Genetic variations in colorectal cancer risk and clinical outcome

Table 1 Genome-wide association study-identified common genetic variants associated with colorectal cancer risk

SNP	Loci	Gene	Full name of gene	OR	P value	Pathway/function	Ref.	Method
Common biological pathway-related
rs12701937	7p14.1	GLI3 and INHBA	GLI family zinc finger 3 and inhibin, beta A	1.36	3.50E-05	MAPK signaling pathways	[11]	G
rs11014993	10p12.1	MYO3A	Myosin IIIA	1.22	2.00E-03	MAPK signaling pathways	[11]	G
rs59336	12q24.21	TBX3	T-box3	1.09	2.46E-06	Wnt pathway	[10]	G + M
rs4444235	14q22.2	BMP4	Bone morphogenetic protein 4	1.09	1.95E-11	BMP pathway	[21]	G
rs1957636	14q22.2	BMP4	Bone morphogenetic protein 4	1.08	1.36E-09	BMP pathway	[21]	G
rs16969681	15q13.3	GREM1	DAN family BMP antagonist	-	5.33E-08	BMP pathway	[21]	G
rs4779584	15q13.3	GREM1	DAN family BMP antagonist	-	5.27E-03	BMP pathway	[21]	G
rs11632715	15q13.3	GREM1	DAN family BMP antagonist	-	2.30E-10	BMP pathway	[21]	G
rs4939827	18q21	SMAD7	SMAD family member 7	1.2	7.80E-28	TGF-β1 pathway, cell arrest, cell proliferation	[5,6,19]	G
rs12953717	18q21	SMAD7	SMAD family member 7	1.17	9.10E-12	TGF-β and Wnt signaling	[5]	G
rs4464148	18q21	SMAD7	SMAD family member 7	1.15	6.66E-08	TGF-β and Wnt signaling	[5]	G
rs961235	20p12.3	BMP2	Bone morphogenetic protein 2	1.12	4.45E-16	BMP pathway	[21]	G
rs4813802	20p12.3	BMP2	Bone morphogenetic protein 2	1.09	7.52E-11	BMP pathway	[21]	G
rs6038071	20p13	CSNK2A1	Casein kinase 2, alpha 1 polypeptide	2.64	3.00E-04	MAPK signaling pathways	[11]	G
Genome instability-related
rs11903757	2q32.3	NABP1	Nucleic acid binding protein 1	1.16	9.50E-08	DNA repair, genomic stability	[10]	G + M
rs647161	5q31.1	PITX1	Paired-like homeodomain transcription factor 1	1.11	1.22E-10	RAS pathway; activate TP53; telomerase activity	[29]	G + M
rs1321311	6p21	CDKN1A	Cyclin-dependent kinase inhibitor 1A	1.1	1.14E-10	Microsatellite instability, DNA repair, genomic instability	[26]	G + M
rs3824999	11q13.4	POLD3	Polymerase DNA- directed δ3	1.08	3.65E-10	DNA mismatch and base-excision repair	[26]	G + M
rs78378222	17p13	TP53	Promotor region of TP53 gene	1.39	1.60E-04	TP53	[63]	G
Cell cycle control-related
rs10911251	1q25.3	LAMC1	Laminin gamma 1	1.09	5.90E-08	Gene transcription	[10]	G + M
rs6691170	1q41	DUSP10	Dual-specificity phosphatase	1.06	9.55E-10	Inactivates p38 and SAPK	[9]	M
rs6687758	1q41	DUSP10	Dual-specificity phosphatase	1.09	2.27E-09	Inactivates p38 and SAPK	[9]	M
rs886774	7q31	LAMB1	Laminin β1	1.17	3.00E-08	Anchoring the single-layered epithelium, ulcerative colitis	[33]	G
rs3802842	11q23	POU2AF1	POU class 2 associating factor 1	1.1	5.80E-10	Growth of multiple myeloma cells	[6]	G
rs10774214	12p13.32	CCND2	Cyclin D2	1.09	3.06E-08	Cell-cycle transition	[29]	G + M
rs3217810	12p13.32	CCND2	Cyclin D2	1.2	3.70E-07	Cell-cycle transition	[10]	G + M
rs3217901	12p13.32	CCND2	Cyclin D2	1.1	< 5.0E-7	Cell-cycle transition	[10]	G + M
rs11169552	12q13.13	DIP2	Disco-interacting protein 2B	1.09	1.89E-10	Cell morphogenesis	[9]	M
rs1728785	16q22	CDH1	E-cadherin,	1.17	2.80E-08	Epithelial restitution, repair following mucosal damage, active colitis	[33]	G
rs10411210	19q13.33	RHPN2	Rho GTPase binding protein 2	1.15	5.00E-09	Actin cytoskeleton	[20]	G + M
rs4925386	20q13.33	LAMA5	Large laminin A5	1.08	1.89E-10	BMP pathway	[9]	M
rs5934683	Xp22.2	SHR00M2	Shroom family member 2	1.07	7.30E-10	Cell morphogenesis	[26]	G + M
Gene expression and regulation-related
rs16892766	8q23.3	EIF3H	Eukaryotic translation initiation factor 3, subunit H	1.25	3.30E-18	Translation initiation	[8]	G
rs7014348	8q24	POU5FIP1	POU class 5 homeobox 1B	1.19	8.60E-26	Weak transcriptional activator	[6]	G
rs7136702	12q13.13	ATF1	Activating transcription factor 1	1.06	4.02E-08	Transcription	[9]	M
rs6017342	20q13.12	HNF4A	Transcription factor hepatocyte nuclear factor 4α	1.11	3.20E-17	Transcription	[33]	G
Gene desert and others
rs7524102	1p36.12	-	-	1.1	3.10E-07	-	[33]	G
rs16823149	1q31	Clorf21	-	-	5.50E-08	-	[11]	G
rs4574118	2q12	PLGLA	Plasminogen-like A, non-coding RNA	-	1.80E-07	-	[11]	G
rs10936599	3q26.2	MYNN	Myoneurn gene	1.08	3.39E-08	Unknown	[9]	M
rs4140904	4p15.3	NCAPC	Non-SMC condensing I complex, subunit G	-	1.40E-07	-	[11]	G
rs7758229	6q26-27	SLC22A3	organic cation transporter	1.28	7.92E-09	Transport of cationic drugs, toxins, and endogenous metabolism	[19]	G
rs6983267	8q24	-	-	1.18	1.51E-08	-	[19]	G
rs7837328	8q24	-	-	1.17	7.44E-08	-	[19]	G
rs2209907	9q21.3	TLE4	Transducin-like enhancer of spit 4	-	3.40E-08	-	[11]	G
rs10795668	10p14	-	-	1.12	2.50E-13	-	[8]	G
rs9548988	13q13.3	-	-	1.1	2.70E-07	-	[33]	G
rs2423279	20p12.3	PLCB1	Phospholipase C-beta 1	1.1	6.64E-09	Unknown	[29]	G + M

SNP: Single nucleotide polymorphisms; G: Genome-wide association study; M: Meta-analysis; G + M: Combination of GWAS and meta-analysis; BMP: Bone morphogenetic protein; MAPK: Mitogen-activated protein kinase; TGF-β: Transforming growth factor; GWAS: Genome-wide association study.

Table 2 Common genetic variants associated with colorectal cancer clinical outcome

Genes/loci	SNP1	Patient population	Clinical outcome	HR (95%CI)	P value	Ref.
MTHFR	glu429ala	Mixed colorectal cancer (CRC) patients	OS	1.71 (1.18-2.49)	0.005	[64]
ESR2	rs2987983	Postmenopausal women with CRC	OS	0.77 (0.60-0.99)	0.002	[65]
SCN1A	rs3812718	Stage II/III patients with adjuvant 5-fuorouracil (5-FU) based chemotherapy	TTR	2.26 (0.89-5.70)	0.039	[66]
SMAD7	rs4939827	Mixed CRC patients	OS	1.16 (1.06-1.27)	0.002	[55]
mir608	rs4919510	Stage III patients with 5-FU based chemotherapy	RE	1.65 (1.13-2.41)	0.01	[67]
	rs4919510		OS	1.96 (1.19-3.21)	0.008
15q13.3	rs10318	Stage II patients with 5-FU based adjuvant chemotherapy	ER	2.98 (1.27-6.99)	0.012	[56]
11q23.1	rs10749971	Stage III patients with 5-FU based adjuvant chemotherapy	ER	0.46 (0.27-0.80)	0.006
20p12.3	rs961253		ER	0.46 (0.22-0.96)	0.038
			OS	0.24 (0.09-0.68)	0.007
20p12.3	rs355527		ER	0.48 (0.23-0.99)	0.048
			OS	0.29 (0.10-0.81)	0.019
18q21.1	rs4464148		OS	4.34 (1.46-12.89)	0.008
8q24.21	rs6983267		OS	4.20 (1.13-15.64)	0.032
	rs10505477		OS	4.20 (1.13-15.64)	0.032
15q13	rs4779584	Chinese CRC patients	OS	0.33 (0.15-0.72)	0.007	[57]
10p14	rs10795668		RE	0.55 (0.30-1.00)	0.05
pre-mi-423	rs6505162	Mixed CRC patients	OS	2.12 (1.34-3.34)	0.001	[68]
	rs6505162		RFS	1.59 (1.08-2.36)	0.019
pre-mi-608	rs4919510		RFS	0.61 (0.41-0.92)	0.017
CLOCK	rs3749474	Resected CRC patients	OS	0.55 (0.37-0.81)	0.003	[69]
	rs1801260		OS	0.31 (0.11-0.88)	0.03
SCD	rs7849	Stage II patients with 5-FU based adjuvant chemotherapy	RE	2.89 (1.54-5.41)	0.001	[70]
VEGF	-2578	Stage II	TTR	2.01 (1.13-3.56)	0.02	[71]
	-460		TTR	0.50 (0.29-0.89)	0.02
KDR	rs10013228	Resected CRC patients	RE	0.53 (0.30-0.95)	0.032	[72]
CD44	rs8193	Stage III and high risk stage II patients with 5-FU based chemotherapy	TTR	0.51 (0.35-0.93)	0.022	[73]
ALCAM	rs1157		TTR	0.56 (0.33-0.94)	0.024
LGR5	rs17109924		TTR	0.33 (0.12-0.90)	0.023

¹Only the most significant single nucleotide polymorphism (SNP) was shown. OS: Overall survival; RE: Recurrence; RFS: Recurrence free survival; TTR: Time to recurrence.