MAPK1/ERK2 as novel target genes for pain in head and neck cancer patients

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Abstract

Background

Genetic susceptibility plays an important role in the risk of developing pain in individuals with cancer. As a complex trait, multiple genes underlie this susceptibility. We used gene network analyses to identify novel target genes associated with pain in patients newly diagnosed with squamous cell carcinoma of the head and neck (HNSCC).

Results

We first identified 36 cancer pain-related genes (i.e., focus genes) from 36 publications based on a literature search. The Ingenuity Pathway Analysis (IPA) analysis identified additional genes that are functionally related to the 36 focus genes through pathway relationships yielding a total of 82 genes. Subsequently, 800 SNPs within the 82 IPA-selected genes on the Illumina HumanOmniExpress-12v1 platform were selected from a large-scale genotyping effort. Association analyses between the 800 candidate SNPs (covering 82 genes) and pain in a patient cohort of 1368 patients with HNSCC (206 patients with severe pain vs. 1162 with non-severe pain) showed the highest significance for MAPK1/ERK2, a gene belonging to the MAP kinase family (rs8136867, p value = 8.92 × 10 ⁻⁴; odds ratio [OR] = 1.33, 95 % confidence interval [CI]: 1.13–1.58). Other top genes were PIK3C2G (a member of PI3K [complex], rs10770367, p value = 1.10 × 10 ⁻³; OR = 1.46, 95 % CI: 1.16–1.82), TCRA (the alpha chain of T-cell receptor, rs6572493, p value = 2.84 × 10 ⁻³; OR = 0.70, 95 % CI: 0.55–0.88), PDGFC (platelet-derived growth factor C, rs6845322, p value = 4.88 × 10 ⁻³; OR = 1.32, 95 % CI: 1.09–1.60), and CD247 (a member of CD3, rs2995082, p value = 7.79 × 10 ⁻³; OR = 0.76, 95 % CI: 0.62–0.93).

Conclusions

Our findings provide novel candidate genes and biological pathways underlying pain in cancer patients. Further study of the variations of these candidate genes could inform clinical decision making when treating cancer pain.

Electronic supplementary material

The online version of this article (doi:10.1186/s12863-016-0348-7) contains supplementary material, which is available to authorized users.

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Most cited references 61

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The large-scale organization of metabolic networks

R. Albert, A L Barabási, H. Jeong … (2000)

In a cell or microorganism the processes that generate mass, energy, information transfer, and cell fate specification are seamlessly integrated through a complex network of various cellular constituents and reactions. However, despite the key role these networks play in sustaining various cellular functions, their large-scale structure is essentially unknown. Here we present the first systematic comparative mathematical analysis of the metabolic networks of 43 organisms representing all three domains of life. We show that, despite significant variances in their individual constituents and pathways, these metabolic networks display the same topologic scaling properties demonstrating striking similarities to the inherent organization of complex non-biological systems. This suggests that the metabolic organization is not only identical for all living organisms, but complies with the design principles of robust and error-tolerant scale-free networks, and may represent a common blueprint for the large-scale organization of interactions among all cellular constituents.

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MAP kinase and pain.

Ru-Rong Ji, Robert W. Gereau, Marzia Malcangio … (2009)

Mitogen-activated protein kinases (MAPKs) are important for intracellular signal transduction and play critical roles in regulating neural plasticity and inflammatory responses. The MAPK family consists of three major members: extracellular signal-regulated kinases (ERK), p38, and c-Jun N-terminal kinase (JNK), which represent three separate signaling pathways. Accumulating evidence shows that all three MAPK pathways contribute to pain sensitization after tissue and nerve injury via distinct molecular and cellular mechanisms. Activation (phosphorylation) of MAPKs under different persistent pain conditions results in the induction and maintenance of pain hypersensitivity via non-transcriptional and transcriptional regulation. In particular, ERK activation in spinal cord dorsal horn neurons by nociceptive activity, via multiple neurotransmitter receptors, and using different second messenger pathways plays a critical role in central sensitization by regulating the activity of glutamate receptors and potassium channels and inducing gene transcription. ERK activation in amygdala neurons is also required for inflammatory pain sensitization. After nerve injury, ERK, p38, and JNK are differentially activated in spinal glial cells (microglia vs astrocytes), leading to the synthesis of proinflammatory/pronociceptive mediators, thereby enhancing and prolonging pain. Inhibition of all three MAPK pathways has been shown to attenuate inflammatory and neuropathic pain in different animal models. Development of specific inhibitors for MAPK pathways to target neurons and glial cells may lead to new therapies for pain management. Although it is well documented that MAPK pathways can increase pain sensitivity via peripheral mechanisms, this review will focus on central mechanisms of MAPKs, especially ERK.

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Genome-wide association study identifies five susceptibility loci for glioma.

Sanjay Shete, Fay J. Hosking, Lindsay Robertson … (2009)

To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 x 10(-17)), 8q24.21 (rs4295627, CCDC26; P = 2.34 x 10(-18)), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 x 10(-15)), 20q13.33 (rs6010620, RTEL1; P = 2.52 x 10(-12)) and 11q23.3 (rs498872, PHLDB1; P = 1.07 x 10(-8)). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.

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Author and article information

Contributors

Cielito C. Reyes-Gibby: creyes@mdanderson.org

Jian Wang: jianwang@mdanderson.org

Mary Rose T. Silvas: MTSilvas@mdanderson.org

Robert Yu: rkyu@mdanderson.org

Sai-Ching J. Yeung: syeung@mdanderson.org

Sanjay Shete: sshete@mdanderson.org

Journal

Journal ID (nlm-ta): BMC Genet

Journal ID (iso-abbrev): BMC Genet

Title: BMC Genetics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2156

Publication date (Electronic): 13 February 2016

Publication date PMC-release: 13 February 2016

Publication date Collection: 2016

Volume: 17

Electronic Location Identifier: 40

Affiliations

[ ]Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 U.S.A.

[ ]Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 U.S.A.

[ ]Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 U.S.A

Article

Publisher ID: 348

DOI: 10.1186/s12863-016-0348-7

PMC ID: 4752805

PubMed ID: 26872611

SO-VID: b89adfb9-3145-4ba1-9eb7-b9e69e1738cd

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 17 July 2015

Date accepted : 5 February 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health (US);

Award ID: R01DE022891

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health (US);

Award ID: R01CA131324

Award Recipient : Sanjay Shete

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health (US);

Award ID: R25DA026120

Award Recipient : Sanjay Shete

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health (US);

Award ID: CA192197

Award Recipient : Jian Wang

Funded by: FundRef http://dx.doi.org/10.13039/100000072, National Institute of Dental and Craniofacial Research;

Award ID: R01DE022891

Award Recipient : Sanjay Shete

Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;

Award ID: CA016672

Award Recipient : Sanjay Shete

Funded by: Barnhart Family Distinguished Professorship in Targeted Therapy

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ScienceOpen disciplines: Genetics

Keywords: cancer pain,head and neck cancer,mapk1/erk2,ingenuity pathway analysis,gene,snp

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ScienceOpen disciplines: Genetics

Keywords: cancer pain, head and neck cancer, mapk1/erk2, ingenuity pathway analysis, gene, snp

MAPK1/ERK2 as novel target genes for pain in head and neck cancer patients

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Abstract

Background

Results

Conclusions

Electronic supplementary material

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Genes & Diseases

Most cited references 61

The large-scale organization of metabolic networks

MAP kinase and pain.

Genome-wide association study identifies five susceptibility loci for glioma.

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