Mutation analysis of 13 driver genes of colorectal cancer-related pathways in Taiwanese patients

Table 1 De novo mutations of 13 driver genes detected in colorectal cancer

Gene	Mutation	Protein change	rs number	Number of mutations, n (%)	Minor allele frequency in cancer	Minor allele frequency in Asian	GMAF
							(global minor allele frequency%)
APC	c.465A>G	p.Lys155=		1 (0.97)	0.49%
	c.573T>C	p.Tyr191=	rs185154886	1 (0.97)	0.49%	NA	C = 0.06
	c.1005A>G	p.Leu335=	rs3797704	1 (0.97)	0.49%	G = 0%	G = 0.06
BMPR1A	c.1578A>G	p.Glu526=	rs202030576	1 (0.97)	0.49%	NA	G = 0.02
MLH1	c.462C>T	p.Asp154=	rs192938577	1 (0.97)	0.49%	NA	T = 0.02
	c.655A>G	p.Ile219Val	rs1799977	7 (6.8)	3.40%	G = 0%-37.5%	G = 12.96
	c.1151T>A	p.Val384Asp	rs63750447	4 (3.88)	1.94%	NA	A = 0.52
	c.1742C>T	p.Pro581Leu	rs63751684	1 (0.97)	0.49%	NA	T = 0.12
	c.2101C>A	p.Gln701Lys	rs63750114	1 (0.97)	0.49%	NA	A = 0.12
MSH2	c.23C>T	p.Thr8Met	rs17217716	3 (2.91)	1.46%	T = 0%-5%	T = 0.52
	c.1886A>G	p.Gln629Arg	rs61756468	3 (2.91)	1.46%	NA	G = 0.22
MSH6	c.3488A>T	p.Glu1163Val	rs63750252	2 (1.94)	0.97%	NA	T = 0.28
	c.4065_4066insTTGA	p.Lys1328Aspfs	rs55740729	1 (0.97)	0.49%	NA	TTGA = 0.8
MUTYH	c.1422G>C	p.Thr474=	rs74318065	1 (0.97)	0.49%	NA	G = 1.04
	c.1440C>T	p.Thr480=	rs150269172	3 (2.91)	1.46%	NA	A = 0.4
PMS2	c.1532C>T	p.Thr511Met	rs74902811	4 (3.88)	1.94%	NA	A = 3.69

Table 2 Polymorphisms of 13 driver genes detected in colorectal cancer

Gene	Mutation	Protein change	rs number	Number of mutations, n (%)	Minor allele frequency in cancer	Minor allele frequency in Asian	GMAF
							(global minor allele frequency%)
BMPR1A	c.4C>A	p.Pro2Thr	rs11528010	41(39.81)	19.9%	NA	A = 49.98
MSH2	c.471C>A	p.Gly157=	rs61756463	5 (4.85)	2.43%	NA	A = 0.24
	c.1168C>T	p.Leu390Phe	rs17224367	5 (4.85)	2.43%	T = 0%-4.7%	T = 0.28
	c.1690A>G	p.Thr564Ala	rs55778204	3 (2.91)	1.46%	NA	G = 0.06
MSH6	c.116G>A	p.Gly39Glu	rs1042821	1 (0.97)	0.49%	NA	A = 20.29
	c.3306T>A	p.Thr1102=	rs2020910	41 (39.81)	37.38%	A = 0%-22.9%	A = 4.93
MUTYH	c.1014G>C	p.Gln338His	rs3219489	51 (49.51)	27.67%	C = 45.2%-46.7%	C = 31.35
PMS2	c.59G>A	p.Arg20Gln	rs10254120	10 (9.71)	4.85%	NA	T = 7.57
	c.288C>T	p.Ala96=	rs12532895	58 (56.31)	33.5%	A = 28.2%-36%	A = 11.36
	c.780C>G	p.Ser260=	rs1805319	17 (16.5)	8.25%	G = 4.8%-8%	G = 16.87
	c.1408C>T	p.Pro470Ser	rs1805321	44 (42.72)	21.36%	T = 0%	T = 35.82
	c.1454C>A	p.Thr485Lys	rs1805323	44 (42.72)	21.36%	NA	T = 11.20
	c.1621G>A	p.Lys541Glu	rs2228006	15 (14.56)	7.28%	A = 4.4%-23%	A = 11.68
	c.2253T>C	p.Phe751=	rs1805325	2 (1.94)	0.97%	NA	NA
	c.2324A>G	p.Asn775Ser	rs17420802	8 (7.77)	3.88%	NA	NA
	c.2340C>T	p.Pro780=	rs142230276	8 (7.77)	3.88%	NA	A = 0.12
	c.2570G>C	p.Gly857ala	rs1802683	1 (0.97)	0.49%	NA	NA
TP53	c.215C>G	p.Pro72Arg	rs1042522	78 (75.73)	50%	G = 48.9%-61.4%	G = 45.71

Table 3 Known pathological mutations of 13 driver genes detected in colorectal cancer

Gene	Mutation	Protein change	rs number in dbSNP/mutation id in COSMIC	Number of mutations, n (%)	Minor allele frequency in cancer	Minor allele frequency in Asian	GMAF
							(global minor allele frequency%)
APC	c.95A>G	p.Asn32Ser	rs539108537	1 (0.97)	0.49%	NA	G = 0.02
	c.646C>T	p.Arg216Stop	rs62619935	1 (0.97)	0.49%	NA	NA
	c.694C>T	p.Arg232Stop	rs397515734	1 (0.97)	0.49%	NA	NA
	c.799G>T	p.Gly267Stop	The UMD-APC mutations database	1 (0.97)	0.49%	NA	NA
	c.832C>T	p.Gln278Stop	The UMD-APC mutations database	1 (0.97)	0.49%	NA	NA
	c.904C>T	p.Arg302Stop	rs137854568	1 (0.97)	0.49%	NA	NA
	c.3907C>T	p.Gln1303Stop	COSM13728	1 (0.97)	0.49%	NA	NA
	c.3914C>A	p.Ala1305Glu	COSM1432302	1 (0.97)	0.49%	NA	NA
	c.3914delC	p.Ala1305Glufs	COSM19687	1 (0.97)	0.49%	NA	NA
	c.3934G>T	p.Gly1312Stop	COSM18817	1 (0.97)	0.49%	NA	NA
	c.3935delG	p.Gly1312Glufs	COSM18796	1 (0.97)	0.49%	NA	NA
	c.3944C>A	p.Ser1315Stop	COSM18777	1 (0.97)	0.49%	NA	NA
	c.3982C>T	p.Gln1328Stop	rs398123121	3 (2.91)	1.46%	NA	NA
	c.4012C>T	p.Gln1338Stop	rs121913327	3 (2.91)	1.46%	NA	NA
	c.4031C>A	p.Ser1344Stop	COSM19135	1 (0.97)	0.49%	NA	NA
BRAF	c.1780G>A	p.Asp594Asn	rs397516896	1 (0.97)	0.49%	NA	NA
	c.1799T>C	p.Val600Glu	rs113488022	3 (2.91)	1.46%	NA	NA
KRAS	c.34G>C	p.Gly12Cys	rs121913530	2 (1.94)	0.97%	NA	NA
	c.34G>T	p.Gly12Ser	rs121913530	2 (1.94)	0.97%	NA	NA
	c.35G>A	p.Gly12Ala	rs121913529	2 (1.94)	0.97%	NA	NA
	c.35G>C	p.Gly12Asp	rs121913529	11 (10.98)	5.34%	NA	NA
	c.35G>T	p.Gly12Val	rs121913529	12 (11.65)	5.83%	NA	NA
	c.38G>C	p.Gly13Asp	rs112445441	5 (4.85)	2.43%	NA	NA
MSH2	c.1480T>C	p.Ser494Pro	rs55653533	1 (0.97)	0.49%	NA	C = 0.02
MUTYH	c.74G>A	p.Gly25Asp	rs75321043	1 (0.97)	0.49%	NA	T = 0.18
PIK3CA	c.1624G>A	p.Glu542Lys	rs121913273	1 (0.97)	0.49%	NA	NA
	c.1633G>A	p.Glu545Lys	rs104886003	1 (0.97)	0.49%	NA	NA
	c.1636C>G	p.Gln546Lys	rs121913286	1 (0.97)	0.49%	NA	NA
	c.3140A>G	p.His1047Arg	rs121913279	2 (1.94)	0.97%	NA	NA
PMS2	c.2437C>T	p.Arg813Trp	rs375968016	1 (0.97)	0.49%	NA	A = 0.02
PTEN	c.19G>T	p.Glu7Stop	COSM5298	1 (0.97)	0.49%	NA	NA
SMAD4	c.1067C>G	p.Pro356Arg	COSM339351	1 (0.97)	0.49%	NA	NA
	c.1069T>C	p.Ser357Pro	COSM189735	1 (0.97)	0.49%	NA	NA
	c.1081C>T	p.Arg361Cys	rs80338963	1 (0.97)	0.49%	NA	NA
TP53	c.318C>G	p.Ser106Arg	COSM45944	1 (0.97)	0.49%	NA	NA
	c.423C>G	p.Cys141Trp	COSM44204	1 (0.97)	0.49%	NA	NA
	c.440T>G	p.Val147Gly	COSM44309	1 (0.97)	0.49%	NA	NA
	c.511G>T	p.Glu171Stop	COSM10996	1 (0.97)	0.49%	NA	NA
	c.514G>T	p.Val172Phe	COSM44240	1 (0.97)	0.49%	NA	NA
	c.524G>A	p.Arg175His	rs28934578	5 (4.85)	2.43%	NA	NA
	c.536A>G	p.His179Arg	COSM10889	1 (0.97)	0.49%	NA	NA
	c.586C>T	p.Arg196Stop	rs397516435	2 (1.94)	0.97%	NA	NA
	c.638G>T	p.Arg213Leu	COSM43650	1 (0.97)	0.49%	NA	NA
	c.646G>A	p.Val216Met	COSM10667	1 (0.97)	0.49%	NA	NA
	c.700T>G	p.Tyr234Asp	COSM43768	1 (0.97)	0.49%	NA	NA
	c.734G>A	p.Gly245Asp	rs121912656	2 (1.94)	0.97%	NA	NA
	c.742C>T	p.Arg248Trp	rs121912651	3 (2.91)	1.46%	NA	NA
	c.761T>G	p.Ile254Ser	COSM45035	1 (0.97)	0.49%	NA	NA
	c.772G>A	p.Glu258Lys	rs121912652	1 (0.97)	0.49%	NA	NA
	c.772G>T	p.Glu258Stop	COSM43568	1 (0.97)	0.49%	NA	NA
	c.817C>T	p.Arg273Cys	rs121913343	1 (0.97)	0.49%	NA	NA
	c.818G>A	p.Arg273His	rs28934576	2 (1.94)	0.97%	NA	T = 0.02
	c.841G>C	p.Asp281His	COSM10943	1 (0.97)	0.49%	NA	NA
	c.844C>T	p.Arg282Trp	rs28934574	5 (4.85)	2.43%	NA	NA
	c.853G>A	p.Glu285Lys	rs112431538	1 (0.97)	0.49%	NA	NA
	c.856G>A	p.Glu286Lys	COSM10726	1 (0.97)	0.49%	NA	NA
	c.857A>G	p.Glu286Gly	COSM43565	1 (0.97)	0.49%	NA	NA
	c.1015G>T	p.Glu339Stop	COSM11286	1 (0.97)	0.49%	NA	NA

NA: Not available.

Table 4 Correlation between clinicopathological features and APC mutation and two or more driver genes mutations

		Mutation of APC				Mutations of two or more driver genes
		No	Yes	Total	P value	No	Yes	Total	P value
Gender	F	27	10	37	0.503	23	14	37	0.435
	M	52	14	66		46	20	66
Grade	Well	4	3	7	0.443	4	3	7	0.579
	Moderate	67	19	86		57	29	86
	Poor	8	2	10		8	2	10
LN	-	32	17	49	0.009	28	21	49	0.043
	+	47	7	54		41	13	54
Stage	I, II	30	16	46	0.013	27	19	46	0.108
	III, IV	49	8	57		42	15	57

P value by χ² test.