Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer

Table 1 Frequency of CpG island methylator phenotype-high in colorectal cancers: A review of the literature

Ref.	Country	CIMP-H CRCs/tested CRCs n (%)
		In all CRCs	In MSI-H CRCs
Western countries
Samowitz et al[22], 2005	United States	250/859 (29.1)	64/78 (82.1)
Weisenberger et al[13], 2006	United States	33/187 (17.6)	NA
Samowitz et al[84], 2006	United States	313/1271 (24.6)	105/170 (61.8)
Barault et al[85], 2008	France	95/578 (16.4)	58/80 (72.5)
Ogino et al[4], 2009	United States	123/631 (19.5)	86/118 (72.9)
Dahlin et al[86], 2010	Sweden	46/411 (11.2)	34/61 (55.7)
Zlobec et al[24], 2011	Switzerland	22/314 (7)	NA
Lochhead et al[63], 2013	United States	205/1173 (17.5)	140/184 (76.1)
Eastern countries
Koinuma et al[101], 2004	Japan	NA	161/28 (57.1)
Nagasaka et al[102], 2008	Japan and Germany	NA	152/36 (41.7)
Kim et al[98], 2009	South Korea	29/271 (10.7)	8/33 (24.2)
Min et al[99], 2011	South Korea	34/245 (13.9)	NA
Bae et al[97], 2013	South Korea	47/734 (6.4)	18/65 (27.7)
Kim et al[25], 2013	South Korea	NA	64/220 (29.1)

¹MLH1-methylated colorectal cancers (CRCs) instead of CpG island methylator phenotype-high (CIMP-H) CRCs;

²Sporadic microsatellite instability-high (MSI-H) CRCs instead of CIMP-H CRCs. NA: Not applicable.

Table 2 Frequency of BRAF V600E mutations in colorectal cancers: A review of the literature

Ref.	Country	BRAF-mutant CRCs/tested CRCs n (%)
		In all CRCs	In MSI-H CRCs
Western countries
Samowitz et al[22], 2005	United States	86/859 (10)	43/78 (55.1)
Weisenberger et al[13], 2006	United States	26/187 (13.9)	NA
Samowitz et al[84], 2006	United States	123/1271 (9.7)	67/170 (39.4)
Goel et al[103], 2007	United States	26/126 (20.6)	17/24 (70.8)
Maestro et al[104], 2007	Spain	12/324 (3.7)	9/49 (18.4)
Barault et al[85], 2008	France	76/578 (13.1)	51/80 (63.8)
French et al[105], 2008	United States	77/490 (15.7)	35/58 (60.3)
Ogino et al[4], 2009	United States	105/631 (16.6)	53/118 (44.9)
Richman et al[106], 2009	United Kingdom	56/710 (7.9)	NA
Kumar et al[107], 2009	United States (African)	7/98 (7.1)	7/30 (23.3)
Vilkin et al[108], 2009	Israel	24/128 (18.8)	6/13 (46.2)
Roth et al[79], 2010	Europe	103/1307 (7.9)	45/188 (23.9)
Dahlin et al[86], 2010	Sweden	55/411 (13.4)	34/61 (55.7)
Zlobec et al[24], 2011	Switzerland	42/314 (13.4)	NA
Tie et al[109], 2011	Australia	52/525 (9.9)	24/75 (32)
Yamauchi et al[110], 2012	United States	183/1276 (14.3)	NA
Kalady et al[111], 2012	United States	56/475 (11.8)	29/76 (38.2)
Tian et al[112], 2013	The Netherland and Spain	42/381 (11)	NA
Lochhead et al[63], 2013	United States	182/1253 (14.5)	101/193 (52.3)
Eastern countries
Koinuma et al[101], 2004	Japan	16/140 (11.4)	12/28 (42.9)
Nagasaka et al[113], 2004	Japan and Australia	21/234 (9)	16/35 (45.7)
Chang et al[114], 2006	Taiwan	9/213 (4.2)	7/19 (36.8)
Nagasaka et al[102], 2008	Japan and Germany	20/243 (8.2)	10/36 (27.8)
Kim et al[98], 2009	South Korea	13/271 (4.8)	3/33 (9.1)
Yagi et al[115], 2010	Japan	13/149 (8.7)	NA
Shen et al[116], 2011	China	2/118 (1.7)	NA
Liou et al[117], 2011	Taiwan	12/314 (3.8)	NA
Yokota et al[118], 2011	Japan	15/229 (6.6)	NA
Aoyagi et al[119], 2011	Japan	1/134 (0.7)	NA
Kwon et al[100], 2011	South Korea	4/92 (4.3)	NA
Min et al[99], 2011	South Korea	11/245 (4.5)	6/49 (12.2)
Hsieh et al[120], 2012	Taiwan	2/182 (1.1)	NA
Nakanishi et al[121], 2012	Japan	17/254 (6.7)	11/31 (35.5)
Bae et al[97], 2013	South Korea	39/728 (5.4)	4/65 (6.2)
Kim et al[25], 2013	South Korea	NA	26/219 (11.9)

CRC: Colorectal cancer; MSI: Microsatellite instability; NA: Not applicable.

Table 3 Potential prognostic molecular factors for microsatellite instability-high colorectal cancer: A review of the literature

Molecular factors	Prognostic implication in MSI-H CRC (molecular alteration)	Ref.
HSP110	Favorable (high expression of mutant HSP110/low expression of wild-type HSP110)	Dorard et al[59], 2011
		Kim et al[96], 2014
Beta2- microglobulin	Favorable (mutation of beta2-microglobulin)	Kloor et al[54], 2007
		Tikidzhieva et al[143], 2012
Myosin 1a	Unfavorable (low expression of myosin 1a)	Mazzolini et al[53], 2012
CDX2/CK20	Unfavorable (loss of CDX2/CK20 expression)	Kim et al[149], 2013
SMAD4	Favorable (high expression of SMAD4)	Isaksson-Mettavainio et al[150], 2012
CIMP	Unfavorable (CIMP-H)	Bae et al[87], 2011
LINE-1	Unfavorable (low LINE-1 methylation level)	Rhee et al[162], 2012

CIMP: CpG island methylator phenotype; CIMP-H: CIMP-high; CRC: Colorectal cancer; LINE-1: Long interspersed nucleotide element-1; MSI-H: Microsatellite instability-high; HSP110: Heat shock protein 110 kDa; CDX2: Caudal-type homeobox 2; CK20: Cytokeratin 20; SMAD4: SMAD family member 4.