Platform-Independent Genome-Wide Pattern of DNA Copy-Number Alterations Predicting Astrocytoma Survival and Response to Treatment Revealed by the GSVD Formulated as a Comparative Spectral Decomposition

Abstract

We use the generalized singular value decomposition (GSVD), formulated as a comparative spectral decomposition, to model patient-matched grades III and II, i.e., lower-grade astrocytoma (LGA) brain tumor and normal DNA copy-number profiles. A genome-wide tumor-exclusive pattern of DNA copy-number alterations (CNAs) is revealed, encompassed in that previously uncovered in glioblastoma (GBM), i.e., grade IV astrocytoma, where GBM-specific CNAs encode for enhanced opportunities for transformation and proliferation via growth and developmental signaling pathways in GBM relative to LGA. The GSVD separates the LGA pattern from other sources of biological and experimental variation, common to both, or exclusive to one of the tumor and normal datasets. We find, first, and computationally validate, that the LGA pattern is correlated with a patient’s survival and response to treatment. Second, the GBM pattern identifies among the LGA patients a subtype, statistically indistinguishable from that among the GBM patients, where the CNA genotype is correlated with an approximately one-year survival phenotype. Third, cross-platform classification of the Affymetrix-measured LGA and GBM profiles by using the Agilent-derived GBM pattern shows that the GBM pattern is a platform-independent predictor of astrocytoma outcome. Statistically, the pattern is a better predictor (corresponding to greater median survival time difference, proportional hazard ratio, and concordance index) than the patient’s age and the tumor’s grade, which are the best indicators of astrocytoma currently in clinical use, and laboratory tests. The pattern is also statistically independent of these indicators, and, combined with either one, is an even better predictor of astrocytoma outcome. Recurring DNA CNAs have been observed in astrocytoma tumors’ genomes for decades, however, copy-number subtypes that are predictive of patients’ outcomes were not identified before. This is despite the growing number of datasets recording different aspects of the disease, and due to an existing fundamental need for mathematical frameworks that can simultaneously find similarities and dissimilarities across the datasets. This illustrates the ability of comparative spectral decompositions to find what other methods miss.

Scaling concepts in ’omics: nuclear lamin-B scales with tumor growth and predicts poor prognosis, whereas fibrosis can be pro-survival

“…Pearson) yield a small fraction of these genes (underlined in plot), but scaling with respect to proliferation marker MKI67 yields 153 well-fit genes, >95% of which are identical to the LMNB1 gene set ( Fig.S2c) -which underscores invertibility. To assess whether LMNB1 transcript levels relate to the number of copies of the LMNB1 gene, genomic data for each liver cancer patient was analyzed 37 , noting that copy number variations are consistent with malignancy and can predict patient survival [38][39][40][41] .…”

Mathematically universal and biologically consistent astrocytoma genotype encodes for transformation and predicts survival phenotype

“…4,5 Only recently, a copy-number genotype predictive of an astrocytoma survival phenotype was discovered and only by using the generalized singular value decomposition (GSVD) to compare patient-matched primary adult GBM and, separately, grades III and II, i.e., lower-grade astrocytoma (LGA) tumor and normal genomes, profiled by Agilent comparative genomic hybridization (CGH) and Affymetrix single nucleotide polymorphism (SNP) microarray platforms, respectively. 6,7 Note that primary GBM and LGA are different types of cancers. Their histopathologies overlap, and GBM is distinguished from LGA by the presence of necrosis or microvascular proliferation in the tumor.…”

tensorBF: an R package for Bayesian tensor factorization

“…Recently, [1] applied tensor factorization to uncover novel gene networks linked to genetic variation in an individuals × tissues × genes tensor. Tensor factorisation has also been shown useful in predicting survival outcomes in cancers using copy number data of individuals × genes × condition tensor [2]. Tensor factorizations also present a novel formulation of precision medicine.…”