Date Published: January 18, 2019
Publisher: Public Library of Science
Author(s): Chia-Min Chung, Chung-Chieh Hung, Chien-Hung Lee, Chi-Pin Lee, Ka-Wo Lee, Mu-Kuan Chen, Kun-Tu Yeh, Ying-Chin Ko, Sakamuri V. Reddy.
A number of genetic variants were suggested to be associated with oral malignancy, few variants can be replicated. The aim of this study was to identify significant variants that enhanced personal risk prediction for oral malignancy. A total of 360 patients diagnosed with oral squamous cell carcinoma, 486 controls and 17 newly diagnosed patients with OPMD including leukoplakia or oral submucous fibrosis were recruited. Fifteen tagSNPs which were derived from somatic mutations were genotyped and examined in associations with the occurrence of oral malignancy. Environmental variables along with the SNPs data were used to developed risk predictive models for oral malignancy occurrence. The stepwise model analysis was conducted to fit the best model in an economically efficient way. Two tagSNPs, rs28647489 in FAT1 gene and rs550675 in COL9A1 gene, were significantly associated with the risk of oral malignancy. The sensitivity and specificity were 85.7% and 85.5%, respectively (area under the receiver operating characteristic curve (AUC) was 0.91) for predicting oral squamous cell carcinoma occurrence with the combined genetic variants, betel-quid, alcohol and age. The AUC for OPMD was only 0.69. The predictive probability of squamous cell carcinoma occurrence for genetic risk score without substance use increased from 10% up to 43%; with substance use increased from 73% up to 92%. Genetic variants with or without substance use may enhance risk prediction for oral malignancy occurrence in male population. The prediction model may be useful as a clinical index for oral malignancy occurrence and its risk assessments.
Oral squamous cell carcinoma (OSCC) is a growing public health problem in the world. Various anatomical sites of oral cavity showed different incidence rates of OSCC and their different treatment strategies, with either single treatment or a combination of surgery, radiotherapy and chemotherapy. The disease continues to have a poor prognosis with a 5-year survival rate of <50%. The survival rate increased with early detection which suggests the importance of the early prevention for OSCC in reducing morbidity and mortality . The proportions of males were 95.3% in the OSCC case group, 97.4% in the control group (P = 0.1037). Percentage of gender was not significant. The proportions of participants were 100% males in the OPMD screening group. The mean age of the OSCC cases and normal control was 54.2 years (SD, 10.5), 51.7 and years (SD, 13.4) respectively (P = 0.01). The mean age was not significant between OPMD and normal group (age = 48.71(9.31), 47.12(12.79); p = 0.7432). Although a number of genetic variants were suggested to be associated with OSCC occurrence by association studies [23, 24] and genome-wide association studies , however, few variants are able to be consistent in association with OSCC among the different population. Even variants in P53 gene in meta-analysis comprised of 2298 OSCC and 2111 controls were not associated with OSCC occurrence . Therefore, attention has turned to the somatic mutations identified by next-generation sequencing approaches which are reported in the Cancer Genome Atlas that has shown promising genes associated with the initiation and progression of OSCC [25, 27–29]. We found tagSNPs in the FAT1 and COL9A1 gene nearby somatic mutations that drive cancer development were associated with oral malignancy occurrence. COL9A1 encodes one of the three alpha chains of type IX collagen. The levels of methylation in COL9A1 were decreased in breast tumor tissue  and variants associated with OSCC occurrence . The FAT1 gene encodes a cadherin-like protein, which is able to potently suppress cancer cell growth [31, 32]. More recently, Morris et al. reported that FAT1 via mutation promotes Wnt signaling that drives the development of many types of human malignancy . High mutation frequency in the FAT1 exclusively associated with HPV-negative head and neck squamous cell carcinoma (HNSCC) [18, 34]. Although a loss of function in FAT1 were identified to be associated with HNSCC and OSCC in cell models, the frequencies of mutations were rare, suggesting that variants with large effect sizes will impact a small proportion of the population. It cannot be applied to screen general populations. Based on 1000 genome database, we identified two SNPs in FAT1 and COL9A1 gene that compared two major allelic frequency (A>G, SNP rs28647489 and C>T, SNP rrs550675) with other ethnic populations and found that were different from those of European, American, African, but the allelic frequency is similar with East Asia. These differences in allelic frequent distribution could be attributed to affect the risk of OC and OPMD occurrence in different ethnic populations. We showed that an interaction between additive genetic risk score of FAT1 and COL9A1 genes and BQ chewing has strong and graded associations with an occurrence of OSCC in case and control study and further confirmed that applied to early detection of OPMD risk.
In summary, our study provided evidence that GRS comprised of FAT1 and COL9A1 genes was associated with oral malignancy occurrence in male population. For the risk prediction models, combined GRS and environmental factor were highly predicting OSCC occurrence. This prediction model can be applied to identify high-risk subjects with habits of betel quid chewing, cigarette smoking and further provide the appropriate intervention to reduce the risk of oral malignancy occurrence in male population.