Journal Article

Genomic landscape of metastatic breast cancer identifies preferentially dysregulated pathways and targets

Pant, Dhruv K., DeMichele, Angela, Pan, Tien-chi, Paul, Matt R., Solomon, Aaron, Belka, George K., Goodman, Noah G., Chodosh, Lewis A., Chen, Yan, Maxwell, Kara N., Clark, Candace, Harvey, Kyra L., Morrissette, Jennifer J.D., Feldman, Michael, Shih, Natalie N.C., Stavropoulos, S. William, Lieberman, David, Soucier-Ernst, Danielle

2020

Overview

Nearly all breast cancer deaths result from metastatic disease. Despite this, the genomic events that drive metastatic recurrence are poorly understood. We performed whole-exome and shallow whole-genome sequencing to identify genes and pathways preferentially mutated or copy-number altered in metastases compared with the paired primary tumors from which they arose. Seven genes were preferentially mutated in metastases - MYLK, PEAK1, SLC2A4RG, EVC2, XIRP2, PALB2, and ESR1 - 5 of which are not significantly mutated in any type of human primary cancer. Four regions were preferentially copy-number altered: loss of STK11 and CDKN2A/B, as well as gain of PTK6 and the membrane-bound progesterone receptor, PAQR8. PAQR8 gain was mutually exclusive with mutations in the nuclear estrogen and progesterone receptors, suggesting a role in treatment resistance. Several pathways were preferentially mutated or altered in metastases, including mTOR, CDK/RB, cAMP/PKA, WNT, HKMT, and focal adhesion. Immunohistochemical analyses revealed that metastases preferentially inactivate pRB, upregulate the mTORC1 and WNT signaling pathways, and exhibit nuclear localization of activated PKA. Our findings identify multiple therapeutic targets in metastatic recurrence that are not significantly mutated in primary cancers, implicate membrane progesterone signaling and nuclear PKA in metastatic recurrence, and provide genomic bases for the efficacy of mTORC1, CDK4/6, and PARP inhibitors in metastatic breast cancer.

• Publisher: American Society for Clinical Investigation
• Subject: Biomedical research / Biopsy / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer genetics / Cancer metastasis / Cancer therapies / Comparative analysis / Cyclin-dependent kinase 4 / Estrogen receptors / Female / Gene Expression Regulation, Neoplastic / Genomes / Genomics / Humans / Localization / Lymphatic system / Metastases / Metastasis / Mortality / Mutation / Neoplasm Metastasis / Neoplasm Proteins - biosynthesis / Neoplasm Proteins - genetics / Patients / Poly(ADP-ribose) polymerase / Progesterone / Progesterone receptors / Protein kinase A / Signal transduction / TOR protein / Treatment resistance / Tumors / Whole genome sequencing / Wnt protein / Wnt Signaling Pathway