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UID:submissions.supercomputing.org_SC22_sess432_ws_cafcw110@linklings.com
SUMMARY:Mathematical Discovery and Computational Validation of Two Orthogo
 nal Mechanistically-Driven Whole-Genome Genotype–Survival Phenotype Relati
 onships in Pediatric Neuroblastoma Nerve Cancer
DESCRIPTION:Workshop\n\nMathematical Discovery and Computational Validatio
 n of Two Orthogonal Mechanistically-Driven Whole-Genome Genotype–Survival 
 Phenotype Relationships in Pediatric Neuroblastoma Nerve Cancer\n\nAlter, 
 Ponnapalli\n\nPrediction, together with understanding and management, of p
 ediatric neuroblastoma (NBL) outcomes, from spontaneous regression to rela
 pse and death, remain limited, and rely mostly on age, stage, and the one-
 gene test for MYCN amplification, none of which are NBL specific. Here, we
  use the generalized singular value decomposition (GSVD), formulated as a 
 multi-tensor decomposition [1], to model whole genomes of patient-matched 
 NBL and blood DNA. The GSVD discovers two orthogonal genome-wide patterns 
 of copy-number alterations (CNAs) in the tumors that are correlated with s
 urvival. First, as in previous, experimentally validated, models of, e.g.,
  adult brain astrocytoma [2], one pattern is exclusive to the tumors. Prev
 iously unseen is a pattern that is common to both the blood and tumor geno
 mes. Second, both patterns predict survival better than and independent of
  the existing predictors as well as independent of each other. In both pat
 terns, differential RNA expression consistently map to the DNA CNAs. Third
 , the GSVD separates these patterns from normal variations that are conser
 ved in the tumors but do not predict outcome, e.g., the male-specific X-ch
 romosome deletion relative to the autosome. We computationally validate bo
 th patterns by using – and demonstrating for the first time – the pseudoin
 verse projection for transfer learning from the ≈3M-bin whole-genome to ≈1
 0K-bin target-capture sequencing profiles of a mutually-exclusive set of p
 atients [3]. We show that the two patterns describe independent, yet compl
 ementary cellular mechanisms that transform human normal to tumor cells, p
 redict new personalized therapies, and may predict the response to existin
 g therapies. The tumor-exclusive pattern includes co-occurrence of MYCN am
 plification with previously unrecognized druggable CNAs, including amplifi
 cations of genes encoding for extra-embryonic transcripts, to jointly pred
 ict survival. The pattern that is common to the blood and tumor genomes de
 scribes an earlier stage in NBL development, where the embryonic program i
 s hijacked toward aneuploidy and where the subsequent tumor development ca
 n spontaneously regress via embryonic self-correction.\n[1] M. W. Bradley,
  K. A. Aiello, S. P. Ponnapalli,* H. A. Hanson* and O. Alter, "GSVD- and T
 ensor GSVD-Uncovered Patterns of DNA Copy-Number Alterations Predict Adeno
 carcinomas Survival in General and in Response to Platinum," Applied Physi
 cs Letters (APL) Bioengineering 3 (3), article 036104 (August 2019); https
 ://doi.org/10.1063/1.5099268\n[2] S. P. Ponnapalli, M. W. Bradley, K. Devi
 ne, J. Bowen, S. E. Coppens, K. M. Leraas, B. A. Milash, F. Li, H. Luo, S.
  Qiu, K. Wu, H. Yang, C. T. Wittwer, C. A. Palmer, R. L. Jensen, J. M. Gas
 tier-Foster, H. A. Hanson, J. S. Barnholtz-Sloan and O. Alter, "Retrospect
 ive Clinical Trial Experimentally Validates Glioblastoma Genome-Wide Patte
 rn of DNA Copy-Number Alterations Predictor of Survival," Applied Physics 
 Letters (APL) Bioengineering 4 (2), article 026106 (May 2020); https://doi
 .org/10.1063/1.5142559\n[3] O. Alter and G. H. Golub, "Integrative Analysi
 s of Genome-Scale Data by Using Pseudoinverse Projection Predicts Novel Co
 rrelation between DNA Replication and RNA Transcription," Proceedings of t
 he National Academy of Sciences (PNAS) USA 101 (47), pp. 16577–16582 (Nove
 mber 2004); https://doi.org/10.1073/pnas.0406767101\n\nSession Format: Rec
 orded\n\nRegistration Category: Workshop Reg Pass
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