Table S1.Scale for quality assessment
Criteria
Score
Representativeness of cases
Consecutive/randomly recruitment from case population
2
No method of selection stated
0
Ascertainment of colorectal cancer
Histological confirmation at the Department of Pathology
2
Not described
0
Representativeness of controls
Consecutive/randomly recruitment from the same sampling
1
No method of selection stated
0
Characteristics of control
Good health without any sorts of diseases
1
No family history of CRC
1
Not described
0
Sample size
≥1000
1
<1000
0
Genotyping examination
Method control*
2
Not described
0
Total
10
*Method control: If the genotyping was done under blinded condition, using random repeat, negative or positive control, or confirmed using two or more genetic methods, a
score of two points could be awarded. Otherwise, it scores zero point.
Table S2.Exon SNPs of MLH1 in CRC
RSID
Genomic
Transcript
Consequence
Region
References＊
Major Findings
NCBI
functional domain
rs41295280
g.5263G>C
c.65G>C
p.Gly22Ala
exon 1
[1]
benign
vus
ATPase domain
rs63749939
g.8353G>A
c.200G>A
p.Gly67Glu
exon 2
[1]
pathogenic
pathogenic
ATP binding and hydrolysis
rs41295282
g.1267A>G
c.277A>G
p.Ser93Gly
exon 3
[1]
benign
vus
ATPase domain
rs28930073
g.18655G>C
c.394G>C
p.Asp132His
exon 5
[2-6]
no significant
other
ATPase domain
benign
ATPase domain
association/not
observed/risk factor
to SCRC in China
rs1799977
g.237284A>G
c.655A>G
p.Ile219Val
exon 8
[3, 4, 7-15]
no significant
association
rs267607808
g.32001C>T
c.925C>T
p.Pro309Ser
exon 11
[1]
benign
vus
ATPase domain
rs63750447
g.37400T>A
c.1151T>A
p.Val384Asp
exon 12
[3, 10, 16-19]
low-penetrance risk
with
none
alleles for CRC
untested
allele
rs41294980
g.37466G>A
c.1217G>A
p.Ser406Asn
exon 12
[1, 9]
benign/neutral
other
none
benign
none
vus
PMS2/MLH3/PMS1interaction
variant
rs267607824
g.37377T>C
c.1128T>C
p.Asp376Asp
exon 12
[20]
significantly
associated with
HNPCC and
early-onset CRC
rs41295284
g.59258T>A
c.1820T>A
p.Leu607His
exon 16
[1]
benign
domain,interaction with hExo1
rs35502531
g.59290:59291
c.1852_1853
delAAinsGC
p.Lys618Ala
exon 16
[1, 9]
benign/no significant
association
vus
PMS2/MLH3/PMS1interaction
domain,interaction with hExo1
PMS2/MLH3/PMS1interaction
rs1800146
g.600230G>T
c.1959G>T
p.Leu653Leu
exon 17
[9]
neutral variant
benign
domain
PMS2/MLH3/PMS1interaction
rs63750217
g.60606G>A
c.2041G>A
p.Ala681Thr
exon 18
[1]
pathogenic
pathogenic
domain
rs63750702
g.60631A>G
c.2066A>G
p.Gln689Arg
exon 18
[1]
possible protective
benign
PMS2/MLH3/PMS1interaction
effect
rs35831931
g.62179G>A
c.2146G>A
p.Val716Met
exon 19
[1]
possible protective
domain
other
effect
rs2020873
g.62185C>T
c.2152C>T
p.His718Tyr
exon 19
[1, 5]
benign/not observed
PMS2/MLH3/PMS1interaction
domain
benign
in the German
PMS2/MLH3/PMS1interaction
domain
population
likely
rs140195825
g.62285A>G
c.2252A>G
p.Lys751Arg
exon 19
＊References in Table S2 were separately listed in the supplementary materials.
[1]
benign
benign
none
Table S3. ORs (95% CI) of sensitivity analysis for MLH1 polymorphisms on CRC risks of different comparison models
Codominant:AA VS BB
Omitted study
Codominant:AB VS BB
Dominant:AA+AB VS BB
Recessive:AA VS AA+AB
OR
95% CI
POR
OR
95% CI
POR
OR
95% CI
POR
OR
95% CI
POR
1.120
0.921-1.363
0.256
1.063
0.965-1.171
0.212
1.075
0.971-1.190
0.162
1.091
0.990-1.202
0.080
rs1800734
Campbell et al.
(2009)
Ito et al. (1999)
1.106
0.927-1.319
0.046
1.056
0.970-1.150
0.221
1.066
0.974-1.168
0.166
1.085
0.990-1.190
0.082
1.107
1.006-1.219
0.038
1.052
1.006-1.101
0.027
1.076
0.990-1.169
0.085
1.105
1.008-1.213
0.034
0.968-1.170
0.197
0.960-1.155
0.274
0.918-1.144
0.400
Muniz-Mendoza et al.
(2012)
Samowitz et al. (2008)
Tulupova et al. (2005)
Raptis et al. (2007)
1.117
1.130
1.121
0.920-1.356
0.941-1.259
0.926-1.357
0.263
0.191
0.242
1.064
1.053
1.041
1.076
1.068
1.056
0.973-1.189
0.969-1.176
0.956-1.166
0.153
0.183
0.080
1.089
1.099
1.097
0.989-1.199
1.001-1.207
0.997-1.207
0.086
0.048
0.057
Zhang et al. (2011)
1.135
0.945-1.364
0.175
1.054
1.007-1.103
0.023
1.076
0.984-1.177
0.107
1.088
0.989-1.197
0.084
Shin et al. (2002)
1.099
0.918-1.316
0.302
1.053
0.964-1.149
0.255
1.062
0.968-1.164
0.202
1.084
0.987-1.190
0.092
Allan et al. (2008)
1.101
0.916-1.323
0.306
1.036
0.948-1.133
0.433
1.048
0.954-1.151
0.328
1.088
0.990-1.195
0.079
Whiffin et al. (2011)
1.127
0.909-1.398
0.275
1.053
0.943-1.176
0.356
1.069
0.953-1.200
0.256
1.100
0.977-1.239
0.116
Koessler et al. (2008)
1.114
0.940-1.383
0.182
1.064
0.964-1.174
0.218
1.078
0.974-1.195
0.147
1.110
1.007-1.224
0.036
Chen et al. (2007)
1.098
0.921-1.309
0.297
1.044
0.998-1.093
0.062
1.056
0.963-1.137
0.289
1.090
0.993-1.195
0.069
van Roon et al. (2010)
1.072
0.974-1.180
0.157
1.045
0.999-1.094
0.054
1.050
1.006-1.097
0.023
1.075
0.980-1.179
0.126
Campbell et al. (2009)
0.947
0.866-1.036
0.237
1.004
0.951-1.060
0.894
0.994
0.944-1.047
0.824
0.948
0.870-1.033
0.221
Kim et al. (2004）
0.960
0.883-1.043
0.336
1.001
0.951-1.053
0.974
0.994
0.948-1.043
0.814
0.961
0.887-1.041
0.329
Mei et al. (2006）
0.959
0.882-1.042
0.322
1.000
0.951-1.052
0.999
0.993
0.946-1.042
0.771
0.960
0.886-1.040
0.316
(2012)
0.958
0.881-1.041
0.312
0.999
0.949-1.051
0.967
0.991
0.945-1.040
0.722
0.959
0.886-1.039
0.307
Berndt et al.（2007）
0.967
0.888-1.052
0.430
1.001
0.951-1.054
0.969
0.996
0.948-1.046
0.865
0.968
0.893-1.049
0.427
rs1799977
Muniz-Mendoza et al.
Raptis et al.（2007）
0.966
0.885-1.054
0.434
1.011
0.958-1.067
0.388
1.004
0.954-1.056
0.888
0.963
0.886-1.047
0.378
Picelli et al.（2010）
0.936
0.856-1.023
0.145
0.985
0.933-1.010
0.578
0.977
0.927-1.028
0.366
0.945
0.867-1.029
0.190
Picelli et al.（2013）
1.009
0.889-1.146
0.888
1.026
0.953-1.106
0.496
1.025
0.955-1.101
0.490
1.000
0.885-1.130
1.000
0.963
0.886-1.049
0.391
0.999
0.949-1.053
0.976
0.994
0.946-1.044
0.797
0.965
0.890-1.048
0.400
Kim et al.（2004）
2.518
1.728-3.669
0.000
2.529
1.736-3.684
0.000
Mei et al. (2006)
2.351
1.603-3.446
0.000
2.361
1.610-3.462
0.000
Ohsawa et al. (2009）
2.085
1.434-3.031
0.000
2.085
1.434-3.031
0.000
Zhang et al. (2004）
2.151
1.617-3.714
0.000
2.463
1.625-3.733
0.000
Wang et al.（2010）
2.180
1.519-3.129
0.000
2.189
1.525-3.142
0.000
Wang et al.（1998）
2.200
1.540-3.143
0.000
2.208
1.546-3.155
0.000
Wang et al.（2000）
2.276
1.573-3.300
0.000
2.288
1.580-3.313
0.000
Christensen et al.
（2008）
rs63750447
References in Table S2
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[9]
L. L. Christensen, B. E. Madsen, F. P. Wikman et al., “The association between genetic variants in hMLH1 and hMSH2 and the development of sporadic colorectal
cancer in the Danish population,” BMC Med Genet, vol. 9, pp. 52, 2008.
[10]
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colorectal cancer patients,” Fam Cancer, vol. 3, no. 2, pp. 129-37, 2004.
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[14]
S. Raptis, M. Mrkonjic, R. C. Green et al., “MLH1 -93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer,” J Natl Cancer Inst, vol.
99, no. 6, pp. 463-74, Mar 21, 2007.
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E. H. van Roon, M. van Puijenbroek, A. Middeldorp et al., “Early onset MSI-H colon cancer with MLH1 promoter methylation, is there a genetic predisposition?,”
BMC Cancer, vol. 10, pp. 180, 2010.
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T. Ohsawa, T. Sahara, S. Muramatsu et al., “Colorectal cancer susceptibility associated with the hMLH1 V384D variant,” Mol Med Rep, vol. 2, no. 6, pp. 887-91,
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Y. Wang, W. Friedl, P. Propping et al., “[Val384Asp in hMLH1 gene in Chinese, Japanese and German and its etiological role in colorectal cancer],” Zhonghua Yi Xue Yi
Chuan Xue Za Zhi, vol. 15, no. 5, pp. 263-6, Oct 10, 1998.
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X. M. Zhang, J. T. Li, M. Zhu et al., “[Study on the relationship between genetic polymorphism Val384Asp in hMLH1 gene and the risk of four different carcinomas],”
Zhonghua Liu Xing Bing Xue Za Zhi, vol. 25, no. 11, pp. 978-81, Nov, 2004.
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D. Wang, L. Song, X. Zhang et al., “Etiological role of Val384Asp in hMLH1 gene in familial colorectal cancer,” Acta Univ Med Nanjing, no. 1, pp. 1-6, 2010.
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