A genome-wide association study of radiotherapy induced toxicity in head and neck cancer patients identifies a susceptibility locus associated with mucositis

Abstract

Purpose A two-stage genome-wide association study was carried out in head and neck cancer (HNC) patients aiming to identify genetic variants associated with either specific radiotherapy-induced (RT) toxicity endpoints or a general proneness to develop toxicity after RT. Materials and methods The analysis included 1780 HNC patients treated with primary RT for laryngeal or oro/hypopharyngeal cancers. In a non-hypothesis-driven explorative discovery study, associations were tested in 1183 patients treated within The Danish Head and Neck Cancer Group. Significant associations were later tested in an independent Dutch cohort of 597 HNC patients and if replicated, summary data obtained from discovery and replication studies were meta-analysed. Further validation of significantly replicated findings was pursued in an Asian cohort of 235 HNC patients with nasopharynx as the primary tumour site. Results We found and replicated a significant association between a locus on chromosome 5 and mucositis with a pooled OR for rs1131769*C in meta-analysis = 1.95 (95% CI 1.48–2.41; ppooled = 4.34 × 10−16). Conclusion This first exploratory GWAS in European cohorts of HNC patients identified and replicated a risk locus for mucositis. A larger Meta-GWAS to identify further risk variants for RT-induced toxicity in HNC patients is warranted.

Germline genetic biomarkers to stratify patients for personalized radiation treatment

“…Similar associations of specific germline variants and toxicity outcomes have been described in prostate and nonsmall cell lung cancer (NSCLC) [22]. In a recent study an association with mucositis RT induced toxicity in HNSCC and a specific locus on chromosome 5 was reported [23]. Here, we proceed to analyze the association of germline variants with HNSCC rtAEs.…”

A two-stage genome-wide association study identifies novel germline genetic variations in CACNA2D3 associated with radiotherapy response in nasopharyngeal carcinoma

“…To date, genome-wide association analysis studies of radiotherapy in head and neck cancers, including nasopharyngeal carcinoma, have focused more on radiotherapy toxicity, and they have revealed a number of genetic variants associated with multiple toxicities, including acute xerostomia [ 17 ], radiotherapy-induced mucositis [ 18 ], and radiotherapy-induced brain injury. [ 19 ] Previously, we also performed a GWAS study of multiple acute radiotherapy toxicities in 1084 patients with nasopharyngeal carcinoma.…”

Systematic Review of Genetic Polymorphisms Associated with Acute Pain and Relevant Acute Toxicities Induced by Radiotherapy for Head and Neck Cancer

“…Other variants in DNA damage and repair genes; XRCC2, XPD, ERCC1, ZNF24, NBN, Ku70, ATM, CHEK1, RAD51C, ERCC2, PMS1, MLH1 were associated with RT-acute toxicities, these results matched our study of the potential mechanisms of inflammatory pain induced by RT 22 . Additionally, 11 studies identified variants in genes involved in inflammatory pathways and immune systems including; TNF-α 60, 96, 99 , STING1 100 , HLA-DQB1 58 , TNFRSF1A 64 , GHRL 65 , PLA2G2F/ IIF 101 , IFNG 80 , IL12RB2 91 and NF-κβ 96 , these variants were associated with RT-induced inflammatory pain and mixed throat pain. Studies showed that activation of inflammatory and immune cells after RT induces release of inflammatory cytokines and chemokines promoting more cell damage inducing inflammatory pain in addition to activation of nociceptors causing nociceptive pain 32, 33, 102–104 .…”

“…Studies included in this review, used either candidate gene approach or genome wide association analysis approach (GWAS), and interestingly through GWAS studies collected, we declared variants in genes involved in different/new pathways other than the common potential mechanisms of RT-induced pain, associated with RT-induced acute pain and toxicities. Sckack et.al conducted GWAS in HNC patients and identified candidate (rs1131769) in DNAJC18 gene regulating a chaperon molecules protecting cellular proteins, significantly associated with oral mucositis (OM) after RT 57 . Yang et.al did GWAS of NPC patients and identified variant (rs117157809) in Tankyrase (TNKS) gene regulating telomere capping and maintenance of telomerase activity, is significantly associated with RT-induced OM 59 .…”