Mutational Profiles Reveal an Aberrant TGF-β-CEA Regulated Pathway in Colon Adenomas

Chen, Jian; Raju, Gottumukkala S.; Jogunoori, Wilma; Menon, Vipin; Majumdar, Avijit; Chen, Jiun Sheng; Gi, Young Jin; Jeong, Yun Seong; Phan, Liem; Belkin, Mitchell; Gu, Shoujun; Kundra, Suchin; Mistry, Nipun A.; Zhang, Jianping; Su, Xiaoping; Li, Shulin; Lin, Sue Hwa; Javle, Milind; McMurray, John S.; Rahlfs, Thomas F.; Mishra, Bibhuti; White, Jon; Rashid, Asif; Beauchemin, Nicole; Weston, Brian; Shafi, Mehnaz A.; Stroehlein, John R.; Davila, Marta; Akbani, Rehan; Weinstein, John N.; Wu, Xifeng; Mishra, Lopa

doi:10.1371/journal.pone.0153933

Cited by 17 publications

(22 citation statements)

References 36 publications

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“…However, all three cases included genes associated with metastasis, cell adhesion, and EMT. Members of the CEACAM family, which consists of proteins involved in pathogen sensing, innate immunity, and metastasis (Chen et al, 2016a; Vitenshtein et al, 2016), were consistently upregulated. TMPRSS4 and ADAMTS19 , encoding cell surface proteases, were upregulated in the PanCancer and GI cohorts, respectively.…”

Section: Resultsmentioning

confidence: 99%

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily

Korkut¹,

Zaidi²,

Kanchi³

et al. 2018

Cell Systems

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148

139

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SUMMARY We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad–mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, BMPR2), and Smads (SMAD2, SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily.

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Section: Resultsmentioning

confidence: 99%

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily

Korkut¹,

Zaidi²,

Kanchi³

et al. 2018

Cell Systems

Self Cite

148

139

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show abstract

“…domain-like receptors (NLRs) on immune cells may then induce pro-inflammatory cytokines [26,147], as well as reactive oxygen and nitrogen species (RONS) [148]. This inflammation response can result in DNA damage and CIN, as well as impairment of the Wnt/βcatenin and base excision repair (BER) pathways, thus resulting in increased risk for cell proliferation, angiogenesis and metastasis [128,149].…”

Section: Interaction Of Microbiota and The Immune System In Crc Tumorigenesismentioning

confidence: 99%

Genomic, Microbial and Immunological Microenvironment of Colorectal Polyps

Tse

Welham

Engel

et al. 2021

Cancers

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Colorectal cancer (CRC) develops from pre-cancerous cellular lesions in the gut epithelium, known as polyps. Polyps themselves arise through the accumulation of mutations that disrupt the function of key tumour suppressor genes, activate proto-oncogenes and allow proliferation in an environment where immune control has been compromised. Consequently, colonoscopic surveillance and polypectomy are central pillars of cancer control strategies. Recent advances in genomic sequencing technologies have enhanced our knowledge of key driver mutations in polyp lesions that likely contribute to CRC. In accordance with the prognostic significance of Immunoscores for CRC survival, there is also a likely role for early immunological changes in polyps, including an increase in regulatory T cells and a decrease in mature dendritic cell numbers. Gut microbiotas are under increasing research interest for their potential contribution to CRC evolution, and changes in the gut microbiome have been reported from analyses of adenomas. Given that early changes to molecular components of bowel polyps may have a direct impact on cancer development and/or act as indicators of early disease, we review the molecular landscape of colorectal polyps, with an emphasis on immunological and microbial alterations occurring in the gut and propose the potential clinical utility of these data.

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“…The most explored target, the glycoprotein carcinoembryonic antigen (CEA), is upregulated in CRC, but also appears in organs outside the GI tract, leading to potential autoimmunity and immunological tolerance [62, 63]. In contrast, GUCY2C has unique anatomic and biological characteristics that appear to circumvent these issues.…”

Section: 0 Gucy2c-targeted Immunotherapies For Metastatic Colorectamentioning

confidence: 99%

Guanylate cyclase C as a target for prevention, detection, and therapy in colorectal cancer

Aka

Rappaport

Pattison

et al. 2017

Expert Review of Clinical Pharmacology

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Introduction Colorectal cancer remains the second leading cause of cancer death in the United States, and new strategies to prevent, detect, and treat the disease are needed. The receptor, guanylate cyclase C (GUCY2C), a tumor suppressor expressed by the intestinal epithelium, has emerged as a promising target. Areas Covered This review outlines the role of GUCY2C in tumorigenesis, and steps to translate GUCY2C-targeting schemes to the clinic. Endogenous GUCY2C-activating ligands disappear early in tumorigenesis, silencing its signaling axis and enabling transformation. Pre-clinical models support GUCY2C ligand supplementation as a novel disease prevention paradigm. With the recent FDA approval of the GUCY2C ligand, linaclotide, and two more synthetic ligands in the pipeline, this strategy can be tested in human trials. In addition to primary tumor prevention, we also review immunotherapies targeting GUCY2C expressed by metastatic lesions, and platforms using GUCY2C as a biomarker for detection and patient staging. Expert Commentary Results of the first GUCY2C targeting schemes in patients will become available in the coming years. The identification of GUCY2C ligand loss as a requirement for colorectal tumorigenesis has the potential to change the treatment paradigm from an irreversible disease of genetic mutation, to a treatable disease of ligand insufficiency.

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Mutational Profiles Reveal an Aberrant TGF-β-CEA Regulated Pathway in Colon Adenomas

Cited by 17 publications

References 36 publications

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily

Genomic, Microbial and Immunological Microenvironment of Colorectal Polyps

Guanylate cyclase C as a target for prevention, detection, and therapy in colorectal cancer

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