Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer

Siegel, Marni B.; He, Xiaping; Hoadley, Katherine A.; Hoyle, Alan P.; Pearce, Julia B.; Garrett, Amy; Kumar, Sunil; Moylan, Vincent; Brady, Claudia; Swearingen, Amanda E.D. Van; Marron, David; Gupta, Gaorav P.; Thorne, Leigh B.; Kieran, Niamh E.; Livasy, Chad; Mardis, Elaine R.; Parker, Joel S.; Chen, Mengjie; Anders, Carey K.; Carey, Lisa A.; Perou, Charles M.

doi:10.1172/jci96153

Cited by 135 publications

(133 citation statements)

References 70 publications

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…We performed a literature review to identify cohorts with genomic sequencing data from matched normals, primary tumors (P) and metastases (M) from patients with three common cancer types, namely, colorectal 16,17,[19][20][21][22] , lung 23,24 and breast 23,[25][26][27][28][29] (Table S1, Fig. S1).…”

Section: The Landscape Of Genomic Alterations In Paired Primary Tumormentioning

confidence: 99%

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

et al. 2019

Preprint

View full text Add to dashboard Cite

Metastasis is the primary cause of cancer-related deaths, but the natural history, clonal evolution and patterns of systemic spread are poorly understood. We analyzed exome sequencing data from 458 paired primary tumors (P) or metastasis (M) samples from 136 breast, colorectal and lung cancer patients, including both untreated (n=98) and treated (n=101) metastases. We find that treated metastases often harbored private driver gene mutations whereas untreated metastases did not, suggesting that treatment promotes clonal evolution. Polyclonal seeding was common in lymph node metastases (n=19/35, 54%; mostly untreated) and untreated distant metastases (n=20/70, 29%), but less frequent in treated metastases (n=9/90, 10%). The low number of metastasis-private clonal mutations is consistent with early metastatic seeding, which commonly occurred several years prior to diagnosis in breast (2.4 years, range 0−3.3), lung (3.6 years, range 2.8 − 3.7) and colorectal (4.1 years, range 3.1 − 4.6) cancers. Thus, this pan-cancer analysis reveals early systemic spread in three common cancer types. Further, these data suggest that the natural course of metastasis is selectively relaxed relative to early tumor development and that metastasis-private mutations are not drivers of cancer spread but are instead associated with drug resistance.

show abstract

Section: The Landscape Of Genomic Alterations In Paired Primary Tumormentioning

confidence: 99%

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…To date several approaches for RNA-seq mutation calling, mostly in combination with matched DNA, have been developed [77,78,79,80,81,82], however calling from RNA-seq alone, particularly from tumor-only samples, is still a challenge. With the advance of targeted and whole exome sequencing into the clinics, and efforts such as TCGA, MSK-Impact, and others, variant calling from DNA-seq has improved in recent years.…”

Section: Discussionmentioning

confidence: 99%

The Mutational Landscape of the SCAN-B Real-World Primary Breast Cancer Transcriptome

Brueffer

Gladchuk

Winter

et al. 2020

Preprint

View full text Add to dashboard Cite

Breast cancer is a disease of genomic alterations, of which the complete panorama of somatic mutations and how these relate to molecular subtypes and therapy response is incompletely understood. Within the Sweden Cancerome Analysis Network-Breast project (SCAN-B; ClinicalTrials.gov NCT02306096), an ongoing study elucidating the tumor transcriptomic profiles for thousands of breast cancers prospectively, we developed an optimized pipeline for detection of single nucleotide variants and small insertions and deletions from RNA sequencing (RNA-seq) data, and profiled a large real-world population-based cohort of 3,217 breast tumors. We use it to describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population-based cohort of patients, and relate it to patient overall survival. We demonstrate that RNA-seq can be used to call mutations in important breast cancer genes such as PIK3CA, TP53, and ERBB2, as well as the status of key molecular pathways and tumor mutational burden, and identify potentially druggable genes in 86.8% percent of tumors. To make this rich and growing mutational portraiture of breast cancer available for the wider research community, we developed an open source web-based application, the SCAN-B MutationExplorer, accessible at http://oncogenomics.bmc.lu.se/MutationExplorer. These results add another dimension to the use of RNA-seq as a potential clinical tool, where both gene expression-based and gene mutation-based biomarkers can be interrogated simultaneously and in real-time within one week of tumor sampling. and sampling of tissue for this study. We also thank the Swedish National Breast Cancer Registry and Regional Cancer Center South for clinical data. The SweGen allele frequency data was generated

show abstract

“…Due to an established role of OXPHOS in TNBC metastasis in pre-clinical models (26), we next examined the expression of candidate OXPHOS genes in the breast cancer patient dataset GSE110590 (27). We analyzed the absolute expression values of RNA derived from RNA sequence normalized counts (RSEM) from matched primary breast cancer, brain metastases and lung metastases (n=6 for lung metastases, n=5 for brain metastases).…”

Section: Marizomib Reduces Spontaneous Metastasis In Murine Tnbc Modementioning

confidence: 99%

Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

Raninga

Lee

Sinha

et al. 2019

Preprint

View full text Add to dashboard Cite

AbstractLacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive with development of metastasis especially brain, and remains clinically challenging breast cancer subtype to treat. Despite the survival dependency on the proteasome pathway genes, FDA-approved proteasome inhibitors induced minimal clinical response in breast cancer patients due to weak proteasome inhibition. Here, we show that a potent proteasome inhibitor Marizomib (Mzb) inhibits multiple proteasome catalytic activities and induces a better anti-tumor response in TNBC cell lines and patient-derived xenografts alone and in combination with the standard-of-care chemotherapy. Mechanistically, Mzb inhibits oxidative phosphorylation (OXPHOS) via PGC-1α suppression in conjunction with proteasome inhibition in TNBC cells. Mzb reduces lung and brain metastases by reducing the number of circulating tumor cells and the expression of multiple genes involved in the epithelial-to-mesenchymal transition. Furthermore, Mzb-induced OXPHOS inhibition upregulates glycolysis to meet the energetic demands of TNBC cells and, hence, combined inhibition of glycolysis with Mzb exposure leads to a synergistic anti-cancer activity. Collectively, our data provide a strong rationale for a clinical evaluation of Mzb in primary and metastatic TNBC patients.One Sentence SummaryMarizomib inhibits primary tumor growth, and also reduces lung and brain metastases in pre-clinical models of triple-negative breast cancer.

show abstract

Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer

Cited by 135 publications

References 70 publications

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

The Mutational Landscape of the SCAN-B Real-World Primary Breast Cancer Transcriptome

Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

Contact Info

Product

Resources

About