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

The level of copy number alteration (CNA), termed CNA burden, in the tumor genome is associated with recurrence of primary prostate cancer. Whether CNA burden is associated with prostate cancer survival or outcomes in other cancers is unknown. We analyzed the CNA landscape of conservatively treated prostate cancer in a biopsy and transurethral resection cohort, reflecting an increasingly common treatment approach. We find that CNA burden is prognostic for cancer-specific death, independent of standard clinical prognosticators. More broadly, we find CNA burden is significantly associated with disease-free and overall survival in primary breast, endometrial, renal clear cell, thyroid, and colorectal cancer in TCGA cohorts. To assess clinical applicability, we validated these findings in an independent pan-cancer cohort of patients whose tumors were sequenced using a clinically-certified next generation sequencing assay (MSK-IMPACT), where prognostic value varied based on cancer type. This prognostic association was affected by incorporating tumor purity in some cohorts. Overall, CNA burden of primary and metastatic tumors is a prognostic factor, potentially modulated by sample purity and measurable by current clinical sequencing.

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

10.7554/elife.37294.026 ◽

2018 ◽

Author(s):

Cory Abate-Shen ◽

Mark A Rubin

Keyword(s):

Prognostic Factor ◽

Copy Number ◽

Copy Number Alteration ◽

Pan Cancer

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

10.7554/elife.37294.027 ◽

2018 ◽

Cited By ~ 2

Author(s):

Haley Hieronymus ◽

Rajmohan Murali ◽

Amy Tin ◽

Kamlesh Yadav ◽

Wassim Abida ◽

...

Keyword(s):

Prognostic Factor ◽

Copy Number ◽

Copy Number Alteration ◽

Author Response ◽

Pan Cancer

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Chromosomal copy number heterogeneity predicts survival rates across cancers

Nature Communications ◽

10.1038/s41467-021-23384-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Erik van Dijk ◽

Tom van den Bosch ◽

Kristiaan J. Lenos ◽

Khalid El Makrini ◽

Lisanne E. Nijman ◽

...

Keyword(s):

Copy Number ◽

Cancer Survival ◽

Survival Rates ◽

Cancer Prognosis ◽

Disease Outcomes ◽

Distinct Disease ◽

Cancer Types ◽

Chromosomal Copy Number ◽

Chromosomal Copy ◽

Pan Cancer

AbstractSurvival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing. Here, we introduce a scalable measure of chromosomal copy number heterogeneity (CNH) that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data and live cell imaging we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 37 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.

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Re: Franclim R. Ribeiro, Rui Henrique, Ana T. Martins, Carmen Jerónimo and Manuel R. Teixeira. Relative Copy Number Gain of MYC in Diagnostic Needle Biopsies is an Independent Prognostic Factor for Prostate Cancer Patients. Eur Urol 2007;52:116–25

European Urology ◽

10.1016/j.eururo.2007.08.017 ◽

2007 ◽

Vol 52 (5) ◽

pp. 1538-1539

Author(s):

AnnaMaria Cianciulli ◽

Roberta Merola ◽

Costantino Leonardo

Keyword(s):

Prostate Cancer ◽

Prognostic Factor ◽

Cancer Patients ◽

Copy Number ◽

Copy Number Gain ◽

Independent Prognostic Factor ◽

Relative Copy Number

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Pan-cancer landscape of homologous recombination deficiency

10.1101/2020.01.13.905026 ◽

2020 ◽

Cited By ~ 5

Author(s):

Luan Nguyen ◽

John Martens ◽

Arne Van Hoeck ◽

Edwin Cuppen

Keyword(s):

Prostate Cancer ◽

Homologous Recombination ◽

Cancer Genomics ◽

Strand Break ◽

Diagnostic Value ◽

Cancer Type ◽

Brca1 And Brca2 ◽

Homologous Recombination Deficiency ◽

A Genome ◽

Pan Cancer

AbstractHomologous recombination deficiency (HRD) results in impaired double strand break repair and is a frequent driver of tumorigenesis. Here, we developed a genome-wide mutational scar-based pan-cancer Classifier of HOmologous Recombination Deficiency (CHORD) that can discriminate BRCA1- and BRCA2-subtypes. Analysis of a metastatic (n=3,504) and primary (n=1,854) pan-cancer cohort revealed HRD was most frequent in ovarian and breast cancer, followed by pancreatic and prostate cancer. Biallelic inactivation of BRCA1, BRCA2, RAD51C or PALB2 was the most common genetic cause of HRD, with RAD51C and PALB2 inactivation resulting in BRCA2-type HRD. While the specific genetic cause of HRD was cancer type specific, biallelic inactivation was predominantly associated with loss-of-heterozygosity (LOH), with increased contribution of deep deletions in prostate cancer. Our results demonstrate the value of pan-cancer genomics-based HRD testing and its potential diagnostic value for patient stratification towards treatment with e.g. poly ADP-ribose polymerase inhibitors (PARPi).

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Abstract 4588: Prognostic association of plasma cell free DNA (cfDNA) copy number variation based algorithmic score with survival in metastatic castration resistant prostate cancer (mCRPC)

10.1158/1538-7445.am2018-4588 ◽

2018 ◽

Author(s):

Manish Kohli ◽

Meijun Du ◽

Liang Wang ◽

Chiang-Ching Huang

Keyword(s):

Prostate Cancer ◽

Copy Number Variation ◽

Plasma Cell ◽

Copy Number ◽

Castration Resistant Prostate Cancer ◽

Cell Free Dna ◽

Castration Resistant ◽

Free Dna ◽

Number Variation ◽

Prognostic Association

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Pan-cancer landscape of homologous recombination deficiency

Nature Communications ◽

10.1038/s41467-020-19406-4 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Luan Nguyen ◽

John W. M. Martens ◽

Arne Van Hoeck ◽

Edwin Cuppen

Keyword(s):

Prostate Cancer ◽

Homologous Recombination ◽

Cancer Genomics ◽

Strand Break ◽

Diagnostic Value ◽

Cancer Type ◽

Homologous Recombination Deficiency ◽

Genome Wide ◽

A Genome ◽

Pan Cancer

Abstract Homologous recombination deficiency (HRD) results in impaired double strand break repair and is a frequent driver of tumorigenesis. Here, we develop a genome-wide mutational scar-based pan-cancer Classifier of HOmologous Recombination Deficiency (CHORD) that can discriminate BRCA1- and BRCA2-subtypes. Analysis of a metastatic (n = 3,504) and primary (n = 1,854) pan-cancer cohort reveals that HRD is most frequent in ovarian and breast cancer, followed by pancreatic and prostate cancer. We identify biallelic inactivation of BRCA1, BRCA2, RAD51C or PALB2 as the most common genetic cause of HRD, with RAD51C and PALB2 inactivation resulting in BRCA2-type HRD. We find that while the specific genetic cause of HRD is cancer type specific, biallelic inactivation is predominantly associated with loss-of-heterozygosity (LOH), with increased contribution of deep deletions in prostate cancer. Our results demonstrate the value of pan-cancer genomics-based HRD testing and its potential diagnostic value for patient stratification towards treatment with e.g. poly ADP-ribose polymerase inhibitors (PARPi).

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A network of epigenetic modifiers and DNA repair genes controls tissue-specific copy number alteration preference

eLife ◽

10.7554/elife.16519 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 5

Author(s):

Dina Cramer ◽

Luis Serrano ◽

Martin H Schaefer

Keyword(s):

Copy Number ◽

Copy Number Alteration ◽

Patient Survival ◽

Cancer Type ◽

Copy Number Alterations ◽

Large Variability ◽

Epigenetic Modifiers ◽

Physical Interactions ◽

Tissue Of Origin ◽

Repair Genes

Copy number alterations (CNAs) in cancer patients show a large variability in their number, length and position, but the sources of this variability are not known. CNA number and length are linked to patient survival, suggesting clinical relevance. We have identified genes that tend to be mutated in samples that have few or many CNAs, which we term CONIM genes (COpy Number Instability Modulators). CONIM proteins cluster into a densely connected subnetwork of physical interactions and many of them are epigenetic modifiers. Therefore, we investigated how the epigenome of the tissue-of-origin influences the position of CNA breakpoints and the properties of the resulting CNAs. We found that the presence of heterochromatin in the tissue-of-origin contributes to the recurrence and length of CNAs in the respective cancer type.

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