The genomic landscape of metastasis in treatment-naïve breast cancer models


Autoři: Christina Ross aff001;  Karol Szczepanek aff001;  Maxwell Lee aff002;  Howard Yang aff002;  Tinghu Qiu aff001;  Jack Sanford aff001;  Kent Hunter aff001;  Jack D. Sanford aff001
Působiště autorů: Laboratory of Cancer Biology and Genetics, Metastasis Susceptibility Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America aff001;  Laboratory of Cancer Biology and Genetics, High-Dimension Data Analysis Group, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America aff002
Vyšlo v časopise: The genomic landscape of metastasis in treatment-naïve breast cancer models. PLoS Genet 16(5): e32767. doi:10.1371/journal.pgen.1008743
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008743

Souhrn

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, whole 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 breast cancer. For instance, we identified recurrent mutations in Kras, a known driver of colorectal and lung tumorigenesis that has not been previously implicated in breast cancer metastasis. However, in a set of in 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 metastasis-targeted therapies.

Klíčová slova:

Breast cancer – Comparative genomics – Genome annotation – Mammalian genomics – Metastasis – Metastatic tumors – Mouse models – RNA sequencing


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Genetika Reprodukční medicína

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