Distinct effects of alcohol consumption and smoking on genetic alterations in head and neck carcinoma

Abstract

Background: Tobacco and alcohol consumption are risk factors for head and neck squamous cell carcinoma (HNSCC). Recently, whole-exome sequencing clarified that smoking increased TP53 and other mutations in HNSCC; however, the effects of alcohol consumption on these genetic alterations remain unknown. We explored the association between alcohol consumption and somatic copy-number alterations (SCNAs) across the whole genome in human papillomavirus (HPV)-negative HNSCCs, and compared with the effects of smoking on genetic alterations.

Methods: SCNA and TP53 mutations in tumor samples were examined by high-resolution comparative genomic hybridization microarray 180K and by direct sequencing, respectively, and statistically analyzed for associations with alcohol consumption and smoking during the 20 years preceding diagnosis of HNSCC. Probes with a corrected p-value (=q-value) less than 0.05 and fold change greater than 1.2 or less than -1.2 were considered statistically significant.

Results: A total of 248 patients with HNSCC were enrolled. In the HPV-negative patients (n=221), heavy alcohol consumption was significantly associated with SCNAs of oncogenes/oncosuppressors that were previously reported to occur frequently in HNSCCs: CDKN2A (q=0.005), FHIT (q=0.005), 11q13 region including CCND1, FADD and CTTN (q=0.005), ERBB2 (HER2) (q=0.009), 3q25-qter including CCNL1, TP63, DCUN1D1 and PIK3CA (q=0.014), and CSMD1 (q=0.019). But, TP53 mutations were not affected. In contrast, smoking was associated with increased risk of TP53 mutations, but did not induce any significant SCNAs of oncogenes/oncosuppressors.

Conclusion: These results suggest that both alcohol consumption and smoking had distinct effects on genetic alterations in HNSCCs. Heavy alcohol consumption may trigger previously known and unknown SCNAs, but may not induce TP53 mutation. In contrast, smoking may induce TP53 mutation, but may not trigger any SCNAs.

Figure 1. Significant SCNAs at 9p21.3 associated with heavy alcohol consumption.

Figure 2. Significant SCNAs at 3p14.2 associated with heavy alcohol consumption.

Figure 3. Significant SCNAs at 17q12 associated with heavy alcohol consumption.

Figure 4. Significant SCNAs at 3q26.32 associated with heavy alcohol consumption.

Figure 5. Significant SCNAs at 8p23 associated with heavy alcohol consumption.

Figure 6. Significant SCNAs at 11q13 associated with heavy alcohol consumption.

Significant q-values (<0.05) (y-axis) are plotted across the chromosome (x-axis). An oncogene or oncosuppressor gene associated with development of HNSCCs in previous studies is indicated in parentheses in each peak region. X and Y chromosomes were excluded for analysis, because alcohol drinkers and smokers were predominantly men.