New Tools For Mapping Genetic Modifiers Of Cancer Risk In The Tumor Microenvironment

The majority of heritable breast cancer risk is unknown. One potential source of “missing heritability” is genetic modifiers in the tumor microenvironment (TME). Although genetic modifiers in the TME have long been suspected, they have rarely been studied and are largely unknown. Here, we used two new techniques: the Consomic Xenograft Model (CXM) and species-specific RNA-seq (SSRS) to map genetic modifiers in the TME. In CXM, human breast cancer xenografts are implanted in immunodeficient consomic rat strains and tracked for tumor progression. Because the rat strains vary by one chromosome (i.e., consomic), whereas the malignant tumor cells do not differ, any observed changes in tumor phenotypes are due to genetic modifiers in the TME and can be localized to one chromosome. The SSRS method uses probabilistic mapping of RNAseq reads to a joint human and rat transcriptome to assess differential expression (DE) in malignant (human) tumor cells and the nonmalignant (rat) TME. Validation of SSRS revealed u003e99.4% specificity in calling human or rat reads, which was significantly better than conventional RNA-seq. Using CXM, we found that BN-derived genetic variant(s) on rat chromosome 3 significantly reduced growth of MDA-MB-231-Luc (231Luc+) tumors by 49% (P 4-fold; P Citation Format: Michael J. Flister, Alexander Stoddard, Shirng-Wern Tsaih, Angela Lemke, Jozef Lazar, Howard Jacob. New tools for mapping genetic modifiers of cancer risk in the tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr PR08.