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

Haley Hieronymus,Charles L Sawyers,Peter Scardino,Howard Scher,Brett Carver,Jack Cuzick,Daniel Berney,Henrik Moller,Amy Tin,Wassim Abida,Andrew Vickers,Nikolaus Schultz,Rajmohan Murali,Kamlesh Yadav,Barry Taylor

doi:10.7554/elife.37294

Abstract

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.

Highlights

Somatic copy number alterations (CNAs) are nearly ubiquitous in cancer (Zack et al, 2013; Heitzer et al, 2016) and alter a greater portion of the cancer genome than any other type of somatic genetic alteration (Heitzer et al, 2016)
Many specific genes altered by CNA have been associated with cancer outcomes (Liang et al, 2016; Wang et al, 2016; Nibourel et al, 2017), the relationship between outcome and the overall level of CNA harbored by a tumor is less well studied
We expanded on our previous work showing that tumor CNA burden is associated with recurrence in surgically treated primary prostate cancer (Taylor et al, 2010; Hieronymus et al, 2014) by showing a significant association with death from prostate cancer, including in conservatively treated patients where the tumor CNA burden measurement was made from biopsies

Summary

Introduction

Somatic copy number alterations (CNAs) are nearly ubiquitous in cancer (Zack et al, 2013; Heitzer et al, 2016) and alter a greater portion of the cancer genome than any other type of somatic genetic alteration (Heitzer et al, 2016). Given the prevalence of CNAs in cancer, significant effort has been directed towards identifying specific CNAs associated with cancer clinical characteristics and prognosis as well as the potential driver genes they contain (Liang et al, 2016; Wang et al, 2016; Nibourel et al, 2017). Most CNAs are large, (Zack et al, 2013; Beroukhim et al, 2010) and their associations with cancer outcome may not be well identified by gene-specific approaches. Increasing evidence indicates that large CNAs harbor multiple drivers (Tschaharganeh et al, 2016; Liu et al, 2016), emphasizing the need to study their biological and clinical significance beyond individual gene-focused standpoints

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