Correlation between gene mutation status and selected clinical features
Overview
Introduction

This pipeline computes the correlation between significantly recurrent gene mutations and selected clinical features.

Summary

Testing the association between mutation status of 69 genes and 4 clinical features across 248 patients, 10 significant findings detected with Q value < 0.25.

  • PTEN mutation correlated to 'HISTOLOGICAL.TYPE'.

  • TP53 mutation correlated to 'AGE' and 'HISTOLOGICAL.TYPE'.

  • KRAS mutation correlated to 'AGE'.

  • PIK3R1 mutation correlated to 'HISTOLOGICAL.TYPE'.

  • CTNNB1 mutation correlated to 'HISTOLOGICAL.TYPE'.

  • CYLC1 mutation correlated to 'HISTOLOGICAL.TYPE'.

  • STEAP4 mutation correlated to 'HISTOLOGICAL.TYPE'.

  • ANKRD31 mutation correlated to 'HISTOLOGICAL.TYPE'.

  • ZNF69 mutation correlated to 'HISTOLOGICAL.TYPE'.

Results
Overview of the results

Table 1.  Get Full Table Overview of the association between mutation status of 69 genes and 4 clinical features. Shown in the table are P values (Q values). Thresholded by Q value < 0.25, 10 significant findings detected.

Clinical
Features 		Time
to
Death 		AGE HISTOLOGICAL
TYPE 		RADIATIONS
RADIATION
REGIMENINDICATION
nMutated (%) nWild-Type logrank test t-test Chi-square test Fisher's exact test
TP53 69 (28%) 179 0.325
(1.00) 		6.15e-06
(0.00168) 		3.98e-23
(1.1e-20) 		0.371
(1.00)
PTEN 161 (65%) 87 0.19
(1.00) 		0.0276
(1.00) 		5.44e-19
(1.5e-16) 		0.0503
(1.00)
KRAS 53 (21%) 195 0.072
(1.00) 		0.000274
(0.0739) 		0.00692
(1.00) 		0.253
(1.00)
PIK3R1 83 (33%) 165 0.871
(1.00) 		0.806
(1.00) 		0.000827
(0.221) 		0.395
(1.00)
CTNNB1 74 (30%) 174 0.878
(1.00) 		0.0017
(0.449) 		1.04e-05
(0.00284) 		0.381
(1.00)
CYLC1 18 (7%) 230 0.198
(1.00) 		0.765
(1.00) 		0.000601
(0.162) 		0.313
(1.00)
STEAP4 12 (5%) 236 0.286
(1.00) 		0.933
(1.00) 		0.000714
(0.191) 		0.756
(1.00)
ANKRD31 16 (6%) 232 0.234
(1.00) 		0.883
(1.00) 		9.81e-05
(0.0267) 		0.588
(1.00)
ZNF69 7 (3%) 241 0.514
(1.00) 		0.0163
(1.00) 		0.000147
(0.0397) 		1
(1.00)
ARID1A 83 (33%) 165 0.008
(1.00) 		0.00721
(1.00) 		0.00127
(0.337) 		0.673
(1.00)
FGFR2 31 (12%) 217 0.9
(1.00) 		0.998
(1.00) 		0.719
(1.00) 		1
(1.00)
PIK3CA 132 (53%) 116 0.055
(1.00) 		0.195
(1.00) 		0.555
(1.00) 		0.593
(1.00)
CTCF 45 (18%) 203 0.405
(1.00) 		0.0198
(1.00) 		0.0021
(0.552) 		0.863
(1.00)
FBXW7 39 (16%) 209 0.772
(1.00) 		0.904
(1.00) 		0.0473
(1.00) 		0.855
(1.00)
SPOP 21 (8%) 227 0.65
(1.00) 		0.527
(1.00) 		0.332
(1.00) 		0.811
(1.00)
PPP2R1A 27 (11%) 221 0.121
(1.00) 		0.0374
(1.00) 		0.00977
(1.00) 		0.52
(1.00)
CHD4 35 (14%) 213 0.361
(1.00) 		0.418
(1.00) 		0.779
(1.00) 		0.565
(1.00)
P2RY11 9 (4%) 239 0.395
(1.00) 		0.396
(1.00) 		0.987
(1.00) 		0.497
(1.00)
CCND1 15 (6%) 233 0.729
(1.00) 		0.0556
(1.00) 		0.413
(1.00) 		0.4
(1.00)
NFE2L2 15 (6%) 233 0.903
(1.00) 		0.191
(1.00) 		0.447
(1.00) 		0.589
(1.00)
FOXA2 12 (5%) 236 0.799
(1.00) 		0.531
(1.00) 		0.972
(1.00) 		0.229
(1.00)
FAM9A 14 (6%) 234 0.378
(1.00) 		0.913
(1.00) 		0.89
(1.00) 		1
(1.00)
SOX17 7 (3%) 241 0.669
(1.00) 		0.848
(1.00) 		0.00567
(1.00) 		0.428
(1.00)
MAX 11 (4%) 237 0.889
(1.00) 		0.336
(1.00) 		0.404
(1.00) 		0.753
(1.00)
ZNF267 16 (6%) 232 0.565
(1.00) 		0.207
(1.00) 		0.0275
(1.00) 		0.79
(1.00)
RBMX 13 (5%) 235 0.336
(1.00) 		0.161
(1.00) 		0.4
(1.00) 		0.142
(1.00)
MORC4 20 (8%) 228 0.152
(1.00) 		0.0204
(1.00) 		0.629
(1.00) 		1
(1.00)
OR4K2 11 (4%) 237 0.304
(1.00) 		0.241
(1.00) 		0.00658
(1.00) 		1
(1.00)
ARID5B 29 (12%) 219 0.642
(1.00) 		0.649
(1.00) 		0.00865
(1.00) 		1
(1.00)
OR5D13 10 (4%) 238 0.895
(1.00) 		0.741
(1.00) 		0.188
(1.00) 		0.318
(1.00)
OR5AS1 10 (4%) 238 0.675
(1.00) 		0.503
(1.00) 		0.396
(1.00) 		0.501
(1.00)
OR4A15 13 (5%) 235 0.213
(1.00) 		0.167
(1.00) 		0.00219
(0.573) 		1
(1.00)
CSDE1 21 (8%) 227 0.802
(1.00) 		0.294
(1.00) 		0.0435
(1.00) 		1
(1.00)
CTXN3 6 (2%) 242 0.512
(1.00) 		0.794
(1.00) 		0.548
(1.00) 		1
(1.00)
PAPD4 13 (5%) 235 0.982
(1.00) 		0.181
(1.00) 		0.962
(1.00) 		0.378
(1.00)
RPL14 7 (3%) 241 0.532
(1.00) 		0.677
(1.00) 		0.991
(1.00) 		0.428
(1.00)
DNER 18 (7%) 230 0.746
(1.00) 		0.0414
(1.00) 		0.0324
(1.00) 		0.44
(1.00)
RASA1 22 (9%) 226 0.127
(1.00) 		0.466
(1.00) 		0.0211
(1.00) 		0.639
(1.00)
TAB3 18 (7%) 230 0.22
(1.00) 		0.107
(1.00) 		0.00686
(1.00) 		0.616
(1.00)
UPF3B 16 (6%) 232 0.735
(1.00) 		0.81
(1.00) 		0.395
(1.00) 		0.588
(1.00)
SGK1 15 (6%) 233 0.925
(1.00) 		0.427
(1.00) 		0.759
(1.00) 		0.158
(1.00)
C1ORF100 9 (4%) 239 0.344
(1.00) 		0.246
(1.00) 		0.376
(1.00) 		0.497
(1.00)
ZNF334 17 (7%) 231 0.95
(1.00) 		0.0232
(1.00) 		0.787
(1.00) 		1
(1.00)
METTL14 10 (4%) 238 0.358
(1.00) 		0.833
(1.00) 		0.707
(1.00) 		1
(1.00)
NRAS 9 (4%) 239 0.354
(1.00) 		0.616
(1.00) 		0.0289
(1.00) 		0.722
(1.00)
HIST1H2BD 6 (2%) 242 0.0836
(1.00) 		0.474
(1.00) 		0.897
(1.00) 		0.415
(1.00)
CLIC2 10 (4%) 238 0.294
(1.00) 		0.855
(1.00) 		0.00231
(0.601) 		1
(1.00)
CNPY1 7 (3%) 241 0.449
(1.00) 		0.18
(1.00) 		0.294
(1.00) 		1
(1.00)
RAE1 11 (4%) 237 0.282
(1.00) 		0.603
(1.00) 		0.0127
(1.00) 		0.34
(1.00)
IGFBP7 6 (2%) 242 0.406
(1.00) 		0.659
(1.00) 		0.228
(1.00) 		0.667
(1.00)
ZNF300 15 (6%) 233 0.222
(1.00) 		0.338
(1.00) 		0.135
(1.00) 		0.275
(1.00)
SNTG1 11 (4%) 237 0.307
(1.00) 		0.506
(1.00) 		0.0644
(1.00) 		0.753
(1.00)
SSX5 11 (4%) 237 0.328
(1.00) 		0.15
(1.00) 		0.00658
(1.00) 		1
(1.00)
FMR1 16 (6%) 232 0.304
(1.00) 		0.643
(1.00) 		0.0688
(1.00) 		0.588
(1.00)
GYPB 5 (2%) 243 0.583
(1.00) 		0.843
(1.00) 		0.149
(1.00) 		0.168
(1.00)
LRRIQ3 12 (5%) 236 0.372
(1.00) 		0.00386
(1) 		0.00221
(0.578) 		0.229
(1.00)
NDN 6 (2%) 242 0.535
(1.00) 		0.487
(1.00) 		0.699
(1.00) 		1
(1.00)
C14ORF118 15 (6%) 233 0.268
(1.00) 		0.0138
(1.00) 		0.369
(1.00) 		0.589
(1.00)
COX19 4 (2%) 244 0.652
(1.00) 		0.269
(1.00) 		0.998
(1.00) 		1
(1.00)
GNPDA2 8 (3%) 240 0.789
(1.00) 		0.175
(1.00) 		0.518
(1.00) 		0.451
(1.00)
GPM6A 11 (4%) 237 0.306
(1.00) 		0.502
(1.00) 		0.545
(1.00) 		1
(1.00)
ZNF449 12 (5%) 236 0.355
(1.00) 		0.95
(1.00) 		0.655
(1.00) 		0.552
(1.00)
OR2M3 10 (4%) 238 0.315
(1.00) 		0.822
(1.00) 		0.707
(1.00) 		0.739
(1.00)
XPA 7 (3%) 241 0.169
(1.00) 		0.9
(1.00) 		0.981
(1.00) 		0.236
(1.00)
BRS3 15 (6%) 233 0.184
(1.00) 		0.133
(1.00) 		0.025
(1.00) 		0.4
(1.00)
GK2 17 (7%) 231 0.202
(1.00) 		0.334
(1.00) 		0.0119
(1.00) 		0.432
(1.00)
TPTE 15 (6%) 233 0.273
(1.00) 		0.167
(1.00) 		0.00648
(1.00) 		1
(1.00)
IL24 7 (3%) 241 0.426
(1.00) 		0.988
(1.00) 		0.00148
(0.392) 		0.428
(1.00)
CCDC160 11 (4%) 237 0.271
(1.00) 		0.34
(1.00) 		0.00658
(1.00) 		1
(1.00)
'PTEN MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 5.44e-19 (Chi-square test), Q value = 1.5e-16

Table S1.  Gene #4: 'PTEN MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1 OR 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 3) MIXED SEROUS AND ENDOMETRIOID SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL 182 3 8 2 5 4 44
PTEN MUTATED 146 2 6 1 4 1 1
PTEN WILD-TYPE 36 1 2 1 1 3 43

Figure S1.  Get High-res Image Gene #4: 'PTEN MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'TP53 MUTATION STATUS' versus 'AGE'

P value = 6.15e-06 (t-test), Q value = 0.0017

Table S2.  Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #2: 'AGE'

nPatients Mean (Std.Dev)
ALL 248 63.1 (11.1)
TP53 MUTATED 69 67.9 (9.4)
TP53 WILD-TYPE 179 61.3 (11.2)

Figure S2.  Get High-res Image Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #2: 'AGE'

'TP53 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 3.98e-23 (Chi-square test), Q value = 1.1e-20

Table S3.  Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1 OR 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 3) MIXED SEROUS AND ENDOMETRIOID SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL 182 3 8 2 5 4 44
TP53 MUTATED 23 0 0 0 4 3 39
TP53 WILD-TYPE 159 3 8 2 1 1 5

Figure S3.  Get High-res Image Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'KRAS MUTATION STATUS' versus 'AGE'

P value = 0.000274 (t-test), Q value = 0.074

Table S4.  Gene #7: 'KRAS MUTATION STATUS' versus Clinical Feature #2: 'AGE'

nPatients Mean (Std.Dev)
ALL 248 63.1 (11.1)
KRAS MUTATED 53 58.8 (8.7)
KRAS WILD-TYPE 195 64.3 (11.4)

Figure S4.  Get High-res Image Gene #7: 'KRAS MUTATION STATUS' versus Clinical Feature #2: 'AGE'

'PIK3R1 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 0.000827 (Chi-square test), Q value = 0.22

Table S5.  Gene #8: 'PIK3R1 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1 OR 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 3) MIXED SEROUS AND ENDOMETRIOID SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL 182 3 8 2 5 4 44
PIK3R1 MUTATED 73 2 3 0 2 1 2
PIK3R1 WILD-TYPE 109 1 5 2 3 3 42

Figure S5.  Get High-res Image Gene #8: 'PIK3R1 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'CTNNB1 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 1.04e-05 (Chi-square test), Q value = 0.0028

Table S6.  Gene #9: 'CTNNB1 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1 OR 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 3) MIXED SEROUS AND ENDOMETRIOID SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL 182 3 8 2 5 4 44
CTNNB1 MUTATED 69 1 2 2 0 0 0
CTNNB1 WILD-TYPE 113 2 6 0 5 4 44

Figure S6.  Get High-res Image Gene #9: 'CTNNB1 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'CYLC1 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 0.000601 (Chi-square test), Q value = 0.16

Table S7.  Gene #22: 'CYLC1 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1 OR 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 3) MIXED SEROUS AND ENDOMETRIOID SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL 182 3 8 2 5 4 44
CYLC1 MUTATED 14 0 0 0 3 0 1
CYLC1 WILD-TYPE 168 3 8 2 2 4 43

Figure S7.  Get High-res Image Gene #22: 'CYLC1 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'STEAP4 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 0.000714 (Chi-square test), Q value = 0.19

Table S8.  Gene #44: 'STEAP4 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1 OR 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 3) MIXED SEROUS AND ENDOMETRIOID SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL 182 3 8 2 5 4 44
STEAP4 MUTATED 8 0 2 0 2 0 0
STEAP4 WILD-TYPE 174 3 6 2 3 4 44

Figure S8.  Get High-res Image Gene #44: 'STEAP4 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'ANKRD31 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 9.81e-05 (Chi-square test), Q value = 0.027

Table S9.  Gene #46: 'ANKRD31 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1 OR 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 3) MIXED SEROUS AND ENDOMETRIOID SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL 182 3 8 2 5 4 44
ANKRD31 MUTATED 12 0 1 0 3 0 0
ANKRD31 WILD-TYPE 170 3 7 2 2 4 44

Figure S9.  Get High-res Image Gene #46: 'ANKRD31 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'ZNF69 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 0.000147 (Chi-square test), Q value = 0.04

Table S10.  Gene #64: 'ZNF69 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1 OR 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 1) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 2) ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA (GRADE 3) MIXED SEROUS AND ENDOMETRIOID SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL 182 3 8 2 5 4 44
ZNF69 MUTATED 5 0 0 0 2 0 0
ZNF69 WILD-TYPE 177 3 8 2 3 4 44

Figure S10.  Get High-res Image Gene #64: 'ZNF69 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

Methods & Data
Input

  • Mutation data file = UCEC-TP.mutsig.cluster.txt

  • Clinical data file = UCEC-TP.clin.merged.picked.txt

  • Number of patients = 248

  • Number of significantly mutated genes = 69

  • Number of selected clinical features = 4

  • Exclude genes that fewer than K tumors have mutations, K = 3

Survival analysis

For survival clinical features, the Kaplan-Meier survival curves of tumors with and without gene mutations were plotted and the statistical significance P values were estimated by logrank test (Bland and Altman 2004) using the 'survdiff' function in R

Student's t-test analysis

For continuous numerical clinical features, two-tailed Student's t test with unequal variance (Lehmann and Romano 2005) was applied to compare the clinical values between tumors with and without gene mutations using 't.test' function in R

Chi-square test

For multi-class clinical features (nominal or ordinal), Chi-square tests (Greenwood and Nikulin 1996) were used to estimate the P values using the 'chisq.test' function in R

Fisher's exact test

For binary or multi-class clinical features (nominal or ordinal), two-tailed Fisher's exact tests (Fisher 1922) were used to estimate the P values using the 'fisher.test' function in R

Q value calculation

For multiple hypothesis correction, Q value is the False Discovery Rate (FDR) analogue of the P value (Benjamini and Hochberg 1995), defined as the minimum FDR at which the test may be called significant. We used the 'Benjamini and Hochberg' method of 'p.adjust' function in R to convert P values into Q values.

References
[1] Bland and Altman, Statistics notes: The logrank test, BMJ 328(7447):1073 (2004)
[2] Lehmann and Romano, Testing Statistical Hypotheses (3E ed.), New York: Springer. ISBN 0387988645 (2005)
[3] Greenwood and Nikulin, A guide to chi-squared testing, Wiley, New York. ISBN 047155779X (1996)
[4] Fisher, R.A., On the interpretation of chi-square from contingency tables, and the calculation of P, Journal of the Royal Statistical Society 85(1):87-94 (1922)
[5] Benjamini and Hochberg, Controlling the false discovery rate: a practical and powerful approach to multiple testing, Journal of the Royal Statistical Society Series B 59:289-300 (1995)
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