Abstract

Our goal is to identify, in situ, the regulatory genes that dictate the onset age and growth rate of spontaneously arising tumors to implement new intervention strategies. For genetic linkage analysis, we crossed HER2(neu) Tg mice with Diversity Outbred (DO) mice, an outbred population comprised of 8 founding strains (A/J, C57BL/6J, 129S1/SvlmJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, WSB/EiJ) maintained by non-sibling crossing to ensure each mouse is genetically unique. Using R/QTL package, we linked Quantitative Trait Loci (QTL) in Chr 1 and X with tumor onset age, and a Chr 10 QTL with tumor growth rate. The Chr1 (=human Chr2) QTL was linked to human breast cancer diagnosis in 11 Genome-Wide Association Studies (GWAS; the human GWAS catalog, https://www.ebi.ac.uk/gwas/). Because human GWAS data is deficient in Chr X mapping and also does not assess tumor growth rate as a trait, the QTL loci identified in mouse Chr X and 10 were discoveries beyond the capacity of human GWAS. In total, we identified 26 candidate genes across the 3 QTL. For clinical validation, the genes were analyzed with CodeAI (Caris LS) which associated cancer patient clinical data with candidate gene expression. We found 21/26 genes significantly associated with the survival of patients with primary (n=3,533) and/or metastatic (n=4,870) breast cancers and 17/26 were associated with lung cancer (n=11,334) survival, with 13 overlapping genes between lung and breast cancer, indicating broad applicability of these candidate genes.