Genomic landscape of metastatic breast cancer identifies preferentially dysregulated pathways and targets
Matt R. Paul, … , Angela DeMichele, Lewis A. Chodosh
Matt R. Paul, … , Angela DeMichele, Lewis A. Chodosh
Published July 13, 2020
Citation Information: J Clin Invest. 2020;130(8):4252-4265. https://doi.org/10.1172/JCI129941.
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Research Article Genetics Oncology

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

Abstract

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.

Authors

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

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Figure 2

Genes preferentially mutated in metastases.

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Genes preferentially mutated in metastases. (A) Mutation frequencies for...
(A) Mutation frequencies for SMGs identified by MutSigCV2 within metastatic tumors in our cohort (red, n = 66) and primary tumors in TCGA-BRCA (blue, n = 1044). Seven SMGs, indicated in bold, have not been reported in TCGA-BRCA primary tumors across nor within subtypes. Eleven SMGs exhibited significantly higher mutation frequencies in metastases within our cohort compared with TCGA-BRCA primary tumors (2-sided Fisher’s exact test; *FDR ≤ 0.10; **FDR < 0.001). Red and orange asterisks respectively denote 3 SMGs that either lose or gain significance when less stringent filtering criteria employed in Ciriello et al. (3) are used. (B) Co-occurrence of MYLK and PEAK1 mutations with ERBB2 mutations and HER2+ status in metastases (2-sided Fisher’s exact test, *P < 0.05; **P < 0.01; FDRs = 0.07–0.36). Each column represents a metastatic tumor. (C) Kaplan-Meier survival analysis showing that TCGA-BRCA patients whose primary tumor had a mutation in MYLK exhibited shorter RFS.