Liver Hepatocellular Carcinoma: Correlation between molecular cancer subtypes and selected clinical features
(primary solid tumor cohort)
Maintained by TCGA GDAC Team (Broad Institute/MD Anderson Cancer Center/Harvard Medical School)
Overview
Introduction

This pipeline computes the correlation between cancer subtypes identified by different molecular patterns and selected clinical features.

Summary

Testing the association between subtypes identified by 4 different clustering approaches and 3 clinical features across 62 patients, one significant finding detected with P value < 0.05 and Q value < 0.25.

- 3 subtypes identified in current cancer cohort by 'CN CNMF'. These subtypes do not correlate to any clinical features.

- 3 subtypes identified in current cancer cohort by 'METHLYATION CNMF'. These subtypes do not correlate to any clinical features.

- CNMF clustering analysis on sequencing-based miR expression data identified 3 subtypes that do not correlate to any clinical features.

- Consensus hierarchical clustering analysis on sequencing-based miR expression data identified 4 subtypes that correlate to 'AGE'.

Results
Overview of the results

Table 1. Get Full Table Overview of the association between subtypes identified by 4 different clustering approaches and 3 clinical features. Shown in the table are P values (Q values). Thresholded by P value < 0.05 and Q value < 0.25, one significant finding detected.

Clinical Features | Time to Death | AGE | GENDER
Statistical Tests | logrank test | ANOVA | Fisher's exact test
CN CNMF | 0.751 (1.00) | 0.871 (1.00) | 0.495 (1.00)
METHLYATION CNMF | 0.199 (1.00) | 0.154 (1.00) | 0.469 (1.00)
MIRseq CNMF subtypes | 0.943 (1.00) | 0.242 (1.00) | 0.158 (1.00)
MIRseq cHierClus subtypes | 0.706 (1.00) | 0.0122 (0.146) | 0.262 (1.00)

Clustering Approach #1: 'CN CNMF'

Table S1. Get Full Table Description of clustering approach #1: 'CN CNMF'

Cluster Labels | 1 | 2 | 3
--- | --- | --- | ---
Number of samples | 15 | 22 | 24

'CN CNMF' versus 'Time to Death'

P value = 0.751 (logrank test), Q value = 1

Table S2. Clustering Approach #1: 'CN CNMF' versus Clinical Feature #1: 'Time to Death'

| nPatients | nDeath | Duration Range (Median), Month
--- | --- | --- | ---
ALL | 55 | 26 | 0.1 - 90.7 (12.8)
subtype1 | 14 | 7 | 0.1 - 90.7 (7.8)
subtype2 | 19 | 8 | 0.4 - 69.6 (14.3)
subtype3 | 22 | 11 | 0.3 - 83.6 (11.3)

Figure S1. Get High-res Image Clustering Approach #1: 'CN CNMF' versus Clinical Feature #1: 'Time to Death'

'CN CNMF' versus 'AGE'

P value = 0.871 (ANOVA), Q value = 1

Table S3. Clustering Approach #1: 'CN CNMF' versus Clinical Feature #2: 'AGE'

| nPatients | Mean (Std.Dev)
--- | --- | ---
ALL | 56 | 61.8 (14.0)
subtype1 | 14 | 60.4 (16.0)
subtype2 | 19 | 61.5 (15.0)
subtype3 | 23 | 62.9 (12.3)

Figure S2. Get High-res Image Clustering Approach #1: 'CN CNMF' versus Clinical Feature #2: 'AGE'

'CN CNMF' versus 'GENDER'

P value = 0.495 (Fisher's exact test), Q value = 1

Table S4. Clustering Approach #1: 'CN CNMF' versus Clinical Feature #3: 'GENDER'

nPatients | FEMALE | MALE
--- | --- | ---
ALL | 22 | 39
subtype1 | 4 | 11
subtype2 | 10 | 12
subtype3 | 8 | 16

Figure S3. Get High-res Image Clustering Approach #1: 'CN CNMF' versus Clinical Feature #3: 'GENDER'

Clustering Approach #2: 'METHLYATION CNMF'

Table S5. Get Full Table Description of clustering approach #2: 'METHLYATION CNMF'

Cluster Labels | 1 | 2 | 3
--- | --- | --- | ---
Number of samples | 19 | 15 | 27

'METHLYATION CNMF' versus 'Time to Death'

P value = 0.199 (logrank test), Q value = 1

Table S6. Clustering Approach #2: 'METHLYATION CNMF' versus Clinical Feature #1: 'Time to Death'

| nPatients | nDeath | Duration Range (Median), Month
--- | --- | --- | ---
ALL | 54 | 25 | 0.1 - 90.7 (12.2)
subtype1 | 15 | 8 | 0.4 - 90.7 (19.8)
subtype2 | 13 | 7 | 0.1 - 53.3 (7.1)
subtype3 | 26 | 10 | 0.3 - 83.6 (8.3)

Figure S4. Get High-res Image Clustering Approach #2: 'METHLYATION CNMF' versus Clinical Feature #1: 'Time to Death'

'METHLYATION CNMF' versus 'AGE'

P value = 0.154 (ANOVA), Q value = 1

Table S7. Clustering Approach #2: 'METHLYATION CNMF' versus Clinical Feature #2: 'AGE'

| nPatients | Mean (Std.Dev)
--- | --- | ---
ALL | 56 | 60.8 (14.7)
subtype1 | 15 | 57.7 (18.8)
subtype2 | 15 | 56.9 (15.8)
subtype3 | 26 | 64.9 (10.2)

Figure S5. Get High-res Image Clustering Approach #2: 'METHLYATION CNMF' versus Clinical Feature #2: 'AGE'

'METHLYATION CNMF' versus 'GENDER'

P value = 0.469 (Fisher's exact test), Q value = 1

Table S8. Clustering Approach #2: 'METHLYATION CNMF' versus Clinical Feature #3: 'GENDER'

nPatients | FEMALE | MALE
--- | --- | ---
ALL | 23 | 38
subtype1 | 9 | 10
subtype2 | 6 | 9
subtype3 | 8 | 19

Figure S6. Get High-res Image Clustering Approach #2: 'METHLYATION CNMF' versus Clinical Feature #3: 'GENDER'

Clustering Approach #3: 'MIRseq CNMF subtypes'

Table S9. Get Full Table Description of clustering approach #3: 'MIRseq CNMF subtypes'

Cluster Labels | 1 | 2 | 3
--- | --- | --- | ---
Number of samples | 22 | 12 | 27

'MIRseq CNMF subtypes' versus 'Time to Death'

P value = 0.943 (logrank test), Q value = 1

Table S10. Clustering Approach #3: 'MIRseq CNMF subtypes' versus Clinical Feature #1: 'Time to Death'

| nPatients | nDeath | Duration Range (Median), Month
--- | --- | --- | ---
ALL | 54 | 25 | 0.1 - 83.6 (12.2)
subtype1 | 19 | 11 | 0.1 - 69.6 (14.4)
subtype2 | 9 | 4 | 1.1 - 83.6 (5.9)
subtype3 | 26 | 10 | 0.3 - 53.3 (11.0)

Figure S7. Get High-res Image Clustering Approach #3: 'MIRseq CNMF subtypes' versus Clinical Feature #1: 'Time to Death'

'MIRseq CNMF subtypes' versus 'AGE'

P value = 0.242 (ANOVA), Q value = 1

Table S11. Clustering Approach #3: 'MIRseq CNMF subtypes' versus Clinical Feature #2: 'AGE'

| nPatients | Mean (Std.Dev)
--- | --- | ---
ALL | 56 | 61.0 (14.8)
subtype1 | 21 | 57.2 (14.9)
subtype2 | 9 | 59.7 (19.4)
subtype3 | 26 | 64.5 (12.7)

Figure S8. Get High-res Image Clustering Approach #3: 'MIRseq CNMF subtypes' versus Clinical Feature #2: 'AGE'

'MIRseq CNMF subtypes' versus 'GENDER'

P value = 0.158 (Fisher's exact test), Q value = 1

Table S12. Clustering Approach #3: 'MIRseq CNMF subtypes' versus Clinical Feature #3: 'GENDER'

nPatients | FEMALE | MALE
--- | --- | ---
ALL | 23 | 38
subtype1 | 11 | 11
subtype2 | 2 | 10
subtype3 | 10 | 17

Figure S9. Get High-res Image Clustering Approach #3: 'MIRseq CNMF subtypes' versus Clinical Feature #3: 'GENDER'

Clustering Approach #4: 'MIRseq cHierClus subtypes'

Table S13. Get Full Table Description of clustering approach #4: 'MIRseq cHierClus subtypes'

Cluster Labels | 1 | 2 | 3 | 4
--- | --- | --- | --- | ---
Number of samples | 8 | 9 | 20 | 24

'MIRseq cHierClus subtypes' versus 'Time to Death'

P value = 0.706 (logrank test), Q value = 1

Table S14. Clustering Approach #4: 'MIRseq cHierClus subtypes' versus Clinical Feature #1: 'Time to Death'

| nPatients | nDeath | Duration Range (Median), Month
--- | --- | --- | ---
ALL | 54 | 25 | 0.1 - 83.6 (12.2)
subtype1 | 8 | 2 | 0.3 - 53.3 (2.3)
subtype2 | 7 | 4 | 1.1 - 83.6 (11.6)
subtype3 | 17 | 11 | 0.1 - 69.6 (14.9)
subtype4 | 22 | 8 | 2.6 - 51.2 (14.0)

Figure S10. Get High-res Image Clustering Approach #4: 'MIRseq cHierClus subtypes' versus Clinical Feature #1: 'Time to Death'

'MIRseq cHierClus subtypes' versus 'AGE'

P value = 0.0122 (ANOVA), Q value = 0.15

Table S15. Clustering Approach #4: 'MIRseq cHierClus subtypes' versus Clinical Feature #2: 'AGE'

| nPatients | Mean (Std.Dev)
--- | --- | ---
ALL | 56 | 61.0 (14.8)
subtype1 | 8 | 64.2 (6.5)
subtype2 | 7 | 60.7 (18.5)
subtype3 | 19 | 52.6 (16.8)
subtype4 | 22 | 67.2 (10.7)

Figure S11. Get High-res Image Clustering Approach #4: 'MIRseq cHierClus subtypes' versus Clinical Feature #2: 'AGE'

'MIRseq cHierClus subtypes' versus 'GENDER'

P value = 0.262 (Fisher's exact test), Q value = 1

Table S16. Clustering Approach #4: 'MIRseq cHierClus subtypes' versus Clinical Feature #3: 'GENDER'

nPatients | FEMALE | MALE
--- | --- | ---
ALL | 23 | 38
subtype1 | 1 | 7
subtype2 | 2 | 7
subtype3 | 9 | 11
subtype4 | 11 | 13

Figure S12. Get High-res Image Clustering Approach #4: 'MIRseq cHierClus subtypes' versus Clinical Feature #3: 'GENDER'

Methods & Data
Input

- Cluster data file = LIHC-TP.mergedcluster.txt

- Clinical data file = LIHC-TP.clin.merged.picked.txt

- Number of patients = 62

- Number of clustering approaches = 4

- Number of selected clinical features = 3

- Exclude small clusters that include fewer than K patients, K = 3

Clustering approaches
CNMF clustering

consensus non-negative matrix factorization clustering approach (Brunet et al. 2004)

Consensus hierarchical clustering

Resampling-based clustering method (Monti et al. 2003)

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

ANOVA analysis

For continuous numerical clinical features, one-way analysis of variance (Howell 2002) was applied to compare the clinical values between tumor subtypes using 'anova' function in R

Fisher's exact test

For binary clinical features, 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

This is an experimental feature. The full results of the analysis summarized in this report can be downloaded from the TCGA Data Coordination Center.

- Analysis Results (MD5 checksum)

- Auxiliary Data (MD5 checksum)

- MAGE-TAB File (MD5 checksum)

References
[1] Brunet et al., Metagenes and molecular pattern discovery using matrix factorization, PNAS 101(12):4164-9 (2004)
[2] Monti et al., Consensus Clustering: A Resampling-Based Method for Class Discovery and Visualization of Gene Expression Microarray Data, Machine Learning 52(1):91-118 (2003)
[3] Bland and Altman, Statistics notes: The logrank test, BMJ 328(7447):1073 (2004)
[4] Howell, D, Statistical Methods for Psychology. (5th ed.), Duxbury Press:324-5 (2002)
[5] 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)
[6] 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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