CNHplus: the chromosomal copy number heterogeneity which respects biological constraints

Motivation Intra-Tumor Heterogeneity (ITH) is a hallmark of cancer. ITH influences evolution of tumors and hence also affects patients survival. There are several methods for quantifying ITH. Recently, van Dijk et al. ( Nat. Commun . 12(1):1-12, 2021) introduced Copy Number Heterogeneity (CNH) method for quantifying ITH from a single tumor sample, based on a copy number profile. The authors demonstrated capability of CNH to stratify patients for survival, across cancers. We aimed to reproduce the authors’ study. Results A deficiency in CNH is pointed out. The absolute copy number (ACN) profile obtained by solving the CNH optimization problem may contain negative number of copies. For a large portion of samples from The Cancer Genome Atlas (TCGA) studies considered by the authors the CNH-recovered ACN profiles are faulty. CNHplus corrects the flaw by imposing the non-negativity constraint. CNHplus is applied to survival stratification of patients from the TCGA studies. Also, it is discussed which other biological constraints should be incorporated into CNHplus. CNHplus estimates of the tumor purity, tumor ploidy are compared with those of the ABSOLUTE method. Availability and implementation R library CNHplus can be accessed here: ### Competing Interest Statement The authors have declared no competing interest.