The genomic landscape of metastasis in treatment-na ïve breast cancer models

by Christina Ross, Karol Szczepanek, Maxwell Lee, Howard Yang, Tinghu Qiu, Jack Sanford, Kent Hunter Metastasis remains the principle cause of mortality for breast cancer and presents a critical challenge because secondary lesions are often refractory to conventional treatments. While specific genetic alterations are tightly linked to primary tumor development and progression, the role of genetic alteration in the metastatic process is not well-understood. The theory of tumor evolution postulated by Peter Nowell in 1976 has yet to be proven in the context of metastasis. Therefore, in order to investigate how somatic evolution contributes to breast cancer metastasis, we performed exome, whol e genome, and RNA sequencing of matched metastatic and primary tumors from pre-clinical mouse models of breast cancer. Here we show that in a treatment-naïve setting, recurrent single nucleotide variants and copy number variation, but not gene fusion events, play key metastasis-driving roles in bre ast cancer. For instance, we identified recurrent mutations inKras, a known driver of colorectal and lung tumorigenesis that has not been previously implicated in breast cancer metastasis. However, in a set ofin vivo proof-of-concept experiments we show that the Kras G12D mutation is sufficient to significantly promote metastasis using three syngeneic allograft models. The work herein confirms the existence of metastasis-driving mutations and presents a novel framework to identify actionable m...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research