Patterns Of DNA Copy Number Alterations Research Articles

Retrospective clinical trial experimentally validates glioblastoma genome-wide pattern of DNA copy-number alterations predictor of survival.

Modeling of genomic profiles from the Cancer Genome Atlas (TCGA) by using recently developed mathematical frameworks has associated a genome-wide pattern of DNA copy-number alterations with a shorter, roughly one-year, median survival time in glioblastoma (GBM) patients. Here, to experimentally test this relationship, we whole-genome sequenced DNA from tumor samples of patients. We show that the patients represent the U.S. adult GBM population in terms of most normal and disease phenotypes. Intratumor heterogeneity affects and profiling technology and reference human genome specifics affect <1% of the classifications of the tumors by the pattern, where experimental batch effects normally reduce the reproducibility, i.e., precision, of classifications based upon between one to a few hundred genomic loci by >30%. With a 2.25-year Kaplan–Meier median survival difference, a 3.5 univariate Cox hazard ratio, and a 0.78 concordance index, i.e., accuracy, the pattern predicts survival better than and independent of age at diagnosis, which has been the best indicator since 1950. The prognostic classification by the pattern may, therefore, help to manage GBM pseudoprogression. The diagnostic classification may help drugs progress to regulatory approval. The therapeutic predictions, of previously unrecognized targets that are correlated with survival, may lead to new drugs. Other methods missed this relationship in the roughly 3B-nucleotide genomes of the small, order of magnitude of 100, patient cohorts, e.g., from TCGA. Previous attempts to associate GBM genotypes with patient phenotypes were unsuccessful. This is a proof of principle that the frameworks are uniquely suitable for discovering clinically actionable genotype–phenotype relationships.

GSVD- and tensor GSVD-uncovered patterns of DNA copy-number alterations predict adenocarcinomas survival in general and in response to platinum

More than a quarter of lung, uterine, and ovarian adenocarcinoma (LUAD, USEC, and OV) tumors are resistant to platinum drugs. Only recently and only in OV, patterns of copy-number alterations that predict survival in response to platinum were discovered, and only by using the tensor GSVD to compare Agilent microarray platform-matched profiles of patient-matched normal and primary tumor DNA. Here, we use the GSVD to compare whole-genome sequencing (WGS) and Affymetrix microarray profiles of patient-matched normal and primary LUAD, USEC, and OV tumor DNA. First, the GSVD uncovers patterns similar to one Agilent OV pattern, where a loss of most of the chromosome arm 6p combined with a gain of 12p encode for transformation. Like the Agilent OV pattern, the WGS LUAD and Affymetrix LUAD, USEC, and OV patterns are correlated with shorter survival, in general and in response to platinum. Like the tensor GSVD, the GSVD separates these tumor-exclusive genotypes from experimental inconsistencies. Second, by identifying the shorter survival phenotypes among the WGS- and Affymetrix-profiled tumors, the Agilent pattern proves to be a technology-independent predictor of survival, independent also of the best other indicator at diagnosis, i.e., stage. Third, like no other indicator, the pattern predicts the overall survival of OV patients experiencing progression-free survival, in general and in response to platinum. We conclude that comparative spectral decompositions, such as the GSVD and tensor GSVD, underlie a mathematically universal description of the relationships between a primary tumor's genotype and a patient's overall survival phenotype, which other methods miss.

Clinical Utility of Prospective Molecular Characterization in Advanced Endometrial Cancer

Advanced-stage endometrial cancers have limited treatment options and poor prognosis, highlighting the need to understand genetic drivers of therapeutic vulnerabilities and/or prognostic predictors. We examined whether prospective molecular characterization of recurrent and metastatic disease can reveal grade and histology-specific differences, facilitating enrollment onto clinical trials. We integrated prospective clinical sequencing and IHC data with detailed clinical and treatment histories for 197 tumors, profiled by MSK-IMPACT from 189 patients treated at Memorial Sloan Kettering Cancer Center. Patients had advanced disease and high-grade histologies, with poor progression-free survival on first-line therapy (PFS1). When matched for histology and grade, the genomic landscape was similar to that of primary untreated disease profiled by TCGA. Using multiple complementary genomic and mutational signature-based methods, we identified patients with microsatellite instability (MSI), even when standard MMR protein IHC staining failed. Tumor and matched normal DNA sequencing identified rare pathogenic germline mutations in BRCA2 and MLH1. Clustering the pattern of DNA copy-number alterations revealed a novel subset characterized by heterozygous losses across the genome and significantly worse outcomes compared with other clusters (median PFS1 9.6 months vs. 17.0 and 17.4 months; P = 0.006). Of the 68% of patients harboring potentially actionable mutations, 27% were enrolled to matched clinical trials, of which 47% of these achieved clinical benefit. Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis and aid treatment decision making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small overall proportion of all patients tested received investigational, genomically matched therapy as part of clinical trials.

Abstract 4267: Patterns of DNA copy-number alterations revealed by the GSVD and tensor GSVD encode for cell transformation and predict survival and response to platinum in adenocarcinomas

Abstract A quarter or more of lung, uterine, and ovarian adenocarcinoma (LUAD, USEC, and OV) tumors are resistant to platinum, the first-line systemic treatment for decades. Only recently, however, patterns of copy-number alterations (CNAs) were discovered that are predictive of OV survival, both in general and in response to platinum, and only by using a comparative spectral decomposition, the tensor generalized singular value decomposition (GSVD). We defined the tensor GSVD to extend the GSVD from two matrices to two tensors. Like the GSVD, the tensor GSVD can simultaneously identify the similar and dissimilar between two datasets recording different aspects of a single phenomenon (1, 2). In a comparison of Agilent microarray platform-matched profiles of patient-matched normal and primary, mostly high-grade OV DNA, the tensor GSVD revealed the tumor-exclusive and platform-consistent patterns across the chromosome arms 7p and Xq and the combination of 6p+12p. No other diagnostic can distinguish a shorter from a longer survival in response to platinum throughout the course of an adenocarcinoma. Here we show that the 6p+12p genotype predicts a survival phenotype in LUAD and USEC in addition to OV. We use the GSVD to compare whole-genome sequencing (WGS) and Affymetrix microarray profiles of patient-matched normal and primary LUAD and primary, mostly high-grade USEC and OV DNA. The GSVD reveals tumor-exclusive patterns of CNAs across the combination of the chromosome arms 6p+12p. We find that, first, like the Agilent OV pattern, the WGS LUAD and Affymetrix LUAD, USEC, and OV patterns identify a biologically consistent shorter survival phenotype, of approximately one and a half years median survival time in LUAD and USEC and three years in OV. Like the Agilent pattern, the WGS and Affymetrix patterns describe a biologically consistent genotype, where loss of the p21-encoding CDKN1A and p38-encoding MAPK14 on 6p, and gain of KRAS on 12p, together, but not separately, encode for human cell transformation. Second, by classifying the WGS and Affymetrix profiles, the Agilent pattern proves to be a technology-independent predictor of a LUAD, USEC, or OV patient's survival, both in general and in response to platinum. The pattern is independent of the tumor's stage, the best indicator of these adenocarcinomas at the time of initial diagnosis. Third, the pattern is a predictor of OV survival and response to platinum beyond the time of initial diagnosis and throughout the disease, even in patients experiencing remission after treatment of the primary tumor, and independent of the time to recurrence or progression. We conclude that comparative spectral decompositions, such as the GSVD and tensor GSVD, underlie a mathematically universal description of the relations between a tumor's genome and a patient's survival and response to treatment, which other methods miss.

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.

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.

Abstract A60: DNA copy-number alterations in primary ovarian serous cystadenocarcinoma encoding for cell transformation and predicting survival and response to platinum therapy throughout the course of the disease.

Abstract Purpose: To examine patterns of primary ovarian serous cystadenocarcinoma (OV) copy-number alterations (CNAs), each of which is correlated with a patient's overall survival (OS) and response to platinum-based chemotherapy at the time of initial diagnosis, over the course of the disease, i.e., in the subpopulations of patients of increasing progression-free survival (PFS) time intervals, from the end of the initial therapy targeting the primary tumor to a diagnosis of tumor recurrence or progression. The patterns of DNA CNAs, across the chromosome arms 7p and, separately, Xq, and across the combination of the two chromosome arms 6p+12p (together but not separately) were recently discovered by using DNA copy-number, i.e., genomic profiles of 249 primary OV tumors, mostly high-grade, from the Cancer Genome Atlas (TCGA) [Sankaranarayanan, Schomay, Aiello and Alter, PLoS One 10 (4), article e0121396 (2015); doi: 10.1371/journal.pone.0121396]. Segmentation of the patterns of DNA CNAs, gene ontology enrichment analyses of the corresponding differential mRNA expression, and mapping of the corresponding differential microRNA and protein expression to the DNA CNAs, linked each pattern with one of three hallmarks of cancer: DNA instability in 7p, cellular immune response suppression in Xq, and a cell's transformation and immortality in 6p+12p (where loss of the p21-encoding CDKN1A and the p38-encoding MAPK14 and gain of KRAS, together but not separately, can lead to transformation of human normal to tumor cells). Survival analyses showed and computationally validated that a combination of the three patterns makes a better predictor of OV survival than the tumor's stage, in the general as well as in the high-grade OV patient population. For &amp;gt;30 years prior, the best predictor of OV survival at the time of initial diagnosis was the tumor's stage. About 25% of primary OV tumors are resistant to platinum therapy, the first-line treatment, yet no diagnostic existed to distinguish resistant from sensitive tumors before the treatment. Methods and Results: By using survival analyses, we find and computationally validate that in the general as well as in the high-grade OV patient population, the three patterns of DNA CNAs are each statistically significantly (log-rank test P-value&amp;lt;0.05) correlated with survival and response to platinum throughout the course of the disease, independent of the primary tumor's stage and other indicators that are determined during treatment, i.e., the residual disease after surgery, the outcome of subsequent therapy, and the neoplasm status, as well as the PFS interval to tumor recurrence or progression. For example, the Kaplan-Meier (KM) median survival times of the 89 high-grade and high-stage patients in the validation set of 148 patients, that were diagnosed with tumor recurrence or progression at any time after the completion of the initial therapy, i.e., PFS&amp;gt;0 months, classified by the combination of the three patterns into three groups A, B, and C, are 72, 55, and 34 months, respectively, such that the median survival time of group A is &amp;gt;3 years greater than, and more than twice that of group C. The KM median survival times of the 56 patients among them with a PFS of &amp;gt;11 months, classified into the same groups, are 72, 58, and 45 months, respectively, such that the median survival time of group A is &amp;gt;2 years greater than that of group C. Conclusion: We find that a primary OV tumor's chromosome arm-wide DNA CNAs, across 7p, Xq, and 6p+12p, can predict a patient's survival and response to platinum beyond the time of initial diagnosis, and throughout the disease, even in patients experiencing complete remission after the treatment of the primary tumor, and independent of the time interval to tumor recurrence or progression. Citation Format: Orly Alter. DNA copy-number alterations in primary ovarian serous cystadenocarcinoma encoding for cell transformation and predicting survival and response to platinum therapy throughout the course of the disease. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A60.