Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastases

Priedigkeit, Nolan; Watters, Rebecca; Lucas, Peter C.; Basudan, Ahmed; Bhargava, Rohit; Horne, William; Kolls, Jay K.; Fang, Zhou; Rosenzweig, Margaret; Brufsky, Adam; Weiß, Kurt; Oesterreich, Steffi; Lee, Adrian V.

doi:10.1172/jci.insight.95703

Cited by 109 publications

(101 citation statements)

References 72 publications

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“…RNA-seq data ( Supplementary Table 1) underwent unsupervised hierarchical clustering of normalized RNA expression values which showed most patient matched pairs clustered transcriptionally with their matched primary-regardless of the length of disease-free survival ( Figure 1A). Unlike a previous transcriptome-wide analysis of primary breast cancers and matched bone metastases 28 , there was no significant correlation in pair transcriptional similarity and time to recurrence-although a trend towards negative correlation was observed (pearson R = -0.37, p-value = 0.236). Only a single recurrence showed marked transcriptional deviation from its matched primary (ERLR_03_R1); whereby it lost ER-positivity and gained HER2-positivity clinically.…”

Section: Expression and Copy Number Changes In Local Recurrencescontrasting

confidence: 96%

“…The most striking changes in long-term estrogen-deprived tumors; however, were highly recurrent (up to 42%), outlier expression changes. An analysis of tumors with the most recurrent outlier loss, Nearly all recurrences are more similar transcriptionally to their matched primaries than to other, long-term estrogen deprived tumors-reinforcing the notion that advanced cancers generally retain their core transcriptional programming, even after nearly a decade of dormancy [26][27][28][29] . Furthermore, amplifications and deletions of recurrences are markedly similar to primaries, supporting recent evidence from breast cancer single-cell sequencing that structural variation is likely an early event and many CNAs, even in metachronous therapy-resistant tumors, may be shared by the majority of subclones 32 .…”

Section: Discussionmentioning

confidence: 88%

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Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences

Priedigkeit

Ding

Horne

et al. 2020

Preprint

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word count: 200ABSTRACT Endocrine therapy resistance is a hallmark of advanced estrogen receptor (ER) positive breast cancer. In this study, we performed DNA/RNA hybrid-capture sequencing on 12 locoregional recurrences after long-term estrogen-deprivation along with each tumor's matched primary.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%]),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. Taken together, this study defines acquired genomic changes in long-term, estrogen-deprived disease, highlights longitudinal RNA-profiling and identifies a common endocrine-resistant breast cancer subtype with basal-like transcriptional reprogramming.

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Section: Expression and Copy Number Changes In Local Recurrencescontrasting

confidence: 96%

Section: Discussionmentioning

confidence: 88%

Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences

Priedigkeit

Ding

Horne

et al. 2020

Preprint

Self Cite

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“…Ethics approval and consent to participate were approved under the University of Pittsburgh IRE # PROIII00645, 14040193, 1500502, 1602030. Exome-capture RNA sequencing (ecRNA-seq) of patient-matched PBTs and METs collected from brain and bone were previously reported (7, 8). Ovarian and GI METs were recently reported (9).…”

Section: Methodsmentioning

confidence: 99%

Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors

Zhu

Narloch

Onkar

et al. 2019

Preprint

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34The interplay between the immune system and tumor progression is well recognized. However, 35 current human breast cancer immunophenotyping studies are mostly focused on primary tumors 36 with metastatic breast cancer lesions remaining largely understudied. To address this gap, we 37 examined exome-capture RNA sequencing data from 50 primary breast tumors (PBTs) and their 38 patient-matched metastatic tumors (METs) in brain, ovary, bone and gastrointestinal tract. We 39 used gene expression signatures as surrogates for tumor infiltrating lymphocytes (TIL) and 40 compared TIL patterns in PBTs and METs. Enrichment analysis and deconvolution methods 41 both revealed that METs have a significantly lower abundance of total immune cells, including 42 CD8+ T cells, regulatory T cells and dendritic cells. An exception was M2-like macrophages, 43 which were significantly higher in METs across the organ sites examined. Multiplex 44 immunohistochemistry results were consistent with data from the in-silico analysis and showed 45 increased macrophages in METs. We confirmed the finding of a significant reduction in immune 46 cells in brain (BRM) METs by pathologic assessment of TILs in a set of 49 patient-matched 47 pairs of PBT/BRMs . These findings indicate that METs have an overall lower infiltration of 48 immune cells relative to their matched PBTs, possibly due to immune escape. RNAseq analysis 49 suggests that the relative levels of M2-like macrophages are increased in METs, and their 50 potential role in promoting breast cancer metastasis warrants further study. 51 52 Inform software (18). The list of antibodies with catalog numbers and dilutions used provided in 129 supplementaryTable S5. 130 131 Evaluation of stromal tumor infiltrating lymphocytes (sTILs) in BRM-sTIL dataset samples. 132 H&E stained sections were manually counted for percent sTILs using standard criteria developed 133 by the international TILs working group (19). sTILs were rounded to the nearest 5% increment. 134Only the stromal compartment within the borders of invasive tumor was evaluated. TILs in zones 135 of necrosis, crushed artifacts, or normal tissue were excluded. Only mononuclear infiltrate was 136

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“…In this algorithm, the expression characteristics of specific genes in immune cells and stromal cells are analyzed to calculate immune and stromal score to predict non-tumor cell invasion. Recent reports indicate that ESTIMATE is used in the study of prostate cancer (20), breast cancer (21), and colon cancer (22). However, the characteristics of the TME evaluated by ESTIMATE were not observed in the AML.…”

Section: Introductionmentioning

confidence: 99%

Screening the Cancer Genome Atlas Database for Genes of Prognostic Value in Acute Myeloid Leukemia

et al. 2020

Front. Oncol.

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Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastases

Cited by 109 publications

References 72 publications

Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences

Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences

Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors

Screening the Cancer Genome Atlas Database for Genes of Prognostic Value in Acute Myeloid Leukemia

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