A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies

Rini, Brian I.; Goddard, Audrey D.; Knezevic, Dejan; Maddala, Tara; Zhou, Ming; Aydın, Hakan; Campbell, Steven C.; Elson, Paul; Koscielny, Serge; Lopatin, Margarita; Svedman, Christer; Martini, Jean-François; Williams, James A.; Verkarre, Virginie; Radulescu, C.; Neuzillet, Y.; Hemmerlé, Isabelle; Timsit, Marc Olivier; Tsiatis, Athanasios C.; Bonham, Michael; Lebrét, Thierry; Méjean, Arnaud; Escudier, Bernard

doi:10.1016/s1470-2045(15)70167-1

Cited by 229 publications

(174 citation statements)

References 41 publications

Supporting

Mentioning

161

Contrasting

Unclassified

Order By: Relevance

“…Clinical prognostic systems are commonly used and include both clinical factors and laboratory data [3, 4]. Models including molecular testing have also received much attention in the prognostication of RCC, including multi-gene expression signatures [5–7]. The most comprehensive molecular analysis to date of clear cell RCC (ccRCC), the most common RCC histologic subtype, was The Cancer Genome Atlas (TCGA) study.…”

Section: Introductionmentioning

confidence: 99%

Patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities

Haake

Brooks

Welsh

et al. 2016

Urologic Oncology: Seminars and Original Investigations

View full text Add to dashboard Cite

Purpose The 34-gene classifier, ClearCode34, identifies prognostically distinct molecular subtypes of clear cell renal cell carcinoma (ccRCC) termed ccA and ccB. The primary objective of this study was to describe clinical characteristics and comorbidities of relevance in patients stratified by ClearCode34. Patients and Methods In this retrospective analysis, 282 patients from Moffitt Cancer Center with ccRCC with gene expression analyses of the primary tumor were identified and ClearCode34 was applied to identify tumors as ccA or ccB. The medical record and institutional databases were queried to define patient characteristics, comorbidities, and outcomes. Results We validated in this external cohort the superior overall survival (OS), cancer specific survival (CSS), and recurrence-free survival of ccA patients relative to ccB patients (p<0.001). Addressing other clinical characteristics, the ccA patients were more likely to be obese (48% versus 34%, p=0.021) and diabetic (26% versus 13%, p=0.035). The ccA patients also trended towards having been more frequent users of angiotensin system inhibitors (ASIs) (71% versus 52%, p=0.055). In multivariate analyses, ccB status is independently associated with inferior CSS (HR 3.26, 95% CI 1.84–5.79) and OS (HR 2.50, 95% CI 1.53–4.08). Conclusions ClearCode34, after considering distinct patterns of comorbidities in each molecular subtype, remains a strong prognostic tool in ccRCC patients. Obesity and DM emerged as factors that may influence ccRCC phenotypes and further studies investigating the impact of these metabolic conditions functionally onto tumor biology are warranted. Additionally, use of ASI could be studied in the context of ccRCC molecular classification in future studies to better understand its impact on ccRCC outcomes.

show abstract

Section: Introductionmentioning

confidence: 99%

Patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities

Haake

Brooks

Welsh

et al. 2016

Urologic Oncology: Seminars and Original Investigations

View full text Add to dashboard Cite

show abstract

“…Furthermore, the expression of these genes may assist in improving the prognostic stratification of patients with localized ccRCC following surgery. Notably, other molecular panels such as the recurrence score and MET gene polymorphisms have been previously reported to improve prognostication of localized ccRCC [50, 51]. We could not evaluate the prognostic impact of kinase gene expression on outcomes with systemic therapy for metastatic disease because information on systemic therapy was unavailable.…”

Section: Discussionmentioning

confidence: 99%

Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets

Ghatalia¹,

Yang²,

Lasseigne³

et al. 2016

PLoS ONE

View full text Add to dashboard Cite

Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA) were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79) compared to those that did not develop metastasis for at least 2 years (n = 187). Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001). The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation.

show abstract

“…However, in routine clinical usage, no such molecule has been verified applicable and remarkable for the survival assessment of RCC patients3. It has been widely accepted that cancer immunoediting and subsequent immune escape played an important role in tumor progression12, and several recent articles also reported that the molecular signatures involving inflammation and immune response in RCC were related to patient survival and drug resistance161718. Thus, exploring the prognostic roles of these immune related molecules might help RCC patient survival prediction and new agent development.…”

Section: Discussionmentioning

confidence: 99%

Dectin-1 predicts adverse postoperative prognosis of patients with clear cell renal cell carcinoma

Liu

Bai

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Dectin-1, a classical pattern-recognition receptor, was now identified as an important regulator in immune homeostasis and cancer immunity through its extensive ligands binding functions and subsequent cytokines production. The aim of this study was to assess the clinical significance of dectin-1 expression in 290 patients with clear cell renal cell carcinoma (ccRCC) through immunohistochemistry on tissue microarrays. We found that dectin-1 was predominantly expressed on ccRCC cells, in accordance with several other online databases. Moreover, Kaplan-Meier method was conducted and high expression of tumoral dectin-1 was associated with shorter patient recurrence free survival (RFS) and overall survival (OS) (P < 0.001 for both). In multivariate analyses, tumoral dectin-1 expression was also confirmed as an independent prognostic factor for patients’ survival together with other clinical parameters (P < 0.001 for RFS and OS). After incorporating these characteristics including tumoral dectin-1 expression, two nomograms were constructed to predict ccRCC patients’ RFS and OS (c-index 0.796 and 0.812, respectively) and performed better than existed integrated models (P < 0.001 for all models comparisons). In conclusion, high tumoral dectin-1 expression was an independent predictor of adverse clinical outcome in ccRCC patients. This molecule and established nomograms might help clinicians in future decision making and therapeutic developments.

show abstract

A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies

Cited by 229 publications

References 41 publications

Patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities

Patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities

Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets

Dectin-1 predicts adverse postoperative prognosis of patients with clear cell renal cell carcinoma

Contact Info

Product

Resources

About