Phenome-Wide Scan Finds Potential Orofacial Risk Markers for Cancer

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Abstract

Cancer is a disease caused by a process that drives the transformation of normal cells into malignant cells. The late diagnosis of cancer has a negative impact on the health care system due to high treatment cost and decreased chances of favorable prognosis. Here, we aimed to identify orofacial conditions that can serve as potential risk markers for cancers by performing a phenome-wide scan (PheWAS). From a pool of 6,100 individuals, both genetic and epidemiological data of 1,671 individuals were selected: 350 because they were previously diagnosed with cancer and 1,321 to match to those individuals that had cancer, based on age, sex, and ethnicity serving as a comparison group. Results of this study showed that when analyzing the individuals affected by cancer separately, tooth loss/edentulism is associated with SNPs in AXIN2 (rs11867417 p = 0.02 and rs2240308 p = 0.02), and leukoplakia of oral mucosa is associated with both AXIN2 (rs2240308 p = 0.03) and RHEB (rs2374261 p = 0.03). These phenotypes did not show the same trends in patients that were not diagnosed with cancer, allowing for the conclusion that these phenotypes are unique to cases with higher cancer risk.

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Targeting mTOR for cancer therapy

Hui Hua, Qingbin Kong, Hongying Zhang … (2019)

Mechanistic target of rapamycin (mTOR) is a protein kinase regulating cell growth, survival, metabolism, and immunity. mTOR is usually assembled into several complexes such as mTOR complex 1/2 (mTORC1/2). In cooperation with raptor, rictor, LST8, and mSin1, key components in mTORC1 or mTORC2, mTOR catalyzes the phosphorylation of multiple targets such as ribosomal protein S6 kinase β-1 (S6K1), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), Akt, protein kinase C (PKC), and type-I insulin-like growth factor receptor (IGF-IR), thereby regulating protein synthesis, nutrients metabolism, growth factor signaling, cell growth, and migration. Activation of mTOR promotes tumor growth and metastasis. Many mTOR inhibitors have been developed to treat cancer. While some of the mTOR inhibitors have been approved to treat human cancer, more mTOR inhibitors are being evaluated in clinical trials. Here, we update recent advances in exploring mTOR signaling and the development of mTOR inhibitors for cancer therapy. In addition, we discuss the mechanisms underlying the resistance to mTOR inhibitors in cancer cells.

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Twenty-five years of mTOR: Uncovering the link from nutrients to growth

David Sabatini (2017)

Significance The mechanisms that regulate organismal growth and coordinate it with the availability of nutrients were unknown until a few decades ago. We now know that one pathway—the mechanistic target of rapamycin (mTOR) pathway—is the major nutrient-sensitive regulator of growth in animals and plays a central role in physiology, metabolism, the aging process, and common diseases. This work describes the development of the mTOR field, from its origins in studies into the mechanism of action of the drug rapamycin to our increasingly sophisticated understanding of how nutrients are sensed.

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Roles for growth factors in cancer progression.

Esther Witsch, Michael Sela, Yosef Yarden (2010)

Under physiological conditions, cells receive fate-determining signals from their tissue surroundings, primarily in the form of polypeptide growth factors. Integration of these extracellular signals underlies tissue homeostasis. Although departure from homeostasis and tumor initiation are instigated by oncogenic mutations rather than by growth factors, the latter are the major regulators of all subsequent steps of tumor progression, namely clonal expansion, invasion across tissue barriers, angiogenesis, and colonization of distant niches. Here, we discuss the relevant growth factor families, their roles in tumor biology, as well as the respective downstream signaling pathways. Importantly, cancer-associated activating mutations that impinge on these pathways often relieve, in part, the reliance of tumors on growth factors. On the other hand, growth factors are frequently involved in evolvement of resistance to therapeutic regimens, which extends the roles for polypeptide factors to very late phases of tumor progression and offers opportunities for cancer therapy.

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Author and article information

Contributors

Alexandre R. Vieira:

ORCID: http://orcid.org/0000-0003-3392-6881

arv11@pitt.edu

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 17 March 2020

Publication date PMC-release: 17 March 2020

Publication date Collection: 2020

Volume: 10

Electronic Location Identifier: 4869

Affiliations

[1 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Oral Biology, , University of Pittsburgh, ; Pittsburgh, PA USA

[2 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Human Genetics, , University of Pittsburgh, ; Pittsburgh, PA USA

[3 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Pediatric Dentistry, , University of Pittsburgh, ; Pittsburgh, PA USA

Author information

Mariana Bezamat http://orcid.org/0000-0001-9397-3167

Vicente Telles http://orcid.org/0000-0001-6297-6760

Alexandre R. Vieira http://orcid.org/0000-0003-3392-6881

Article

Publisher ID: 61654

DOI: 10.1038/s41598-020-61654-3

PMC ID: 7078198

PubMed ID: 32184411

SO-VID: 5b98ac74-84ad-4d0d-ae55-41aaa989d1f5

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 7 November 2019

Date accepted : 21 February 2020

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ScienceOpen disciplines: Uncategorized

Keywords: cancer,genetics,biomarkers,dental diseases

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ScienceOpen disciplines: Uncategorized

Keywords: cancer, genetics, biomarkers, dental diseases

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Phenome-Wide Scan Finds Potential Orofacial Risk Markers for Cancer

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Cancer Metabolism

Most cited references 35

Targeting mTOR for cancer therapy

Twenty-five years of mTOR: Uncovering the link from nutrients to growth

Roles for growth factors in cancer progression.

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