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

Abstract

Pain is often one of the first signs of squamous cell carcinoma of the head and neck (HNSCC). Pain at diagnosis is an important prognostic marker for the development of chronic pain, and importantly, for the overall survival time. To identify variants influencing severe pre-treatment pain in 1,368 patients newly diagnosed with HNSCC, we conducted a genome-wide association study based on 730,525 tagging SNPs. The patients were all previously untreated for cancer. About 15% of the patients had severe pre-treatment pain, defined as pain score ≥7 (0 = “no pain” and 10 = “worst pain”). We identified 3 common genetic variants in high linkage disequilibrium for severe pre-treatment pain, representing one genomic region at 1q44 (rs3862188, P = 3.45 × 10−8; rs880143, P = 3.45 × 10−8; and rs7526880, P = 4.92 × 10−8), which maps to the RP11-634B7.4 gene, a novel antisense gene to three olfactory receptor genes. Olfactory receptor genes, upstream effectors of the MAPK signaling cascade, might be novel target genes for pain in HNSCC patients. Future experimental validation to explore biological mechanisms will be key to defining the role of the intronic variants and non-coding RNA for pain in patients with HNSCC.

Genome-wide association study identifies genes associated with neuropathy in patients with head and neck cancer

“…This study included patients with newly diagnosed and histologically confirmed HNSCC. The details of patient recruitment (including inclusion and exclusion criteria), the demographic characteristics and clinical data collection have been described in our previous study 34 .…”

“…These procedures were previously described 34 . In brief, genomic DNA was genotyped using Illumina HumanOmniExpress-12v1 BeadChip (Illumina, San Diego, CA) 35 .…”

Reverse-genetics studies of lncRNAs—what we have learnt and paths forward

“…In fact, the greatest known risk factor for atherosclerosis mapped by GWAS to 9p21.3 was attributed to the lncRNA ANRIL, believed to function by regulating multiple genes in trans [180,181]. Single nucleotide polymorphisms in the antisense lncRNA RP11-634B7.4 have been associated with severity of pre-treatment pain in head and neck cancer patients [182]. Furthermore, through extensive analysis of expression profiles of human lncRNAs, the FANTOM consortium found that 1970 lncRNA genes associate with at least one GWAS trait [183].…”

Genome-wide enriched pathway analysis of acute post-radiotherapy pain in breast cancer patients: a prospective cohort study

“…In 2016, Reyes-Gibby et al reported another genome-wide significant SNP, rs3862188 in RP11-634B7.4 gene for severe pre-treatment pain in head and neck cancer patients ( N = 1368; p = 3 × 10 −8 ) [39]. Reyes-Gibby et al identified 2 years later additional four SNPs which had statistically significant associations with neuropathic pain in head and neck cancer patients ( N = 1043; rs10950641, p = 3 × 10 −14 ; rs4804217, p = 3 × 10 −9 ; rs6796803, p = 6 × 10 −9 ; rs4775319, p = 1 × 10 −8 ) [40].…”

“…We also found three additional olfactory receptor genes ( OR52N1, OR4C12, OR4A47 ) included in the top 30 genes. Recently, Reyes-Gibby et al have reported that genetic variants in RP11-634B7.4 gene, which is annotated as antisense to the three olfactory receptor genes, OR13G1, OR6F1 , and OR14A2 , were significantly associated with severe pre-treatment pain among patients with head and neck cancer at genome-wide significance levels [39]. The olfactory receptors are members of G-protein-coupled receptors, which are involved in signal transduction and play important roles in many physiological processes including sensory perception, regulation of behavior and mood, regulation of immune system activity and inflammation, and tumor growth and metastasis.…”