Integration of cytogenetic aberrations and in silico pathway enrichment identifies novel candidate genes in esophageal squamous cell carcinoma

Table 1 Cytogenetic aberrations in patients with esophageal cancer and controls, mean ± SD

Item	Patients (n = 135)	Controls (n = 135)	P value
Mean (%) aberrant metaphases	27.45 ± 9.7	11.6 ± 4.1	< 0.0001
Mean (%) metaphases with structural aberrations	8.6 ± 5.7	4.7 ± 2.7	< 0.0001
Mean (%) metaphases with numerical aberrations	15.4 ± 7.1	5.8 ± 3.1	< 0.0001
Mean (%) metaphases with both structural and numerical aberrations	3.3 ± 2.7	2.3 ± 0.9	< 0.0001

Table 2 Stage wise comparison of chromosomal aberrations in males and female patients and in controls, mean ± SD

Chromosomal aberration	Controls		Patients with esophageal cancer
			Stage I		Stage II		Stage III		Stage IV
	Males (n = 59)	Females (n = 76)	Males (n = 4)	Females (n = 4)	Males (n = 19)	Females (n = 22)	Males (n = 30)	Females (n = 21)	Males (n = 6)	Females (n = 3)
Mean (%) aberrant metaphases	10.53 ± 3.0	12.3 ± 4.7	19.15 ± 4.62	17.25 ± 4.90	25.52 ± 4.9	23.52 ± 8.4	27.06 ± 8.73	27.46 ± 9.00	33.7 ± 4.86	34.3 ± 3.8
P value	0.01a		0.59		0.36		0.87		0.75
Mean (%) metaphases with structural aberrations	4.6 ± 2.9	4.8 ± 2.5	12.07 ± 3.41	7.0 ± 3.60	7.35 ± 4.28	6.01 ± 6.24	8.17 ± 5.10	13.04 ± 13.81	10.18 ± 4.39	17.66 ± 3.29
P value	0.66		0.08		0.43		0.08		0.23
Mean (%) metaphases with numerical aberrations	4.9 ± 2.0	6.5 ± 3.8	9.07 ± 3.55	8.0 ± 2.73	15.82 ± 4.49	15.54 ± 5.86	15.55 ± 8.54	15.75 ± 8.79	16.35 ± 4.46	14.43 ± 0.80
P value	0.004b		0.64		0.89		0.93		0.49
Mean (%) metaphases with both structural and numerical aberrations	2.2 ± 1.1	2.4 ± 0.9	1.0 ± 0.0	3.0 ± 1.41	2.66 ± 1.34	2.33 ± 1.31	3.23 ± 1.62	3.45 ± 4.83	4.83 ± 3.34	2.6 ± 205
P value	0.24		-		0.43		0.81		0.33

^aP < 0.05.

^bP < 0.01.

Table 3 Prioritized candidate genes derived from recurrent cytobands and validated in The Cancer Genome Atlas esophageal squamous cell carcinoma cohort

Gene	Cytoband	Functional role	TCGA alteration type	TCGA frequency (%)	Supporting evidence
TP53	17p13	Linker gene/tumor suppressor	Mutation	84%	Established ESCC driver
STAT3	17q21	Linker gene/signaling	Amplification	4%	Copy-number gene-dosage (increase)
MAPK3	16p11	Pathway gene/MAPK signaling	Amplification	2%	Copy-number gene-dosage (increase)
WWOX	16q23	Tumor suppressor	Deep deletion	36%	Copy-number gene-dosage (reduce)
JUP	17q21	Linker gene/adhesion	Mutation/copy number alterations	10%	Network hub connectivity
AR	Xq12	Linker gene/hormone signaling	Amplification	4%	Hormonal pathway involvement
GATA2	3q21	Pathway gene/transcription	Low-frequency alteration	7%	Significant co-expression (ρ = 0.41)
MAL	2q11	Linker gene/tumor suppressor	Deletion (low frequency)	2%	Silenced in ESCC (literature)
GALNT3	2q24	Linker gene/glycosylation	Low-frequency alteration	2%	Network connectivity

The Cancer Genome Atlas dataset: Esophageal squamous cell carcinoma (Firehose Legacy), n-184 tumors. ESCC: Esophageal squamous cell carcinoma; TCGA: The Cancer Genome Atlas.