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Mol Cancer Res. 2019 Feb;17(2):457-468. doi: 10.1158/1541-7786.MCR-18-0946. Epub 2018 Oct 24.

Frequent ESR1 and CDK Pathway Copy-Number Alterations in Metastatic Breast Cancer.

Author information

1
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
2
Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
3
Department of Clinical Lab Sciences, King Saud University, Riyadh, Saudi Arabia.
4
School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
5
Foundation Medicine, Cambridge, Massachusetts.
6
Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
7
Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
8
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
9
Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, Pennsylvania.
10
Magee-Women Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania.
11
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
12
Department of Surgical Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania.
13
Charité-Universitätsmedizin Berlin, Berlin, Germany.
14
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
15
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
16
Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania. oesterreichs@upmc.edu.

Abstract

: DNA sequencing has identified a limited number of driver mutations in metastatic breast cancer beyond single base-pair mutations in the estrogen receptor (ESR1). However, our previous studies and others have observed that structural variants, such as ESR1 fusions, may also play a role. Therefore, we expanded upon these observations by performing a comprehensive and highly sensitive characterization of copy-number (CN) alterations in a large clinical cohort of metastatic specimens. NanoString DNA hybridization was utilized to measure CN gains, amplifications, and deletions of 67 genes in 108 breast cancer metastases, and in 26 cases, the patient-matched primary tumor. For ESR1, a copyshift algorithm was applied to identify CN imbalances at exon-specific resolution and queried large data sets (>15,000 tumors) that had previously undergone next-generation sequencing (NGS). Interestingly, a subset of ER+ tumors showed increased ESR1 CN (11/82, 13%); three had CN amplifications (4%) and eight had gains (10%). Increased ESR1 CN was enriched in metastatic specimens versus primary tumors, and this was orthogonally confirmed in a large NGS data set. ESR1-amplified tumors showed a site-specific enrichment for bone metastases and worse outcomes than nonamplified tumors. No ESR1 CN amplifications and only one gain was identified in ER- tumors. ESR1 copyshift was present in 5 of the 11 ESR1-amplified tumors. Other frequent amplifications included ERBB2, GRB7, and cell-cycle pathway members CCND1 and CDK4/6, which showed mutually exclusivity with deletions of CDKN2A, CDKN2B, and CDKN1B. IMPLICATIONS: Copy-number alterations of ESR1 and key CDK pathway genes are frequent in metastatic breast cancers, and their clinical relevance should be tested further.

PMID:
30355675
PMCID:
PMC6359977
[Available on 2020-02-01]
DOI:
10.1158/1541-7786.MCR-18-0946

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