Abstract A2-64: A signature catalog to classify tumor mixtures: Application to recognition of metastatic disease in prostate cancer
Authors: Graim Kiley , Newton Yulia , Bivol Adrian , Sokolov Artem , Ellrott Kyle , Baertsch Robert , Stuart Joshua 
Published: November 2015

Abstract
Background: Molecular-based subtypes most certainly play a role in cancer progression and treatment. The recent results from the The Cancer Genome Atlas (TCGA) Pan-Cancer-12 analyses revealed connections between the cell of origin and patient outcomes. For example, bladder cancers were found to relate to three major Pan-Cancer integrative subtypes, with adeno-like and squamous-like bladder cancers associated with poorer prognosis than tumors with bladder-distinct profiles. Furthermore, both adeno-like lung and squamous-like bladder cancers were found to be associated with the most aggressive form of the disease.
Methods: We are collecting a catalog of molecular signatures for each subtype found from Pan-Cancer analyses in TCGA and from relevant external datasets. Our goal is to map every tumor sample to one or more signatures in this collection using machine-learning methods. This mapping will allow us to predict the subclonal composition of primary tumor biopsies and to compare them to inferences from the variant allele frequency analysis, shedding light on the gene expression changes associated with key events in tumor evolution.
As a pilot study, we compared signatures derived from metastatic prostate samples to subtypes of primary prostate tumors. Our goal is to test whether a molecular profile of metastatic disease can be recognized early on in primary tumors. To do so, we used unsupervised classification of mRNA expression profiles to define clusters of metastatic disease from external datasets as well as separately for primary tumors including the TCGA prostate adenocarcinoma dataset. We then performed an all-against-all comparison of signatures derived from metastatic subtypes to signatures derived from primary tumor subtypes.
Results: The majority of metastatic tumors are most closely associated with one out of four primary subtypes, suggesting we have identified a possible primary signature associated with more aggressive disease. The finding is supported by enrichment analysis of clinical variables in the primary subtypes. Specifically, the primary subtype most often associated with the metastatic tumors have higher Gleason scores and higher tumor grade. In addition, several molecular pathways (e.g. BioCarta Vitamin D Receptor and KEGG Integrins in Angiogenesis pathways) and genes (e.g. MMP9, FGA, and LYZ) were found to be associated with the location of metastasis.
Conclusions: Training molecular subtype recognizers may hold promise for detecting minor populations of subclones in primary and metastatic tumors. The subclone decomposition can be used to detect the presence of more aggressive disease that may resist standard treatment regimens. We are now expanding our signature catalog to include a more comprehensive collection and applying to additional subtypes of interest. We will make all datasets and signatures available through a mature version of the UCSC TumorMap portal.
Citation Format: Kiley Graim, Yulia Newton, Adrian Bivol, Artem Sokolov, Kyle Ellrott, Robert Baertsch, Joshua Stuart. A signature catalog to classify tumor mixtures: Application to recognition of metastatic disease in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-64.