Table 4. . A comparison of DNA methylation changes, mutations, single nucleotide polymorphism, and copy number variations in genome-wide association studies and epigenome-wide association studies conducted in aerodigestive tumor types.

Tumor type	GWAS/EWAS	Mutations	SNPs	CNVs
Colorectal cancer	EWAS by profiling genome-wide mRNA and miRNA expression [43] Identified several potential regulatory networks; targeting relevant mRNA–miRNA networks as a potential therapeutic approach for CRC (for example is targeting EZH2) [43] Genome-wide epigenetic profiling [48] Deregulation of the prostaglandin synthase pathway. More specifically, PTGIS, PTGER3, PTGFR, and AKR1B1 were inactivated due to hypermethylation, along with other prostaglandins and their receptors in tumors [48]	Several mutations at 23 susceptibility loci [44] mutations in KRAS and BRFF along with high microsatellite instability [46]	Polymorphism rs17716310 Histone modifications are predicted [45] rs11987193 in Han Chinese population; may be useful in colorectal cancer pathology [47] Out of 22 polymorphism identified, rs1321311 was found associated with survival; suggested to be a prognostic marker [49] Polymorphism rs16892766 (8q23.3), rs10505477 (8q24.21), rs10795668 (10p14), rs3802842 (11q23), rs929218 (16q22.11), rs10411210 (19q13.11) [22,50,51]	Copy number variations at 5q31.1 [45] Variation at 8q12 [47] Meta-analysis from 1000 genome project; at 1p36.2 marked by rs72647484 and at 16q24.1 marked by rs16941835 within the lncRNA [44]
Esophageal cancer	Genome-wide methylation [52]; the major genes affected were PTK2, RND1, and UBL3 which regulate recurrence of cancer [52]	Sensitive locus for mutations 4q21 [22]	4q21 [22] SNP rs1229984 in ADH1B [22] SNP rs7922612 related with survival [22]	Germline copy number loss of UGT28 and gain of PLEC [53]
Gastric cancer	FAT4, a novel tumor suppressor identified by exome sequencing gets inactivated due to hypermethylation (field canerization) [54] Epigenetic silencing of GLDC [57]	Susceptibility locus 8q24 [55] 8q24.3 [58]	SNP rs4733616 [55] SNP rs2294008 was associated with decreased risk of duodenal cancer [55] SNP rs2294008 was found to be associated with increased risk of gastric cancer and decreased risk of duodenal cancer [58] SNP rs2976392 [22]	Loss of CNV at 5q22 region surrounding APC [56]
Hepatocellular carcinoma (liver cancer)	Epigenetic silencing of FOXD3 involved in proliferation, invasion and metastasis [59] Hypermethylation of p15, p16, p21, p27, and RASSF1A [62]	Susceptibility locus 1p36.22 [60]	SNP rs17401966 in KIF1B on chromosome 1p36.22 that was highly associated with HBV-related HCC [60]	Loss of DNA copy number affecting expression of RGS17 and NR2E1 in liver cancer [61]
Lung cancer	miRNA profiling and HOXA9 promoter methylation as biomarkers of lung cancer recurrence as determined by EWAS [63] Genomic loss of KAT6B coding histone H3 lysine acetyltransferase [66]	COPD with lung cancer Sensitive loci at 15q25, 4q31, 4q22, 6q21, and 1q23 [64] Several loci, 5p15.33 and 3q28 [22,69] 15q25, 20q13.2, 22q12.2, and 5p15.33 [71] Different loci [73]	In a study with 1400 participants sub-phenotyped for the presence of COPD and matched for smoking exposure [64] Polymorphism rs7963551 (study conducted in Chinese population) [67] Polymorphism rs2736100 and rs7727912 in 5p15.33, rs805297 and rs1802127 in 6p21.33, and rs8034191 and rs12440014 in 15q25.1 [70] Gene promoter hypermethylation in smokers (in sputum samples); polymorphism rs73371737 and rs7179575 drove gene methylation resulting in inactivation of GRBAB3 (epigenetic silencing) [72] SNPs rs2395185, rs4488809, and rs4600802 were found associated with lung cancer in never smoker Chinese females exposed to coal [69] Polymorphism rs401681 (5p15.33), rs3117582 (6p21.33), rs8034191 (15q24), rs75388767 (1p36.13), rs7023329 (9q210, rs1126809 (11q14), rs11170164 (12q12), rs910873 and rs1885120 (20q11.22) [22] 20q13.2 (rs4809957G >A), 22q12.2 (rs36600C >T) and 5p15.33 (rs401681C >T) linked to patient survivor [71]	High copy number variation of cancer-related miRNAs and DICER1 [65] Somatic genomic rearrangements of TP73 resulting its oncogenic activities [68]
Oral cancer	Lymph node metastasis of oral squamous cell carcinoma prediction by hypomethylation of WISP1 [74]	4q23 [34]	SNP rs991316, located in the ADH gene region of 4q23 indicated susceptibility to oral cancer [34] Polymorphism rs1412115 on chromosome 10 affecting NRP1 expression associated with increased risk of oral cancer [76]	CNV at 11q14.3 and 6p21.3 associated with cancer pre-disposition [75]

CNV: Copy number variation; COPD: Chronic obstructive pulmonary disease; CRC: Colorectal cancer; EWAS: Epigenome-wide association studies; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; GWAS: Genome-wide association studies; SNP: Single nucleotide polymorphism.