In:
Breast Cancer Research, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2021-12)
Abstract:
Endocrine therapy resistance is a hallmark of advanced estrogen receptor (ER)-positive breast cancer. In this study, we aimed to determine acquired genomic changes in endocrine-resistant disease. Methods We performed DNA/RNA hybrid-capture sequencing on 12 locoregional recurrences after long-term estrogen deprivation and identified acquired genomic changes versus each tumor’s matched primary. Results Despite being up to 7 years removed from the primary lesion, most recurrences harbored similar intrinsic transcriptional and copy number profiles. Only two genes, AKAP9 and KMT2C , were found to have single nucleotide variant (SNV) enrichments in more than one recurrence. Enriched mutations in single cases included SNVs within transcriptional regulators such as ARID1A , TP53 , FOXO1 , BRD1 , NCOA1 , and NCOR2 with one local recurrence gaining three PIK3CA mutations. In contrast to DNA-level changes, we discovered recurrent outlier mRNA expression alterations were common—including outlier gains in TP63 ( n = 5 cases [42%]), NTRK3 ( n = 5 [42%]), NTRK2 ( n = 4 [33%]), PAX3 ( n = 4 [33%]), FGFR4 ( n = 3 [25%]), and TERT ( n = 3 [25%]) . Recurrent losses involved ESR1 ( n = 5 [42%]), RELN ( n = 5 [42%]), SFRP4 ( n = 4 [33%]), and FOSB ( n = 4 [33%]). ESR1- depleted recurrences harbored shared transcriptional remodeling events including upregulation of PROM1 and other basal cancer markers. Conclusions Taken together, this study defines acquired genomic changes in long-term, estrogen-deprived disease; highlights the importance of longitudinal RNA profiling; and identifies a common ESR1- depleted endocrine-resistant breast cancer subtype with basal-like transcriptional reprogramming.
Type of Medium:
Online Resource
ISSN:
1465-542X
DOI:
10.1186/s13058-020-01379-3
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2021
detail.hit.zdb_id:
2041618-0
Permalink