RECONSTRUCTING TUMOR PHYLOGENIES FROM HETEROGENEOUS SINGLE-CELL DATA

Author:

PENNINGTON GREGORY1,SMITH CHARLES A.2,SHACKNEY STANLEY2,SCHWARTZ RUSSELL3

Affiliation:

1. Computer Science Department, Carnegie Mellon University, 4400 Fifth Ave., Pittsburgh, PA 15213, USA

2. Allegheny Singer Research Institute, Allegheny General Hospital, Pittsburgh, PA 15212, USA

3. Department of Biological Sciences, Carnegie Mellon University, 4400 Fifth Ave., Pittsburgh, PA 15213, USA

Abstract

Studies of gene expression in cancerous tumors have revealed that tumors presenting indistinguishable symptoms in the clinic can be substantially different entities at the molecular level. The ability to distinguish between these genetically distinct cancers will make possible more accurate prognoses and more finely targeted therapeutics, provided we can characterize commonly occurring cancer sub-types and the specific molecular abnormalities that produce them. We develop a new method for identifying these common tumor progression pathways by applying phylogeny inference algorithms to single-cell assays, taking advantage of information on tumor heterogeneity lost to prior microarray-based approaches. We combine this approach with expectation maximization to infer unknown parameters used in the phylogeny construction. We further develop new algorithms to merge inferred trees across different assays. We validate the expectation maximization method on simulated data and demonstrate the combined approach on a set of fluorescent in situ hybridization (FISH) data measuring cell-by-cell gene and chromosome copy numbers in a large sample of breast cancers. The results further validate the proposed computational methods by showing consistency with several previous findings on these cancers and provide novel insights into the mechanisms of tumor progression in these patients.

Publisher

World Scientific Pub Co Pte Lt

Subject

Computer Science Applications,Molecular Biology,Biochemistry

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