Correlation between copy number variation genes and molecular subtypes

Overview

Introduction

This pipeline computes the correlation between significant copy number variation (cnv) genes and molecular subtypes.

Summary

Testing the association between copy number variation of 22 peak regions and 8 molecular subtypes across 117 patients, 21 significant findings detected with Q value < 0.25.

Amp Peak 2(3p14.1) cnvs correlated to 'CN_CNMF', 'MRNASEQ_CHIERARCHICAL', and 'MIRSEQ_CHIERARCHICAL'.
Amp Peak 5(7q22.1) cnvs correlated to 'CN_CNMF', 'MRNASEQ_CNMF', and 'MRNASEQ_CHIERARCHICAL'.
Amp Peak 6(17q25.2) cnvs correlated to 'CN_CNMF'.
Amp Peak 7(19p13.2) cnvs correlated to 'CN_CNMF'.
Del Peak 1(1p36.31) cnvs correlated to 'CN_CNMF'.
Del Peak 4(3p22.1) cnvs correlated to 'CN_CNMF' and 'METHLYATION_CNMF'.
Del Peak 5(4q31.22) cnvs correlated to 'CN_CNMF' and 'METHLYATION_CNMF'.
Del Peak 6(5q35.2) cnvs correlated to 'MRNASEQ_CNMF' and 'MRNASEQ_CHIERARCHICAL'.
Del Peak 8(9p21.3) cnvs correlated to 'METHLYATION_CNMF' and 'MRNASEQ_CNMF'.
Del Peak 9(14q11.2) cnvs correlated to 'CN_CNMF'.
Del Peak 10(14q23.3) cnvs correlated to 'CN_CNMF'.
Del Peak 11(14q32.2) cnvs correlated to 'CN_CNMF'.
Del Peak 13(Xq21.31) cnvs correlated to 'CN_CNMF'.

Results

Overview of the results

Table 1. Get Full Table Overview of the association between significant copy number variation of 22 regions and 8 molecular subtypes. Shown in the table are P values (Q values). Thresholded by Q value < 0.25, 21 significant findings detected.


		Molecular subtypes	MRNA CNMF	MRNA CHIERARCHICAL	CN CNMF	METHLYATION CNMF	MRNASEQ CNMF	MRNASEQ CHIERARCHICAL	MIRSEQ CNMF	MIRSEQ CHIERARCHICAL
	nCNV (%)	nWild-Type	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
Amp Peak 2(3p14 1)	31 (26%)	86	1 (1.00)	0.537 (1.00)	2.36e-17 (3.76e-15)	0.0858 (1.00)	0.00279 (0.373)	1.79e-06 (0.000274)	0.00534 (0.688)	0.000228 (0.0335)
Amp Peak 5(7q22 1)	68 (58%)	49	1 (1.00)	0.808 (1.00)	3.56e-09 (5.52e-07)	0.00792 (1.00)	0.00172 (0.239)	0.000515 (0.0746)	0.0134 (1.00)	0.0157 (1.00)
Del Peak 4(3p22 1)	8 (7%)	109	0.438 (1.00)		0.000862 (0.122)	0.000694 (0.0985)	0.0206 (1.00)	0.00417 (0.547)	0.0159 (1.00)	0.111 (1.00)
Del Peak 5(4q31 22)	13 (11%)	104	1 (1.00)		0.000304 (0.0444)	0.000543 (0.0782)	0.00681 (0.872)	0.024 (1.00)	0.582 (1.00)	0.61 (1.00)
Del Peak 6(5q35 2)	8 (7%)	109	1 (1.00)		0.319 (1.00)	0.00185 (0.253)	0.000616 (0.088)	0.00116 (0.162)	0.394 (1.00)	0.12 (1.00)
Del Peak 8(9p21 3)	18 (15%)	99	1 (1.00)	0.75 (1.00)	0.00471 (0.612)	4.27e-05 (0.00636)	3.4e-05 (0.0051)	0.00182 (0.251)	0.0341 (1.00)	0.0922 (1.00)
Amp Peak 6(17q25 2)	80 (68%)	37	0.585 (1.00)	1 (1.00)	2.9e-06 (0.000438)	0.233 (1.00)	0.28 (1.00)	0.0388 (1.00)	0.826 (1.00)	0.477 (1.00)
Amp Peak 7(19p13 2)	14 (12%)	103	0.0885 (1.00)	0.615 (1.00)	4.94e-09 (7.61e-07)	0.161 (1.00)	0.0683 (1.00)	0.765 (1.00)	0.722 (1.00)	0.682 (1.00)
Del Peak 1(1p36 31)	25 (21%)	92	0.585 (1.00)	1 (1.00)	2.27e-06 (0.000346)	0.172 (1.00)	0.0316 (1.00)	0.0382 (1.00)	0.255 (1.00)	0.124 (1.00)
Del Peak 9(14q11 2)	26 (22%)	91	0.596 (1.00)	0.167 (1.00)	2.56e-10 (3.99e-08)	0.3 (1.00)	0.0934 (1.00)	0.177 (1.00)	0.835 (1.00)	0.953 (1.00)
Del Peak 10(14q23 3)	25 (21%)	92	1 (1.00)	0.385 (1.00)	2.2e-12 (3.48e-10)	0.139 (1.00)	0.0351 (1.00)	0.0295 (1.00)	0.719 (1.00)	0.886 (1.00)
Del Peak 11(14q32 2)	25 (21%)	92	1 (1.00)	0.385 (1.00)	1.29e-11 (2.02e-09)	0.3 (1.00)	0.0775 (1.00)	0.0648 (1.00)	0.719 (1.00)	0.886 (1.00)
Del Peak 13(Xq21 31)	17 (15%)	100	1 (1.00)		0.000118 (0.0175)	0.00263 (0.355)	0.00278 (0.373)	0.0354 (1.00)	0.768 (1.00)	0.806 (1.00)
Amp Peak 1(2q32 1)	20 (17%)	97	0.55 (1.00)	0.75 (1.00)	0.00237 (0.322)	0.397 (1.00)	0.942 (1.00)	1 (1.00)	0.832 (1.00)	0.439 (1.00)
Amp Peak 3(5q35 2)	15 (13%)	102	0.0625 (1.00)	0.141 (1.00)	0.2 (1.00)	0.0369 (1.00)	0.678 (1.00)	0.0565 (1.00)	0.566 (1.00)	0.0452 (1.00)
Amp Peak 4(6p12 3)	4 (3%)	113			0.438 (1.00)	0.199 (1.00)	0.114 (1.00)	0.35 (1.00)	0.165 (1.00)	0.186 (1.00)
Amp Peak 8(19q13 11)	4 (3%)	113			0.69 (1.00)	0.199 (1.00)	0.201 (1.00)	0.13 (1.00)	0.331 (1.00)	0.473 (1.00)
Del Peak 2(2p11 2)	3 (3%)	114			0.884 (1.00)	0.791 (1.00)			0.028 (1.00)	0.0273 (1.00)
Del Peak 3(2q37 3)	5 (4%)	112	1 (1.00)		0.331 (1.00)	0.163 (1.00)	0.684 (1.00)	0.35 (1.00)	0.704 (1.00)	0.84 (1.00)
Del Peak 7(6q22 31)	13 (11%)	104	1 (1.00)		0.0489 (1.00)	0.114 (1.00)	0.0976 (1.00)	0.175 (1.00)	0.787 (1.00)	0.337 (1.00)
Del Peak 12(19q13 42)	10 (9%)	107			0.163 (1.00)	0.885 (1.00)	0.732 (1.00)	0.232 (1.00)	0.471 (1.00)	0.438 (1.00)
Del Peak 14(Xq28)	16 (14%)	101	1 (1.00)		0.00368 (0.486)	0.045 (1.00)	0.0436 (1.00)	0.253 (1.00)	0.713 (1.00)	0.941 (1.00)

'Amp Peak 2(3p14.1) mutation analysis' versus 'CN_CNMF'

P value = 2.36e-17 (Fisher's exact test), Q value = 3.8e-15

Table S1. Gene #2: 'Amp Peak 2(3p14.1) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	24	20	28	45
AMP PEAK 2(3P14.1) MUTATED	23	4	0	4
AMP PEAK 2(3P14.1) WILD-TYPE	1	16	28	41

Figure S1. Get High-res Image Gene #2: 'Amp Peak 2(3p14.1) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

'Amp Peak 2(3p14.1) mutation analysis' versus 'MRNASEQ_CHIERARCHICAL'

P value = 1.79e-06 (Fisher's exact test), Q value = 0.00027

Table S2. Gene #2: 'Amp Peak 2(3p14.1) mutation analysis' versus Clinical Feature #6: 'MRNASEQ_CHIERARCHICAL'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	18	37	21
AMP PEAK 2(3P14.1) MUTATED	1	19	0
AMP PEAK 2(3P14.1) WILD-TYPE	17	18	21

Figure S2. Get High-res Image Gene #2: 'Amp Peak 2(3p14.1) mutation analysis' versus Clinical Feature #6: 'MRNASEQ_CHIERARCHICAL'

'Amp Peak 2(3p14.1) mutation analysis' versus 'MIRSEQ_CHIERARCHICAL'

P value = 0.000228 (Fisher's exact test), Q value = 0.033

Table S3. Gene #2: 'Amp Peak 2(3p14.1) mutation analysis' versus Clinical Feature #8: 'MIRSEQ_CHIERARCHICAL'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	27	45	12	33
AMP PEAK 2(3P14.1) MUTATED	2	8	8	13
AMP PEAK 2(3P14.1) WILD-TYPE	25	37	4	20

Figure S3. Get High-res Image Gene #2: 'Amp Peak 2(3p14.1) mutation analysis' versus Clinical Feature #8: 'MIRSEQ_CHIERARCHICAL'

'Amp Peak 5(7q22.1) mutation analysis' versus 'CN_CNMF'

P value = 3.56e-09 (Fisher's exact test), Q value = 5.5e-07

Table S4. Gene #5: 'Amp Peak 5(7q22.1) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	24	20	28	45
AMP PEAK 5(7Q22.1) MUTATED	21	20	9	18
AMP PEAK 5(7Q22.1) WILD-TYPE	3	0	19	27

Figure S4. Get High-res Image Gene #5: 'Amp Peak 5(7q22.1) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

'Amp Peak 5(7q22.1) mutation analysis' versus 'MRNASEQ_CNMF'

P value = 0.00172 (Fisher's exact test), Q value = 0.24

Table S5. Gene #5: 'Amp Peak 5(7q22.1) mutation analysis' versus Clinical Feature #5: 'MRNASEQ_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	27	24	25
AMP PEAK 5(7Q22.1) MUTATED	22	8	13
AMP PEAK 5(7Q22.1) WILD-TYPE	5	16	12

Figure S5. Get High-res Image Gene #5: 'Amp Peak 5(7q22.1) mutation analysis' versus Clinical Feature #5: 'MRNASEQ_CNMF'

'Amp Peak 5(7q22.1) mutation analysis' versus 'MRNASEQ_CHIERARCHICAL'

P value = 0.000515 (Fisher's exact test), Q value = 0.075

Table S6. Gene #5: 'Amp Peak 5(7q22.1) mutation analysis' versus Clinical Feature #6: 'MRNASEQ_CHIERARCHICAL'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	18	37	21
AMP PEAK 5(7Q22.1) MUTATED	8	29	6
AMP PEAK 5(7Q22.1) WILD-TYPE	10	8	15

Figure S6. Get High-res Image Gene #5: 'Amp Peak 5(7q22.1) mutation analysis' versus Clinical Feature #6: 'MRNASEQ_CHIERARCHICAL'

'Amp Peak 6(17q25.2) mutation analysis' versus 'CN_CNMF'

P value = 2.9e-06 (Fisher's exact test), Q value = 0.00044

Table S7. Gene #6: 'Amp Peak 6(17q25.2) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	24	20	28	45
AMP PEAK 6(17Q25.2) MUTATED	22	20	14	24
AMP PEAK 6(17Q25.2) WILD-TYPE	2	0	14	21

Figure S7. Get High-res Image Gene #6: 'Amp Peak 6(17q25.2) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

'Amp Peak 7(19p13.2) mutation analysis' versus 'CN_CNMF'

P value = 4.94e-09 (Fisher's exact test), Q value = 7.6e-07

Table S8. Gene #7: 'Amp Peak 7(19p13.2) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	24	20	28	45
AMP PEAK 7(19P13.2) MUTATED	0	11	3	0
AMP PEAK 7(19P13.2) WILD-TYPE	24	9	25	45

Figure S8. Get High-res Image Gene #7: 'Amp Peak 7(19p13.2) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

'Del Peak 1(1p36.31) mutation analysis' versus 'CN_CNMF'

P value = 2.27e-06 (Fisher's exact test), Q value = 0.00035

Table S9. Gene #9: 'Del Peak 1(1p36.31) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	24	20	28	45
DEL PEAK 1(1P36.31) MUTATED	2	0	16	7
DEL PEAK 1(1P36.31) WILD-TYPE	22	20	12	38

Figure S9. Get High-res Image Gene #9: 'Del Peak 1(1p36.31) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

'Del Peak 4(3p22.1) mutation analysis' versus 'CN_CNMF'

P value = 0.000862 (Fisher's exact test), Q value = 0.12

Table S10. Gene #12: 'Del Peak 4(3p22.1) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	24	20	28	45
DEL PEAK 4(3P22.1) MUTATED	0	0	7	1
DEL PEAK 4(3P22.1) WILD-TYPE	24	20	21	44

Figure S10. Get High-res Image Gene #12: 'Del Peak 4(3p22.1) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

'Del Peak 4(3p22.1) mutation analysis' versus 'METHLYATION_CNMF'

P value = 0.000694 (Fisher's exact test), Q value = 0.098

Table S11. Gene #12: 'Del Peak 4(3p22.1) mutation analysis' versus Clinical Feature #4: 'METHLYATION_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	21	27	39
DEL PEAK 4(3P22.1) MUTATED	0	6	0
DEL PEAK 4(3P22.1) WILD-TYPE	21	21	39

Figure S11. Get High-res Image Gene #12: 'Del Peak 4(3p22.1) mutation analysis' versus Clinical Feature #4: 'METHLYATION_CNMF'

'Del Peak 5(4q31.22) mutation analysis' versus 'CN_CNMF'

P value = 0.000304 (Fisher's exact test), Q value = 0.044

Table S12. Gene #13: 'Del Peak 5(4q31.22) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	24	20	28	45
DEL PEAK 5(4Q31.22) MUTATED	3	0	9	1
DEL PEAK 5(4Q31.22) WILD-TYPE	21	20	19	44

Figure S12. Get High-res Image Gene #13: 'Del Peak 5(4q31.22) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

'Del Peak 5(4q31.22) mutation analysis' versus 'METHLYATION_CNMF'

P value = 0.000543 (Fisher's exact test), Q value = 0.078

Table S13. Gene #13: 'Del Peak 5(4q31.22) mutation analysis' versus Clinical Feature #4: 'METHLYATION_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	21	27	39
DEL PEAK 5(4Q31.22) MUTATED	0	8	1
DEL PEAK 5(4Q31.22) WILD-TYPE	21	19	38

Figure S13. Get High-res Image Gene #13: 'Del Peak 5(4q31.22) mutation analysis' versus Clinical Feature #4: 'METHLYATION_CNMF'

'Del Peak 6(5q35.2) mutation analysis' versus 'MRNASEQ_CNMF'

P value = 0.000616 (Fisher's exact test), Q value = 0.088

Table S14. Gene #14: 'Del Peak 6(5q35.2) mutation analysis' versus Clinical Feature #5: 'MRNASEQ_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	27	24	25
DEL PEAK 6(5Q35.2) MUTATED	0	6	0
DEL PEAK 6(5Q35.2) WILD-TYPE	27	18	25

Figure S14. Get High-res Image Gene #14: 'Del Peak 6(5q35.2) mutation analysis' versus Clinical Feature #5: 'MRNASEQ_CNMF'

'Del Peak 6(5q35.2) mutation analysis' versus 'MRNASEQ_CHIERARCHICAL'

P value = 0.00116 (Fisher's exact test), Q value = 0.16

Table S15. Gene #14: 'Del Peak 6(5q35.2) mutation analysis' versus Clinical Feature #6: 'MRNASEQ_CHIERARCHICAL'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	18	37	21
DEL PEAK 6(5Q35.2) MUTATED	5	0	1
DEL PEAK 6(5Q35.2) WILD-TYPE	13	37	20

Figure S15. Get High-res Image Gene #14: 'Del Peak 6(5q35.2) mutation analysis' versus Clinical Feature #6: 'MRNASEQ_CHIERARCHICAL'

'Del Peak 8(9p21.3) mutation analysis' versus 'METHLYATION_CNMF'

P value = 4.27e-05 (Fisher's exact test), Q value = 0.0064

Table S16. Gene #16: 'Del Peak 8(9p21.3) mutation analysis' versus Clinical Feature #4: 'METHLYATION_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	21	27	39
DEL PEAK 8(9P21.3) MUTATED	4	10	0
DEL PEAK 8(9P21.3) WILD-TYPE	17	17	39

Figure S16. Get High-res Image Gene #16: 'Del Peak 8(9p21.3) mutation analysis' versus Clinical Feature #4: 'METHLYATION_CNMF'

'Del Peak 8(9p21.3) mutation analysis' versus 'MRNASEQ_CNMF'

P value = 3.4e-05 (Fisher's exact test), Q value = 0.0051

Table S17. Gene #16: 'Del Peak 8(9p21.3) mutation analysis' versus Clinical Feature #5: 'MRNASEQ_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	27	24	25
DEL PEAK 8(9P21.3) MUTATED	1	12	2
DEL PEAK 8(9P21.3) WILD-TYPE	26	12	23

Figure S17. Get High-res Image Gene #16: 'Del Peak 8(9p21.3) mutation analysis' versus Clinical Feature #5: 'MRNASEQ_CNMF'

'Del Peak 9(14q11.2) mutation analysis' versus 'CN_CNMF'

P value = 2.56e-10 (Fisher's exact test), Q value = 4e-08

Table S18. Gene #17: 'Del Peak 9(14q11.2) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	24	20	28	45
DEL PEAK 9(14Q11.2) MUTATED	5	0	19	2
DEL PEAK 9(14Q11.2) WILD-TYPE	19	20	9	43

Figure S18. Get High-res Image Gene #17: 'Del Peak 9(14q11.2) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

'Del Peak 10(14q23.3) mutation analysis' versus 'CN_CNMF'

P value = 2.2e-12 (Fisher's exact test), Q value = 3.5e-10

Table S19. Gene #18: 'Del Peak 10(14q23.3) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	24	20	28	45
DEL PEAK 10(14Q23.3) MUTATED	4	0	20	1
DEL PEAK 10(14Q23.3) WILD-TYPE	20	20	8	44

Figure S19. Get High-res Image Gene #18: 'Del Peak 10(14q23.3) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

'Del Peak 11(14q32.2) mutation analysis' versus 'CN_CNMF'

P value = 1.29e-11 (Fisher's exact test), Q value = 2e-09

Table S20. Gene #19: 'Del Peak 11(14q32.2) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	24	20	28	45
DEL PEAK 11(14Q32.2) MUTATED	3	0	20	2
DEL PEAK 11(14Q32.2) WILD-TYPE	21	20	8	43

Figure S20. Get High-res Image Gene #19: 'Del Peak 11(14q32.2) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

'Del Peak 13(Xq21.31) mutation analysis' versus 'CN_CNMF'

P value = 0.000118 (Fisher's exact test), Q value = 0.018

Table S21. Gene #21: 'Del Peak 13(Xq21.31) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	24	20	28	45
DEL PEAK 13(XQ21.31) MUTATED	4	0	11	2
DEL PEAK 13(XQ21.31) WILD-TYPE	20	20	17	43

Figure S21. Get High-res Image Gene #21: 'Del Peak 13(Xq21.31) mutation analysis' versus Clinical Feature #3: 'CN_CNMF'

Methods & Data

Input

Copy number data file = All Lesions File (all_lesions.conf_##.txt, where ## is the confidence level). The all lesions file is from GISTIC pipeline and summarizes the results from the GISTIC run. It contains data about the significant regions of amplification and deletion as well as which samples are amplified or deleted in each of these regions. The identified regions are listed down the first column, and the samples are listed across the first row, starting in column 10.
Molecular subtype file = KIRP-TP.transferedmergedcluster.txt
Number of patients = 117
Number of copy number variation regions = 22
Number of molecular subtypes = 8
Exclude regions that fewer than K tumors have alterations, K = 3

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] 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)

[2] 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)

[3] GISTIC_version2

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