Genefu: an R/Bioconductor package for computation of gene expression-based signatures in breast cancer

Gendoo, Deena M.A.; Ratanasirigulchai, Natchar; Schröder, Markus; Paré, Laia; Parker, Joel S.; Prat, Aleix; Haibe‐Kains, Benjamin

doi:10.1093/bioinformatics/btv693

Cited by 281 publications

(279 citation statements)

References 16 publications

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“…The expression levels were made comparable to those of HER2-positive samples from The Cancer Genome Atlas (TCGA) 33 by using the cross-studies normalization of the R package genefu 34 (R package version 2.3.0). A merged data set was obtained by adding the renormalized NeoALTTO samples to all TCGA samples.…”

Section: Methodsmentioning

confidence: 99%

RNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy

et al. 2017

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IMPORTANCE In neoadjuvant trials, treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancers with dual HER2 blockade resulted in increased pathologic complete response (pCR) rates compared with each targeted agent alone. Amplification and/or overexpression of HER2 currently remains the only biomarker for therapeutic decisions, but it is insufficient to explain the heterogeneous response to anti-HER2 agents. OBJECTIVE To investigate the ability of clinically and biologically relevant genes and gene signatures (GSs) measured by RNA sequencing to predict the efficacy of anti-HER2 agents. DESIGN, SETTING, AND PARTICIPANTS The neoadjuvant NeoALTTO trial randomized 455 women with HER2-positive early-stage breast cancer to trastuzumab, lapatinib, or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. The present substudy, which was planned in the NeoALTTO main protocol, evaluated the association of pretreatment gene expression levels defined using RNA sequencing with pCR and event-free survival (EFS). MAIN OUTCOMES AND MEASURES Gene expression–based biomarkers using RNA sequencing were examined for their association with response to anti-HER2 therapy and long-term outcome. RESULTS Sequencing data were available for 254 (56%) of the NeoALTTO participants (mean [SD] age of substudy participants, 48.8 [11.2] years). The expression of ERBB2/HER2 was the most significant predictor of pCR, followed by HER2-enriched subtype, ESR1, treatment arm, ER immunohistochemical analysis scores, Genomic Grade Index, immune, proliferation, and AKT/mTOR GSs. Adjusting for clinicopathological variables and treatment arms, ERBB2/HER2, HER2-enriched subtype, ESR1, and Genomic Grade Index remained significant. Immune GSs were associated with higher pCR only in the combination arm (odds ratio, 2.1; 95%CI, 1.2–4.0; interaction test P = .01), while the stroma GSs were significantly associated with higher pCR in the single arms and with lower pCR in the combination arm (odds ratio, 0.46; 95%CI, 0.25–0.84; P = .009). None of the evaluated variables was associated with EFS after correction for multiple testing, but this analysis was underpowered. CONCLUSIONS AND RELEVANCE High levels of ERBB2/HER2 and low levels of ESR1 were associated with pCR in all treatment arms. In the combination arm, high expression of immune and stroma GSs were significantly associated with higher and lower pCR rates, respectively, and should be further explored as candidate predictive markers. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00553358

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Section: Methodsmentioning

confidence: 99%

RNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy

et al. 2017

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“…This resulted in a compendium comprising 3,661 unique samples from 25 independent cohorts. Intrinsic molecular subtypes were assigned using the intrinsic.cluster.predict function of genefu R package68 using the ‘50 intrinsic gene list' as proposed by Parker and colleagues (PAM50; ref. 69).…”

Section: Methodsmentioning

confidence: 99%

Glucocorticoid receptor signalling activates YAP in breast cancer

et al. 2017

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The Hippo pathway is an oncosuppressor signalling cascade that plays a major role in the control of cell growth, tissue homoeostasis and organ size. Dysregulation of the Hippo pathway leads to aberrant activation of the transcription co-activator YAP (Yes-associated protein) that contributes to tumorigenesis in several tissues. Here we identify glucocorticoids (GCs) as hormonal activators of YAP. Stimulation of glucocorticoid receptor (GR) leads to increase of YAP protein levels, nuclear accumulation and transcriptional activity in vitro and in vivo. Mechanistically, we find that GCs increase expression and deposition of fibronectin leading to the focal adhesion-Src pathway stimulation, cytoskeleton-dependent YAP activation and expansion of chemoresistant cancer stem cells. GR activation correlates with YAP activity in human breast cancer and predicts bad prognosis in the basal-like subtype. Our results unveil a novel mechanism of YAP activation in cancer and open the possibility to target GR to prevent cancer stem cells self-renewal and chemoresistance.

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“…Hierarchical clustering was performed using the heatmap.3 function (https://raw.githubusercontent.com/obigriffith/biostar-tutorials/master/Heatmaps/heatmap.3.R) in R on log2normCPM values of the top 5% most variable genes (defined by IQR) with 1 minus Pearson correlations as distance measurements and the "average" agglomeration method. PAM50 calls were generated using the molecular.subtyping function in genefu (62). A separate cohort of exome-capture RNA-sequencing expression data from primary tumors (n = 12 ER negative, 9 ER positive) was merged with the bone metastasis cohort to help account for test set bias and increase the stability of the PAM50 assignments (63).…”

Section: Methodsmentioning

confidence: 99%