Epigenetic reduction of DNA repair in progression to gastrointestinal cancer

Table 1 Inherited mutations in DNA repair genes that increase the risk of gastrointestinal cancer

DNA repair gene(s)	Repair pathway(s) affected	Cancers with increased risk
BLM	HRR[1]	Leukemia, lymphoma, colon, breast, skin, lung, auditory canal, tongue, esophagus, stomach, tonsil, larynx, uterus[2]
WRN	HRR, NHEJ, long patch BER[3]	Soft tissue sarcoma, colorectal, skin, thyroid, pancreatic[4]
Fanconi's anemia genes FANCA, B, C, D1, D2, E, F, G, I, J, L, M, N	HRR and TLS[5]	Leukemia, liver tumors, solid tumors in many areas including esophagus, stomach and colon[6]
MSH2, MSH6, MLH1, PMS2	MMR[7]	Colorectal, endometrial[7]
MUTYH	BER of A mispaired with 8-OHdG[8]	Colon[8]
P53	HRR, BER, NER, NHEJ, MMR[9]	Sarcoma, breast, osteo-sarcoma, brain, adreno-cortical carcinomas[10] and colon and pancreas[11]

HRR: Homologous recombinational repair; NHEJ: Non-homologous end joining; BER: Base excision repair; TLS: Translesion synthesis; MMR: Mismatch repair; DDR: DNA damage response.

Table 2 Endogenous DNA damages/cell/day for humans

DNA damages	Reported rate of occurrence
Oxidative damages	10000[24]
Depurinations	9000[25]
Depyrimidations	696[26]
Single-strand breaks	55000[26]
Double-strand breaks	Approximately 50/cell cycle[27]
O6-methylguanine	3120[26]
Cytosine deamination	192[26]

Table 3 Epigenetic deficiency of DNA repair genes in gastrointestinal cancers and field defects

Cancer	Gene	Frequency in cancer	Frequency in adjacentfield defect
Colorectal[17]	MGMT	46%	34%
Colorectal[19]	MGMT	47%	11%
Colorectal[60]	MGMT with MSI	70%	60%
Colorectal[19]	MSH2	13%	5%
Colorectal[61]	MBD4	Frequent	Frequent
Colorectal[62]	ERCC1	100%	40%
Colorectal[62]	PMS2	88%	50%
Colorectal[62]	XPF	55%	40%
Colorectal[63]	WRN	29%	13%
Stomach[64]	MGMT	88%	78%
Stomach[65]	MLH1	73%	20%
Esophagus[66]	MLH1	77%-100%	23%-79%

MSI: Microsatellite instability.

Table 4 CpG island hyper- (and hypo-) methylation of DNA repair genes in cancers

Cancer	Gene	Frequency of promoter hyper-(or hypo-) methylation in cancer
Colorectal	LIG4	82%[78]
	MGMT	40%-90%[17-21]
	ERCC1	38%[79]
	WRN	29%-38%[63,80]
	MLH1	9%-10%[22,81]
	FEN1	Frequent (hypo-)[82]
	MBD4	Frequent (hyper-)[61]
Esophageal	MGMT	23%-79%[65,83,84]
	MLH1	43%[82], 64%[85]
	MSH2	29%[83], 75%[84]
Stomach	MGMT	88%[60]
	MLH1	73%[64]
	WRN	24%-25%[80,86]
	FEN1	Frequent (hypo-)[82]
Gastric lymphoma	ATM	11%[87]

Table 5 Epigenetic ↑ or ↓ miRNAs, altered in cancers, targeting DNA repair genes

Specific miRNA	DNA repair gene targets	Cancers affected (frequency if measured)	References indicating epigenetic control of miRNA	References indicating target gene(s) of miRNAs	References indicating cancer type(s) affected
miR-103 miR-107	RAD51, RAD51D	Osteosarcoma, lung, endometrial, stomach	[100]	[101]	[101]
miR-34c	UNG	Gastric (70%) field defect gastric (27%) colon (98%) field defect colon (60%) chronic lymphocytic leukemia (18%) small-cell lung cancer (67%) NSCLC (26%)	[102,104]	[103]	[102,105,106]
miR-31	PARP1MLH1SMUG1MMS19	Esophagus (47%) colon	[72]	[21]	[71,107,108]
miR-124	KU70	Colon	[109]	[110]	[109]
miR-155	RAD51MLH1MSH2MSH6	Breast Colon	[90,111]	[23,112]	[23,90]
let-7a repression increases HMGA2; HMGA2 alters chromatin architecture of and represses ERCC1)	ERCC1	(Colon) Anaplastic astrocytoma	[90]	[92,113]	[113]
Let-7b repression increases HMGA1; HMGA1 targets P53	P53	Prostate Colon	[90]	[114,115]	[114,115]
miR-182	BRCA1NBNRAD17	Breast Colon	[116]	[117,118]	[107,117,119]

Table 6 Median mutation frequencies and ranges

Parent/child per generation orcancer type	Mutation frequency per million bases	Mutation frequency per diploid genome
Parent/child per generation	0.00000023	30-70
Colorectal carcinoma	Approximately 5	Approximately 30000
MSS colon cancer	2.8	16800
MSI colon cancer (mismatch DNA repair deficient)	47	282000
Hepatocellular carcinoma	4.2	25200
Esophageal carcinoma (single nucleotide variants)	2.8	16994
	Range 0.7-9.3	Range 4516-56528
Esophageal carcinoma (small insertions and deletions)		994 Range 262-3573

MSS: Microsatellite stable; MSI: Microsatellite instable.