X-chromosome association study reveals genetic susceptibility loci of nasopharyngeal carcinoma

Abstract

BackgroundThe male predominance in the incidence of nasopharyngeal carcinoma (NPC) suggests the contribution of the X chromosome to the susceptibility of NPC. However, no X-linked susceptibility loci have been examined by genome-wide association studies (GWASs) for NPC by far.MethodsTo understand the contribution of the X chromosome in NPC susceptibility, we conducted an X chromosome-wide association analysis on 1615 NPC patients and 1025 healthy controls of Guangdong Chinese, followed by two validation analyses in Taiwan Chinese (n = 562) and Malaysian Chinese (n = 716).ResultsFirstly, the proportion of variance of X-linked loci over phenotypic variance was estimated in the discovery samples, which revealed that the phenotypic variance explained by X chromosome polymorphisms was estimated to be 12.63% (non-dosage compensation model) in males, as compared with 0.0001% in females. This suggested that the contribution of X chromosome to the genetic variance of NPC should not be neglected. Secondly, association analysis revealed that rs5927056 in DMD gene achieved X chromosome-wide association significance in the discovery sample (OR = 0.81, 95% CI 0.73–0.89, P = 1.49 × 10−5). Combined analysis revealed rs5927056 for DMD gene with suggestive significance (P = 9.44 × 10−5). Moreover, the female-specific association of rs5933886 in ARHGAP6 gene (OR = 0.62, 95%CI: 0.47–0.81, P = 4.37 × 10−4) was successfully replicated in Taiwan Chinese (P = 1.64 × 10−2). rs5933886 also showed nominally significant gender × SNP interaction in both Guangdong (P = 6.25 × 10−4) and Taiwan datasets (P = 2.99 × 10−2).ConclusionOur finding reveals new susceptibility loci at the X chromosome conferring risk of NPC and supports the value of including the X chromosome in large-scale association studies.Electronic supplementary materialThe online version of this article (10.1186/s13293-019-0227-9) contains supplementary material, which is available to authorized users.

The Duchenne muscular dystrophy gene and cancer

“…Its incidence is highest among males and its occurrence is particularly frequent in China. An X chromosome-wide association study for SNPs in 1590 Chinese NPC patients and 994 controls revealed an association within the DMD gene (intronic SNP rs5927056, p = 1.49 × 10 − 5 ), which was validated in Taiwanese and Malaysian replication cohorts [ 26 ]. Combination analyses revealed a consistent association in males and showed that the DMD SNP rs5927056 is associated with a reduced risk of NPC (odds ratio: 0.85, p = 9.44 × 10 − 5 ) [ 26 ].…”

“…An X chromosome-wide association study for SNPs in 1590 Chinese NPC patients and 994 controls revealed an association within the DMD gene (intronic SNP rs5927056, p = 1.49 × 10 − 5 ), which was validated in Taiwanese and Malaysian replication cohorts [ 26 ]. Combination analyses revealed a consistent association in males and showed that the DMD SNP rs5927056 is associated with a reduced risk of NPC (odds ratio: 0.85, p = 9.44 × 10 − 5 ) [ 26 ]. Additionally, NPC risk association with X chromosome SNPs was found to be decreased by 8.3% after excluding rs5927056, suggesting a strong effect of this locus on NPC susceptibility.…”

“…IF Δ3–29, IF Δ17–30, OOF Δ42–43 Reduced Dp427m expression, Dp71 maintained, Dp116 frequently absent Tumour suppressor role for Dp427 + [ 21 , 43 ] Lymphoma nd DMD downregulated in tumour vs. progenitor cells. DMD upregulated in EBV-positive vs. EBV-negative tumours nd ++ [ 19 , 43 ] Lymphocytic leukaemia nd DMD upregulated Oncogenic ++(+) [ 20 , 43 , 57 – 59 ] Lung adenocarcinoma nd DMD downregulated Oncogenic role for Dp71 ++ [ 24 , 43 ] Gastric adenocarcinoma nd DMD downregulated, attributed to Dp71 Tumour suppressive role for Dp71 ++ [ 25 ] Nasopharyngeal carcinoma Intronic SNP rs5927056 nd nd, SNP associated with reduced risk ++ [ 26 ] Oropharyngeal squamous cell carcinoma nd DMD downregulated Tumour suppressive ++(+) [ 61 , 62 ] Renal cell carcinoma nd …”

“…Between 2007 and 2011 several studies have emerged showing that muscular dystrophy mouse models are prone to develop spontaneous soft tissue sarcomas (STS) [15][16][17]. Since then, numerous reports, of increasing frequency, have characterised DMD gene mutations and/or expression changes associated with the development, progression and/or survival of patients with a wide range of cancers including sarcomas, carcinomas, melanomas, lymphomas and leukaemia's, as well as brain tumours [18][19][20][21][22][23][24][25][26]. Although a question of cause or effect remains, it is now clear that a role for DMD in cancer extends beyond just myogenic or musculoskeletal tumours and that the ratio of Dp427 to Dp71 may have particular importance.…”

LncRNA FOXD3-AS1/miR-135a-5p function in nasopharyngeal carcinoma cells

“…Nasopharyngeal carcinoma (NPC), an epithelial malignancy, is related to Epstein–Barr virus infection [ 1 ]. The pathogenesis of NPC is multifactorial, such as genetic susceptibility [ 2 ], social practices, and environmental factors [ 3 , 4 ]. NPC is frequent in southern China and Southeast Asia with an incidence of 40 cases per 1,00,000 individuals yearly; however, it is infrequent in Western Europe and North America [ 5 ].…”