Evaluation of copy number signature profiles in a City of Hope pan-cancer cohort
DNA copy number variations occur in cancer and range from focal gain or loss of DNA segments to complete genomic restructuring. Last year, Steele et al. introduced a method of arranging patterns of copy number variations into 24 copy number “signatures” (CNS). Several links have been identified between CNS and cancer characteristics, such as age of diagnosis, disease progression, and response to treatments. Here, we assessed the relationship between CNS, cancer features, and treatment response within a pan-cancer City of Hope cohort (n=853). The SigProfilerAssignment tool sorted allele-specific copy number profiles into CNS profiles. CNS profiling revealed a pan-cohort association with copy number signature 9 (CN9) and an enrichment of copy number signatures 17-19 (CN17-19) in certain cancers. CN17-19 are associated with homologous recombination deficiency (HRD), an important DNA repair defect (p < 0.0001, Fisher’s exact test). 41.5% of patients with HRD-positive tumors carried CN17-19 while only 10.6% of HRD-negative tumors carried one of those signatures. PARP inhibitors (PARPi) are FDA-approved for treatment of HRD-associated cancers. Because of their association with HRD, CN17-19 may have applicability in predicting patient response to PARPi. In a cohort of 12 patients who received PARPi, 83% who carried CN17-19 experienced clinical benefit from PARPi. Only 17% of patients without one of these signatures saw clinical benefit. These results suggest that CNS may be an additional tool to identify patients who would benefit from PARPi. Overall, CNS is an exciting new tool that can add a layer of specificity to a cancer diagnosis, and can better group and evaluate patients.
