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Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death

  1. Haley Hieronymus
  2. Rajmohan Murali
  3. Amy Tin
  4. Kamlesh Yadav
  5. Wassim Abida
  6. Henrik Moller
  7. Daniel Berney
  8. Howard Scher
  9. Brett Carver
  10. Peter Scardino
  11. Nikolaus Schultz
  12. Barry Taylor
  13. Andrew Vickers
  14. Jack Cuzick
  15. Charles L Sawyers  Is a corresponding author
  1. Memorial Sloan Kettering Cancer Center, United States
  2. Icahn School of Medicine at Mount Sinai, United States
  3. King's College London, United Kingdom
  4. Barts Cancer Institute, Queen Mary University of London, United Kingdom
  5. Weill Cornell Medical College, United States
  6. Queen Mary University of London, United Kingdom
  7. Howard Hughes Medical Institute, United States
https://doi.org/10.7554/eLife.37294
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Cite this article
  1. Haley Hieronymus
  2. Rajmohan Murali
  3. Amy Tin
  4. Kamlesh Yadav
  5. Wassim Abida
  6. Henrik Moller
  7. Daniel Berney
  8. Howard Scher
  9. Brett Carver
  10. Peter Scardino
  11. Nikolaus Schultz
  12. Barry Taylor
  13. Andrew Vickers
  14. Jack Cuzick
  15. Charles L Sawyers
(2018)
Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death
eLife 7:e37294.
https://doi.org/10.7554/eLife.37294
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2 figures, 3 tables and 10 additional files

Figures

Figure 1
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Tumor copy number landscape of conservatively treated primary prostate cancer, compared to other primary prostate cancer cohorts.

(a) Heat map of copy number alterations in conservative treatment CNA cohort, as well as TCGA, MSKCC, and IMPACT primary prostate cancer cohorts. (b) Frequency distribution of CNA burden, as log of percentage of genome copy number altered, for the conservative treatment prostate cancer cohort and three other primary prostate cancer cohorts.

https://doi.org/10.7554/eLife.37294.003
Figure 2 with 5 supplements
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Tumor copy number alteration burden is associated with death from prostate cancer in conservatively treated patients.

(a) Cumulative Incidence of death from disease (dashed lines) and death from other causes (solid lines) based in cases with high CNA burden (red lines, CNA Burden greater than or equal to the median CNA burden of this cohort, 1.48) or non-high CNA burden (black lines, CNA Burden < median). (b) Risk for death from prostate cancer within 5 years of diagnosis. Univariate risk for 5 year prostate cancer-specific death, calculated by locally weighted Kaplan–Meier estimates (solid black line) with 95% confidence interval (dashed black lines) overlaid on the distribution of CNA burden (gray). (c) Association of tumor CNA burden with available cancer outcomes in the conservative treatment primary prostate cancer TAPG1 cohort, TCGA primary cancer cohorts, and the MSK-IMPACT clinical sequencing prostate and pan-cancer cohorts of primary and metastatic tumors. Forest plot of hazard ratio (per 5% CNA burden) with 95% confidence interval shown for cancer-specific mortality (dark blue), overall mortality (light blue), and cancer recurrence (green). Supplementary Tables and Figures.

https://doi.org/10.7554/eLife.37294.004
Figure 2—figure supplement 1
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Kaplan-Meier plot of biochemical recurrence in TCGA primary prostate cohort.

The highest quartile tumor CNA burden (above 75 percentile CNA burden, green) is compared to lower three quartiles (blue) with risk table showing the number of patients present at each time point.

https://doi.org/10.7554/eLife.37294.005
Figure 2—figure supplement 2
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Tumor CNA burden in multiple cancers is associated with disease free survival and overall survival.

Kaplan-Meier plot of disease free survival (left) and overall survival (right) of TCGA cohorts of (a) endometrial cancer and (b) colorectal cancer. The highest quartile CNA (above 75 percentile CNA burden, green) is compared to lower three quartiles (blue).

https://doi.org/10.7554/eLife.37294.006
Figure 2—figure supplement 3
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Correlation between CNA burden from IMPACT targeted sequencing assay and whole exome sequencing (WES) of same samples, pan-cancer.

The relationship between CNA burden determined by IMPACT targeted sequencing and WES in a subset of pan-cancer IMPACT cohort samples analyzed by both approaches (n = 1005) is shown (rho = 0.88, p-value=0).

https://doi.org/10.7554/eLife.37294.007
Figure 2—figure supplement 4
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Tumor CNA burden in primary prostate cancer is prognostic for overall survival when assayed by clinically approved sequencing panel.

Kaplan-Meier plot of overall survival of IMPACT primary prostate cancer cohort by CNA burden quartile in (a) primary and (b) metastatic tumors. The highest quartile CNA (above 75 percentile CNA burden, green) is compared to lower three quartiles (blue).

https://doi.org/10.7554/eLife.37294.008
Figure 2—figure supplement 5
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Forest Plot of Hazard Ratios (individual and pooled) for meta-analysis assessing the association between tumor CNA burden and overall survival in (a) primary cancer and (b) patients with metastatic cancer in the pan-cancer IMPACT cohort.
https://doi.org/10.7554/eLife.37294.009

Tables

Table 1
Tumor CNA burden is associated with prostate cancer-specific death in conservative treatment cohort independent of Gleason sum score and CAPRA score.

Cox Regression model assessing the association between CNA burden (per 5%) and cancer specific survival. N = 107*

https://doi.org/10.7554/eLife.37294.010
ModelHR95% CIP-value
Univariate, tumor CNA burden1.491.30, 1.70<0.0001
Multivariable – adjusting for Gleason sum (≤6, 7, ≥8)1.441.24, 1.67<0.0001
Multivariable – adjusting for UCSF-CAPRA score utilizing multiple imputation1.441.24, 1.68<0.0001
Multivariable – adjusting for UCSF-CAPRA score without utilizing multiple imputation
* N = 60 (excludes 47 patients with unknown stage)		1.571.29, 1.92<0.0001
Table 2
Tumor CNA burden is associated with recurrence and overall survival independent of disease stage in multiple cancer types
https://doi.org/10.7554/eLife.37294.011
CohortModelDisease free TimeOverall Survival
CasesHR95% CIPCasesHR95% CIP
Prostate cancer TCGATumor CNA burden, per 5% tumor CNA burden, univariate2801.271.13, 1.42<0.0001Insufficient events


Tumor CNA burden, per 5% tumor CNA burden, adjusted for Gleason grade and mutation burden2791.181.03, 1.350.015
Tumor CNA burden, per 5% tumor CNA burden, adjusted for purity (ABSOLUTE)*2431.221.07, 1.400.003
Tumor CNA burden, per 5% tumor CNA burden, adjusted for ploidy2431.321.11, 1.560.002
Breast cancer TCGATumor CNA burden, per 5% tumor CNA burden, univariate7091.071.01, 1.140.0287941.081.03, 1.130.0005
Tumor CNA burden, per 5% tumor CNA burden, Multivariable, adjusted for disease stage6951.071.00, 1.140.0497771.081.03, 1.130.002
Endometrial Cancer TCGATumor CNA burden, per 5% tumor CNA burden, univariate4961.101.06, 1.14<0.00015361.131.08, 1.17<0.0001
Tumor CNA burden, per 5% tumor CNA burden, multivariable, adjusted for disease stage4961.081.04, 1.13<0.00015361.101.05, 1.15<0.0001
Renal clear cell cancer TCGATumor CNA burden, per 5% tumor CNA burden, univariate4251.051.01, 1.090.0285251.020.98, 1.06NS (0.4)
Tumor CNA burden, per 5% tumor CNA burden, multivariable, adjusted for disease stage4231.051.00, 1.110.0355221.010.97, 1.06NS (0.7)
Thyroid cancer TCGATumor CNA burden, per 5% tumor CNA burden, univariate4831.171.01, 1.350.0334971.301.04, 1.630.021
Tumor CNA burden, per 5% tumor CNA burden, multivariable, adjusted for disease stage4811.181.00, 1.390.048Insufficient events
Colorectal cancer TCGATumor CNA burden, per 5% tumor CNA burden, univariate5121.051.00, 1.110.0375871.061.01, 1.120.012
Tumor CNA burden, per 5% tumor CNA burden, multivariable, adjusted for disease stage4961.030.98, 1.09NS (0.3)5671.030.97, 1.09NS (0.3)
Tumor CNA burden, per 5% tumor CNA burden, multivariable, adjusted for tumor stage5111.061.01, 1.120.0285851.071.02, 1.130.009

  1. *Result differed with similar adjustment in IMPACT prostate cancer cohort utilizing FACETS, see Supplementary file 3.

Table 3
Tumor CNA burden determined by clinically approved sequencing panel is associated with overall survival in primary and metastatic tumors
https://doi.org/10.7554/eLife.37294.012
ModelOverall Survival
Primary tumorsMetastatic tumors
HR95%PHR95%P
Prostate Cancer*,†
Univariate, tumor CNA burden, per 5%1.171.04, 1.310.0071.071.01, 1.140.020
Multivariable
Tumor CNA burden, per 5%
Mutation burden (per mutation)		1.11
1.22		0.98, 1.26
1.12, 1.33		0.10
<0.0001		1.08
1.05		1.02, 1.15
1.02, 1.08		0.011
0.001
Multivariable
Tumor CNA burden, per 5%
TP53 CN loss or mutation		1.17
4.12		1.04, 1.31
2.02, 8.41		0.007
<0.0001		1.06
1.24		1.00, 1.13
0.76, 2.02		NS (0.069)
NS (0.4)
Multivariable
Tumor CNA burden, per 5%
RB1 CN loss or mutation		1.15
3.24		1.02, 1.30
0.70, 14.98		0.026
NS (0.13)		1.06
1.68		0.99, 1.13
0.94, 2.99		NS (0.091)
NS (0.080)
Multivariable
Tumor CNA burden, per 5%
PTEN CN loss or mutation		1.17
2.38		1.04, 1.32
1.03, 5.51		0.008
0.042		1.07
1.15		1.01, 1.14
0.70, 1.89		0.023
NS (0.6)
Pan- Cancer
Univariate, tumor CNA burden, per 5%‡§1.041.02, 1.05<0.00011.021.01, 1.030.005
Univariate, mutation burden (per five units)‡§0.980.97, 1.00NS (0.072)0.990.97, 1.01NS (0.4)
Meta-analysis, tumor CNA burden (per 5%)#1.041.02, 1.05<0.0001**1.021.01, 1.040.005††
Meta-analysis, tumor CNA burden (per 5%), excluding outlier cancer types‡‡1.051.03, 1.07<0.0001§§1.031.01, 1.040.002##

  1. *Prostate primary tumors: patient n = 261 for all models except multivariable model with mutation burden, where n = 227; event n = 33; median follow-up time for survivors 40 (IQR 25,81) months.

    †Prostate metastatic tumors: patient n = 216 for all models except multivariable model with mutation burden, where n = 205; event n = 80; median follow-up time for survivors 59.5 (IQR 32, 129) months.

  2. ‡Pan-cancer primary tumors, univariate models: patient n = 6610, event n = 1535, median follow-up time for survivors 24 (IQR 11, 61) months

    §Pan-cancer metastatic tumors, univariate models: patient n = 4864, event n = 1467, median follow-up time for survivors 51 (IQR 23, 109) months.

  3. #Pan-cancer meta-analysis, among ten most prevalent cancer types: primary tumor patient n = 4863, metastatic tumor patient n = 3676. Estimates are based on overall fixed effects.

    **p-value corresponds with test of effects size. Chi-square test for heterogeneity p-value=0.003.

  4. ††p-value corresponds with test of effects size. Chi-square test for heterogeneity p-value=0.024.

    ‡‡Exclusion of cancer types to reduce heterogeneity: primary tumor patient n = 3887, metastatic tumor patient n = 3098. Estimates are based on overall fixed effects.

  5. §§Excluding pancreatic and colorectal cancer, test of effects size p-value. Chi-square test for heterogeneity p-value=0.3.

    ##Excluding pancreatic and prostate cancer, test of effects size p-value. Chi-square test for heterogeneity p-value=0.8.

Additional files

Supplementary file 1

Cohort characteristics.

https://doi.org/10.7554/eLife.37294.013
Supplementary file 2

Distribution of cancer types in IMPACT cohorts.

https://doi.org/10.7554/eLife.37294.014
Supplementary file 3

Association between overall survival and CNA burden after adjustment for purity in IMPACT prostate and pan-cancer cohorts.

Purity was determined by FACETS (Shen and Seshan, 2016).

https://doi.org/10.7554/eLife.37294.015
Supplementary file 4

TAPG1 conservative treatment primary prostate CNA cohort.

https://doi.org/10.7554/eLife.37294.016
Supplementary file 5

MSK-IMPACT primary prostate tumor cohort annotation.

https://doi.org/10.7554/eLife.37294.017
Supplementary file 6

MSK-IMPACT metastatic prostate tumor cohort annotation.

https://doi.org/10.7554/eLife.37294.018
Supplementary file 7

MSK-IMPACT primary pan-cancer cohort annotation.

https://doi.org/10.7554/eLife.37294.019
Supplementary file 8

MSK-IMPACT metastatic pan-cancer cohort annotation.

https://doi.org/10.7554/eLife.37294.020
Supplementary file 9

TCGA Cohort statistics: patient exclusion, events, and follow-up.

https://doi.org/10.7554/eLife.37294.021
Transparent reporting form
https://doi.org/10.7554/eLife.37294.022

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  1. Haley Hieronymus
  2. Rajmohan Murali
  3. Amy Tin
  4. Kamlesh Yadav
  5. Wassim Abida
  6. Henrik Moller
  7. Daniel Berney
  8. Howard Scher
  9. Brett Carver
  10. Peter Scardino
  11. Nikolaus Schultz
  12. Barry Taylor
  13. Andrew Vickers
  14. Jack Cuzick
  15. Charles L Sawyers
(2018)
Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death
eLife 7:e37294.
https://doi.org/10.7554/eLife.37294