fecal microbiomes did not differ by metabolic health group, which was in contrast to the VAT bacterial communities. Conclusions: Immune activation with gram-negative VAT microbial communities is a consistent feature in elevated MetS risk in both lean and obesity states.
MeSH term(s)	Animals ; Obesity ; Metabolic Syndrome ; Adipose Tissue ; Biopsy ; Primates
Language	English
Publishing date	2023-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2230457-5
ISSN	1930-739X ; 1071-7323 ; 1930-7381
ISSN (online)	1930-739X
ISSN	1071-7323 ; 1930-7381
DOI	10.1002/oby.23870
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Zs.A 4061: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Comprehensive gene cluster analysis of head and neck squamous cell carcinoma TCGA RNA-seq data defines B cell immunity-related genes as a robust survival predictor.

Feng, Xin / Zhang, Tan / Chou, Jeff / Liu, Liang / Miller, Lance D / Sullivan, Christopher A / Browne, James D

Head & neck

2021 Volume 44, Issue 2, Page(s) 443–452

Abstract: Background: The authors aimed to define novel gene expression signatures that are associated with patients' survival with head and neck squamous cell carcinoma (HNSCC).: Methods: TCGA RNA-seq data were used for gene expression clusters extraction ... ...

Abstract	Background: The authors aimed to define novel gene expression signatures that are associated with patients' survival with head and neck squamous cell carcinoma (HNSCC). Methods: TCGA RNA-seq data were used for gene expression clusters extraction from 499 tumor samples by the "EPIG" method. Tumor samples were then partitioned into lower and higher than median level groups for survival relevant analysis by Kaplan-Meier estimator. Results: We found that two gene clusters (_1, _2) are favorably, while two (_3, _4) are unfavorably, associated with patients' survival with HNSCC. Notably, most genes on the top lists of cluster_2 are associated with B cells. A gene expression signature with combined genes from cluster_2 and _4 was further determined to be associated with HNSCC survival rate. Conclusion: Our work strongly supported a favorable role of B cells in patients' survival with HNSCC and identified a novel coexpressed gene signature as prognostic biomarker for patients' survival with HNSCC estimation.
MeSH term(s)	Biomarkers, Tumor/genetics ; Cluster Analysis ; Gene Expression Regulation, Neoplastic ; Head and Neck Neoplasms/genetics ; Humans ; Multigene Family ; Prognosis ; RNA-Seq ; Squamous Cell Carcinoma of Head and Neck/genetics
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2021-11-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	645165-2
ISSN	1097-0347 ; 0148-6403 ; 1043-3074
ISSN (online)	1097-0347
ISSN	0148-6403 ; 1043-3074
DOI	10.1002/hed.26944
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Zs.A 1493: Show issues

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Article ; Online: Macrophage Phenotypes and Gene Expression Patterns Are Unique in Naturally Occurring Metabolically Healthy Obesity.

Ruggiero, Alistaire D / Vemuri, Ravichandra / Block, Masha / DeStephanis, Darla / Davis, Matthew / Chou, Jeff / Williams, Abigail / Brock, Ashlynn / Das, Swapan Kumar / Kavanagh, Kylie

International journal of molecular sciences

2022 Volume 23, Issue 20

Abstract: Obesity impacts 650 million individuals globally, often co-occurring with metabolic syndrome. Though many obese individuals experience metabolic abnormalities (metabolically unhealthy obese [MUO]), ~30% do not (metabolically healthy obese [MHO]). ... ...

Abstract	Obesity impacts 650 million individuals globally, often co-occurring with metabolic syndrome. Though many obese individuals experience metabolic abnormalities (metabolically unhealthy obese [MUO]), ~30% do not (metabolically healthy obese [MHO]). Conversely, >10% of lean individuals are metabolically unhealthy (MUL). To evaluate the physiologic drivers of these phenotypes, a 44-animal African green monkey cohort was selected using metabolic syndrome risk criteria to represent these four clinically defined health groups. Body composition imaging and subcutaneous adipose tissue (SQ AT) biopsies were collected. Differences in adipocyte size, macrophage subtype distribution, gene expression, vascularity and fibrosis were analyzed using digital immunohistopathology, unbiased RNA-seq, endothelial CD31, and Masson’s trichrome staining, respectively. MHO AT demonstrated significant increases in M2 macrophages (p = 0.02) and upregulation of fatty acid oxidation-related terms and transcripts, including FABP7 (p = 0.01). MUO AT demonstrated downregulation of these factors and co-occurring upregulation of immune responses. These changes occurred without differences in AT distributions, adipocyte size, AT endothelial cells, collagen I deposition, or circulating cytokine levels. Without unhealthy diet consumption, healthy obesity is defined by an increased SQ AT M2/M1 macrophage ratio and lipid handling gene expression. We highlight M2 macrophages and fatty acid oxidation as targets for improving metabolic health with obesity.
MeSH term(s)	Animals ; Chlorocebus aethiops ; Obesity, Metabolically Benign ; Metabolic Syndrome/genetics ; Endothelial Cells/metabolism ; Obesity/genetics ; Obesity/metabolism ; Phenotype ; Macrophages/metabolism ; Lipids ; Cytokines/genetics ; Gene Expression ; Fatty Acids ; Collagen/genetics ; Risk Factors ; Body Mass Index
Chemical Substances	Lipids ; Cytokines ; Fatty Acids ; Collagen (9007-34-5)
Language	English
Publishing date	2022-10-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232012680
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Article ; Online: Phase II trial of cytarabine and mitoxantrone with devimistat in acute myeloid leukemia.

Anderson, Rebecca / Miller, Lance D / Isom, Scott / Chou, Jeff W / Pladna, Kristin M / Schramm, Nathaniel J / Ellis, Leslie R / Howard, Dianna S / Bhave, Rupali R / Manuel, Megan / Dralle, Sarah / Lyerly, Susan / Powell, Bayard L / Pardee, Timothy S

Nature communications

2022 Volume 13, Issue 1, Page(s) 1673

Abstract: Devimistat is a TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML showed promising response rates. Here we report the results of a single ... ...

Abstract	Devimistat is a TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML showed promising response rates. Here we report the results of a single arm phase II study (NCT02484391). The primary outcome of feasibility of maintenance devimistat following induction and consolidation with devimistat in combination with high dose cytarabine and mitoxantrone was not met, as maintenance devimistat was only administered in 2 of 21 responders. The secondary outcomes of response (CR + CRi) and median survival were 44% (21/48) and 5.9 months respectively. There were no unexpected toxicities observed. An unplanned, post-hoc analysis of the phase I and II datasets suggests a trend of a dose response in older but not younger patients. RNA sequencing data from patient samples reveals an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis and we find a correlation between mitochondrial membrane potential and sensitivity to chemotherapy. Devimistat also induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. We find that pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These findings suggest that an age related decline in mitochondrial quality and autophagy may be associated with response to devimistat however this needs to be confirmed in larger cohorts with proper trial design.
MeSH term(s)	Aged ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Caprylates ; Cytarabine/therapeutic use ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Mitoxantrone ; Sulfides ; Treatment Outcome
Chemical Substances	Caprylates ; Sulfides ; Cytarabine (04079A1RDZ) ; Mitoxantrone (BZ114NVM5P) ; devimistat (E76113IR49)
Language	English
Publishing date	2022-03-30
Publishing country	England
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-29039-4
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Article ; Online: Discernment of possible mechanisms of hepatotoxicity via biological processes over-represented by co-expressed genes.

Chou, Jeff W / Bushel, Pierre R

BMC genomics

2009 Volume 10, Page(s) 272

Abstract: Background: Hepatotoxicity is a form of liver injury caused by exposure to stressors. Genomic-based approaches have been used to detect changes in transcription in response to hepatotoxicants. However, there are no straightforward ways of using co- ... ...

Abstract	Background: Hepatotoxicity is a form of liver injury caused by exposure to stressors. Genomic-based approaches have been used to detect changes in transcription in response to hepatotoxicants. However, there are no straightforward ways of using co-expressed genes anchored to a phenotype or constrained by the experimental design for discerning mechanisms of a biological response. Results: Through the analysis of a gene expression dataset containing 318 liver samples from rats exposed to hepatotoxicants and leveraging alanine aminotransferase (ALT), a serum enzyme indicative of liver injury as the phenotypic marker, we identified biological processes and molecular pathways that may be associated with mechanisms of hepatotoxicity. Our analysis used an approach called Coherent Co-expression Biclustering (cc-Biclustering) for clustering a subset of genes through a coherent (consistency) measure within each group of samples representing a subset of experimental conditions. Supervised biclustering identified 87 genes co-expressed and correlated with ALT in all the samples exposed to the chemicals. None of the over-represented pathways related to liver injury. However, biclusters with subsets of samples exposed to one of the 7 hepatotoxicants, but not to a non-toxic isomer, contained co-expressed genes that represented pathways related to a stress response. Unsupervised biclustering of the data resulted in 1) four to five times more genes within the bicluster containing all the samples exposed to the chemicals, 2) biclusters with co-expression of genes that discerned 1,4 dichlorobenzene (a non-toxic isomer at low and mid doses) from the other chemicals, pathways and biological processes that underlie liver injury and 3) a bicluster with genes up-regulated in an early response to toxic exposure. Conclusion: We obtained clusters of co-expressed genes that over-represented biological processes and molecular pathways related to hepatotoxicity in the rat. The mechanisms involved in the response of the liver to the exposure to 1,4-dichlorobenzene suggest non-genotoxicity whereas the exposure to the hepatotoxicants could be DNA damaging leading to overall genomic instability and activation of cell cycle check point signaling. In addition, key pathways and biological processes representative of an inflammatory response, energy production and apoptosis were impacted by the hepatotoxicant exposures that manifested liver injury in the rat.
MeSH term(s)	Alanine Transaminase/metabolism ; Animals ; Biomarkers ; Chlorobenzenes/toxicity ; Cluster Analysis ; Gene Expression ; Gene Expression Profiling/methods ; Liver/drug effects ; Liver/metabolism ; Male ; Rats ; Rats, Inbred F344
Chemical Substances	Biomarkers ; Chlorobenzenes ; 4-dichlorobenzene (D149TYB5MK) ; Alanine Transaminase (EC 2.6.1.2)
Language	English
Publishing date	2009-06-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural
ISSN	1471-2164
ISSN (online)	1471-2164
DOI	10.1186/1471-2164-10-272
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Article ; Online: The Presence and Potential Role of ALDH1A2 in the Glioblastoma Microenvironment.

Sanders, Stephanie / Herpai, Denise M / Rodriguez, Analiz / Huang, Yue / Chou, Jeff / Hsu, Fang-Chi / Seals, Darren / Mott, Ryan / Miller, Lance D / Debinski, Waldemar

Cells

2021 Volume 10, Issue 9

Abstract: Glioblastoma (GBM) is the most aggressive malignant glioma. Therapeutic targeting of GBM is made more difficult due to its heterogeneity, resistance to treatment, and diffuse infiltration into the brain parenchyma. Better understanding of the tumor ... ...

Abstract	Glioblastoma (GBM) is the most aggressive malignant glioma. Therapeutic targeting of GBM is made more difficult due to its heterogeneity, resistance to treatment, and diffuse infiltration into the brain parenchyma. Better understanding of the tumor microenvironment should aid in finding more effective management of GBM. GBM-associated macrophages (GAM) comprise up to 30% of the GBM microenvironment. Therefore, exploration of GAM activity/function and their specific markers are important for developing new therapeutic agents. In this study, we identified and evaluated the expression of ALDH1A2 in the GBM microenvironment, and especially in M2 GAM, though it is also expressed in reactive astrocytes and multinucleated tumor cells. We demonstrated that M2 GAM highly express ALDH1A2 when compared to other ALDH1 family proteins. Additionally, GBM samples showed higher expression of ALDH1A2 when compared to low-grade gliomas (LGG), and this expression was increased upon tumor recurrence both at the gene and protein levels. We demonstrated that the enzymatic product of ALDH1A2, retinoic acid (RA), modulated the expression and activity of MMP-2 and MMP-9 in macrophages, but not in GBM tumor cells. Thus, the expression of ALDH1A2 may promote the progressive phenotype of GBM.
MeSH term(s)	Aldehyde Dehydrogenase 1 Family/genetics ; Aldehyde Dehydrogenase 1 Family/immunology ; Aldehyde Dehydrogenase 1 Family/metabolism ; Apoptosis ; Brain Neoplasms/genetics ; Brain Neoplasms/immunology ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Cell Movement ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Glioblastoma/genetics ; Glioblastoma/immunology ; Glioblastoma/metabolism ; Glioblastoma/pathology ; Humans ; Macrophages/immunology ; Matrix Metalloproteinase 2/genetics ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/genetics ; Matrix Metalloproteinase 9/metabolism ; Retinal Dehydrogenase/genetics ; Retinal Dehydrogenase/immunology ; Retinal Dehydrogenase/metabolism ; Tretinoin/metabolism ; Tumor Cells, Cultured ; Tumor Microenvironment
Chemical Substances	Tretinoin (5688UTC01R) ; Aldehyde Dehydrogenase 1 Family (EC 1.2.1) ; ALDH1A2 protein, human (EC 1.2.1.36) ; Retinal Dehydrogenase (EC 1.2.1.36) ; MMP2 protein, human (EC 3.4.24.24) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; MMP9 protein, human (EC 3.4.24.35) ; Matrix Metalloproteinase 9 (EC 3.4.24.35)
Language	English
Publishing date	2021-09-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10092485
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Article ; Online: Epigenetic MLH1 silencing concurs with mismatch repair deficiency in sporadic, naturally occurring colorectal cancer in rhesus macaques.

Deycmar, Simon / Johnson, Brendan J / Ray, Karina / Schaaf, George W / Ryan, Declan Patrick / Cullin, Cassandra / Dozier, Brandy L / Ferguson, Betsy / Bimber, Benjamin N / Olson, John D / Caudell, David L / Whitlow, Christopher T / Solingapuram Sai, Kiran Kumar / Romero, Emily C / Villinger, Francois J / Burgos, Armando G / Ainsworth, Hannah C / Miller, Lance D / Hawkins, Gregory A /

Chou, Jeff W / Gomes, Bruno / Hettich, Michael / Ceppi, Maurizio / Charo, Jehad / Cline, J Mark

Journal of translational medicine

2024 Volume 22, Issue 1, Page(s) 292

Abstract: Background: Naturally occurring colorectal cancers (CRC) in rhesus macaques share many features with their human counterparts and are useful models for cancer immunotherapy; but mechanistic data are lacking regarding the comparative molecular ... ...

Abstract	Background: Naturally occurring colorectal cancers (CRC) in rhesus macaques share many features with their human counterparts and are useful models for cancer immunotherapy; but mechanistic data are lacking regarding the comparative molecular pathogenesis of these cancers. Methods: We conducted state-of-the-art imaging including CT and PET, clinical assessments, and pathological review of 24 rhesus macaques with naturally occurring CRC. Additionally, we molecularly characterized these tumors utilizing immunohistochemistry (IHC), microsatellite instability assays, DNAseq, transcriptomics, and developed a DNA methylation-specific qPCR assay for MLH1, CACNA1G, CDKN2A, CRABP1, and NEUROG1, human markers for CpG island methylator phenotype (CIMP). We furthermore employed Monte-Carlo simulations to in-silico model alterations in DNA topology in transcription-factor binding site-rich promoter regions upon experimentally demonstrated DNA methylation. Results: Similar cancer histology, progression patterns, and co-morbidities could be observed in rhesus as reported for human CRC patients. IHC identified loss of MLH1 and PMS2 in all cases, with functional microsatellite instability. DNA sequencing revealed the close genetic relatedness to human CRCs, including a similar mutational signature, chromosomal instability, and functionally-relevant mutations affecting KRAS (G12D), TP53 (R175H, R273), APC, AMER1, ALK, and ARID1A. Interestingly, MLH1 mutations were rarely identified on a somatic or germline level. Transcriptomics not only corroborated the similarities of rhesus and human CRCs, but also demonstrated the significant downregulation of MLH1 but not MSH2, MSH6, or PMS2 in rhesus CRCs. Methylation-specific qPCR suggested CIMP-positivity in 9/16 rhesus CRCs, but all 16/16 exhibited significant MLH1 promoter hypermethylation. DNA hypermethylation was modelled to affect DNA topology, particularly propeller twist and roll profiles. Modelling the DNA topology of a transcription factor binding motif (TFAP2A) in the MLH1 promoter that overlapped with a methylation-specific probe, we observed significant differences in DNA topology upon experimentally shown DNA methylation. This suggests a role of transcription factor binding interference in epigenetic silencing of MLH1 in rhesus CRCs. Conclusions:* These data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. We consider this spontaneous, uninduced CRC in immunocompetent, treatment-naïve rhesus macaques to be a uniquely informative model for human CRC.
MeSH term(s)	Humans ; Animals ; Macaca mulatta/genetics ; Macaca mulatta/metabolism ; Microsatellite Instability ; MutL Protein Homolog 1/genetics ; Mismatch Repair Endonuclease PMS2/genetics ; Mismatch Repair Endonuclease PMS2/metabolism ; Colorectal Neoplasms/pathology ; DNA Methylation/genetics ; Epigenesis, Genetic ; Transcription Factors/genetics ; Transcription Factors/metabolism ; DNA/metabolism ; DNA Mismatch Repair/genetics ; Brain Neoplasms ; Neoplastic Syndromes, Hereditary
Chemical Substances	MutL Protein Homolog 1 (EC 3.6.1.3) ; Mismatch Repair Endonuclease PMS2 (EC 3.6.1.3) ; Transcription Factors ; DNA (9007-49-2) ; MLH1 protein, human
Language	English
Publishing date	2024-03-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-024-04869-6
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Article: Country survey

Liu, Heidi / Chou, Jeff / Chou, Sophie

Derivatives & financial instruments Bd. 15.2013, Special issue, S. 105-116

Taiwan

2013

Author's details	Heidi Liu, Sophie Chou and Jeff Chou
Language	English
Publisher	IBFD Publ. BV
Publishing place	Amsterdam
Document type	Article
ZDB-ID	1470976-4
ISSN	1389-1863
Database	ECONomics Information System

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