Correlation between gene mutation status and selected clinical features
Thyroid Adenocarcinoma (Primary solid tumor)
15 January 2014 | analyses__2014_01_15
Maintainer Information
Citation Information
doi:10.7908/C1R20ZTX
Maintained by TCGA GDAC Team (Broad Institute/MD Anderson Cancer Center/Harvard Medical School)
Cite as Broad Institute TCGA Genome Data Analysis Center (2014): Correlation between gene mutation status and selected clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1R20ZTX
Overview
Introduction

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

Summary

Testing the association between mutation status of 6 genes and 15 clinical features across 392 patients, 8 significant findings detected with Q value < 0.25.

- NRAS mutation correlated to 'PATHOLOGY.N.STAGE', 'HISTOLOGICAL.TYPE', and 'NUMBER.OF.LYMPH.NODES'.

- BRAF mutation correlated to 'NEOPLASM.DISEASESTAGE', 'PATHOLOGY.T.STAGE', 'PATHOLOGY.N.STAGE', 'HISTOLOGICAL.TYPE', and 'EXTRATHYROIDAL.EXTENSION'.

Results
Overview of the results

Table 1. Get Full Table Overview of the association between mutation status of 6 genes and 15 clinical features. Shown in the table are P values (Q values). Thresholded by Q value < 0.25, 8 significant findings detected.

|  | Clinical Features | Time to Death | AGE | NEOPLASM DISEASESTAGE | PATHOLOGY T STAGE | PATHOLOGY N STAGE | PATHOLOGY M STAGE | GENDER | HISTOLOGICAL TYPE | RADIATIONS RADIATION REGIMENINDICATION | RADIATIONEXPOSURE | EXTRATHYROIDAL EXTENSION | COMPLETENESS OF RESECTION | NUMBER OF LYMPH NODES | MULTIFOCALITY | TUMOR SIZE
| nMutated (%) | nWild-Type | logrank test | t-test | Chi-square test | Fisher's exact test | Fisher's exact test | Fisher's exact test | Fisher's exact test | Fisher's exact test | Fisher's exact test | Fisher's exact test | Fisher's exact test | Fisher's exact test | t-test | Fisher's exact test | t-test
BRAF | 236 (60%) | 156 | 0.91 (1.00) | 0.661 (1.00) | 0.00202 (0.166) | 0.000607 (0.0504) | 0.00043 (0.0362) | 0.0835 (1.00) | 0.408 (1.00) | 1.94e-19 (1.73e-17) | 0.0323 (1.00) | 0.592 (1.00) | 3.75e-07 (3.3e-05) | 0.365 (1.00) | 0.567 (1.00) | 0.753 (1.00) | 0.349 (1.00)
NRAS | 34 (9%) | 358 | 0.469 (1.00) | 0.448 (1.00) | 0.0493 (1.00) | 0.149 (1.00) | 0.000138 (0.0117) | 0.492 (1.00) | 0.84 (1.00) | 4.97e-05 (0.00432) | 0.611 (1.00) | 1 (1.00) | 0.192 (1.00) | 0.654 (1.00) | 5.23e-05 (0.0045) | 0.369 (1.00) | 0.651 (1.00)
HRAS | 13 (3%) | 379 | 0.507 (1.00) | 0.595 (1.00) | 0.464 (1.00) | 0.439 (1.00) | 0.549 (1.00) | 0.286 (1.00) | 0.746 (1.00) | 0.0128 (1.00) | 1 (1.00) | 1 (1.00) | 0.691 (1.00) | 0.171 (1.00) | 0.507 (1.00) | 0.779 (1.00) | 0.954 (1.00)
EIF1AX | 6 (2%) | 386 | 0.0961 (1.00) | 0.137 (1.00) | 0.967 (1.00) | 1 (1.00) | 0.625 (1.00) | 0.473 (1.00) | 0.176 (1.00) | 0.0737 (1.00) | 1 (1.00) | 1 (1.00) | 1 (1.00) | 0.275 (1.00) | 0.769 (1.00) | 0.668 (1.00) | 0.69 (1.00)
NUP93 | 4 (1%) | 388 | 0.909 (1.00) | 0.408 (1.00) | 0.781 (1.00) | 0.736 (1.00) | 0.348 (1.00) | 0.659 (1.00) | 1 (1.00) | 0.0148 (1.00) | 1 (1.00) | 1 (1.00) | 1 (1.00) | 0.512 (1.00) | 0.61 (1.00) | 0.343 (1.00) | 0.985 (1.00)
NLRP6 | 3 (1%) | 389 | 0.644 (1.00) | 0.0328 (1.00) | 0.812 (1.00) | 0.17 (1.00) | 0.605 (1.00) | 0.134 (1.00) | 1 (1.00) | 0.66 (1.00) | 1 (1.00) | 1 (1.00) | 1 (1.00) | 1 (1.00) | 0.525 (1.00) | 0.601 (1.00) |

'NRAS MUTATION STATUS' versus 'PATHOLOGY.N.STAGE'

P value = 0.000138 (Fisher's exact test), Q value = 0.012

Table S1. Gene #1: 'NRAS MUTATION STATUS' versus Clinical Feature #5: 'PATHOLOGY.N.STAGE'

nPatients | 0 | 1
--- | --- | ---
ALL | 185 | 166
NRAS MUTATED | 27 | 5
NRAS WILD-TYPE | 158 | 161

Figure S1. Get High-res Image Gene #1: 'NRAS MUTATION STATUS' versus Clinical Feature #5: 'PATHOLOGY.N.STAGE'

'NRAS MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 4.97e-05 (Fisher's exact test), Q value = 0.0043

Table S2. Gene #1: 'NRAS MUTATION STATUS' versus Clinical Feature #8: 'HISTOLOGICAL.TYPE'

nPatients | OTHER SPECIFY | THYROID PAPILLARY CARCINOMA - CLASSICAL/USUAL | THYROID PAPILLARY CARCINOMA - FOLLICULAR (>= 99% FOLLICULAR PATTERNED) | THYROID PAPILLARY CARCINOMA - TALL CELL (>= 50% TALL CELL FEATURES)
--- | --- | --- | --- | ---
ALL | 6 | 274 | 83 | 29
NRAS MUTATED | 0 | 15 | 19 | 0
NRAS WILD-TYPE | 6 | 259 | 64 | 29

Figure S2. Get High-res Image Gene #1: 'NRAS MUTATION STATUS' versus Clinical Feature #8: 'HISTOLOGICAL.TYPE'

'NRAS MUTATION STATUS' versus 'NUMBER.OF.LYMPH.NODES'

P value = 5.23e-05 (t-test), Q value = 0.0045

Table S3. Gene #1: 'NRAS MUTATION STATUS' versus Clinical Feature #13: 'NUMBER.OF.LYMPH.NODES'

| nPatients | Mean (Std.Dev)
--- | --- | ---
ALL | 306 | 3.3 (6.0)
NRAS MUTATED | 26 | 0.9 (2.4)
NRAS WILD-TYPE | 280 | 3.5 (6.2)

Figure S3. Get High-res Image Gene #1: 'NRAS MUTATION STATUS' versus Clinical Feature #13: 'NUMBER.OF.LYMPH.NODES'

'BRAF MUTATION STATUS' versus 'NEOPLASM.DISEASESTAGE'

P value = 0.00202 (Chi-square test), Q value = 0.17

Table S4. Gene #2: 'BRAF MUTATION STATUS' versus Clinical Feature #3: 'NEOPLASM.DISEASESTAGE'

nPatients | STAGE I | STAGE II | STAGE III | STAGE IV | STAGE IVA | STAGE IVC
--- | --- | --- | --- | --- | --- | ---
ALL | 223 | 44 | 83 | 2 | 32 | 6
BRAF MUTATED | 129 | 18 | 59 | 0 | 25 | 4
BRAF WILD-TYPE | 94 | 26 | 24 | 2 | 7 | 2

Figure S4. Get High-res Image Gene #2: 'BRAF MUTATION STATUS' versus Clinical Feature #3: 'NEOPLASM.DISEASESTAGE'

'BRAF MUTATION STATUS' versus 'PATHOLOGY.T.STAGE'

P value = 0.000607 (Fisher's exact test), Q value = 0.05

Table S5. Gene #2: 'BRAF MUTATION STATUS' versus Clinical Feature #4: 'PATHOLOGY.T.STAGE'

nPatients | T1 | T2 | T3 | T4
--- | --- | --- | --- | ---
ALL | 115 | 134 | 126 | 15
BRAF MUTATED | 67 | 66 | 89 | 13
BRAF WILD-TYPE | 48 | 68 | 37 | 2

Figure S5. Get High-res Image Gene #2: 'BRAF MUTATION STATUS' versus Clinical Feature #4: 'PATHOLOGY.T.STAGE'

'BRAF MUTATION STATUS' versus 'PATHOLOGY.N.STAGE'

P value = 0.00043 (Fisher's exact test), Q value = 0.036

Table S6. Gene #2: 'BRAF MUTATION STATUS' versus Clinical Feature #5: 'PATHOLOGY.N.STAGE'

nPatients | 0 | 1
--- | --- | ---
ALL | 185 | 166
BRAF MUTATED | 97 | 118
BRAF WILD-TYPE | 88 | 48

Figure S6. Get High-res Image Gene #2: 'BRAF MUTATION STATUS' versus Clinical Feature #5: 'PATHOLOGY.N.STAGE'

'BRAF MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 1.94e-19 (Fisher's exact test), Q value = 1.7e-17

Table S7. Gene #2: 'BRAF MUTATION STATUS' versus Clinical Feature #8: 'HISTOLOGICAL.TYPE'

nPatients | OTHER SPECIFY | THYROID PAPILLARY CARCINOMA - CLASSICAL/USUAL | THYROID PAPILLARY CARCINOMA - FOLLICULAR (>= 99% FOLLICULAR PATTERNED) | THYROID PAPILLARY CARCINOMA - TALL CELL (>= 50% TALL CELL FEATURES)
--- | --- | --- | --- | ---
ALL | 6 | 274 | 83 | 29
BRAF MUTATED | 3 | 191 | 15 | 27
BRAF WILD-TYPE | 3 | 83 | 68 | 2

Figure S7. Get High-res Image Gene #2: 'BRAF MUTATION STATUS' versus Clinical Feature #8: 'HISTOLOGICAL.TYPE'

'BRAF MUTATION STATUS' versus 'EXTRATHYROIDAL.EXTENSION'

P value = 3.75e-07 (Fisher's exact test), Q value = 3.3e-05

Table S8. Gene #2: 'BRAF MUTATION STATUS' versus Clinical Feature #11: 'EXTRATHYROIDAL.EXTENSION'

nPatients | MINIMAL (T3) | MODERATE/ADVANCED (T4A) | NONE | VERY ADVANCED (T4B)
--- | --- | --- | --- | ---
ALL | 101 | 11 | 266 | 1
BRAF MUTATED | 79 | 11 | 140 | 0
BRAF WILD-TYPE | 22 | 0 | 126 | 1

Figure S8. Get High-res Image Gene #2: 'BRAF MUTATION STATUS' versus Clinical Feature #11: 'EXTRATHYROIDAL.EXTENSION'

Methods & Data
Input

- Mutation data file = transformed.cor.cli.txt

- Clinical data file = THCA-TP.merged_data.txt

- Number of patients = 392

- Number of significantly mutated genes = 6

- Number of selected clinical features = 15

- 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.

Download Results

In addition to the links below, the full results of the analysis summarized in this report can also be downloaded programmatically using firehose_get, or interactively from either the Broad GDAC website or TCGA Data Coordination Center Portal.

- Analysis Results (MD5 checksum)

- Auxiliary Data (MD5 checksum)

- MAGE-TAB File (MD5 checksum)

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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