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

Abstract

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

Genome-wide association study suggests common variants within RP11-634B7.4 gene influencing severe pre-treatment pain in head and neck cancer patients

“…Consistent with previous studies, our current GWAS for pre-treatment pain in HNSCC patients supports the non-olfactory functions of olfactory receptor genes. Based on our findings from this study, together with the previously shown effects of odorant activated olfactory receptor genes on MAPK signaling pathways 16 24 25 28 , and our group’s recent report on MAPK1/ERK2 as novel target genes for cancer pain 29 , it could be hypothesized that olfactory receptor genes, upstream effectors of the MAPK signaling cascade, may serve as novel target genes for pre-treatment pain in HNSCC patients. The transcriptional control mechanism of how the intronic variants rs3862188, rs880143 and rs7526880 affect pre-treatment pain in HNSCC patients is unknown.…”

“…For instance, it was demonstrated that odorant activated olfactory receptor genes activate MAP kinases 25 26 that are important to olfactory sensory neurons, prostate cancer cell proliferation 16 , the wound healing process 27 , and hepatocellular carcinoma progression 28 . In our previous study, we identified a SNP within MAPK1/ERK2 that was potentially associated with pre-treatment pain in head and neck cancer patients 29 through a comprehensive literature search and gene network analysis (Ingenuity Pathway Analysis [IPA], Ingenuity ® Systems, www.ingenuity.com ), as well as a genetic association analysis between the common SNPs within the IPA-derived genes and cancer pain in HNSCC patients. Because of the prior established effects of olfactory receptor genes on MAP kinases, we speculate that these olfactory receptor genes may be upstream regulators of MAPK1/ERK2 in terms of eliciting pain signals associated with HNSCC.…”

The Association between Plasma Omega-6/Omega-3 Ratio and Anthropometric Traits Differs by Racial/Ethnic Groups and NFKB1 Genotypes in Healthy Young Adults

“…The rs1609798 variant has been associated with apolipoprotein B concentrations, a marker of cardiovascular disease [34]. The two other variants (s11722146 and rs1609798) have been associated with risk of cancer [35,36,37]. Finally, we found gene–diet interactions between n-6/n-3 ratio and two NFKB1 genotypes (rs4648090 and rs4648022) on BMI and WC.…”

Genetic studies of human neuropathic pain conditions: a review

“…Last, mitogen-activated protein kinase 1 ( MAPK1 )—a broad-spectrum regulator—has also been implicated in cancer pain. 118 …”