Analysis of RSPO gene expression in solid tumors.
2016; Lippincott Williams & Wilkins; Volume: 34; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2016.34.15_suppl.e23235
ISSN1527-7755
AutoresAna Vivancos, Héctor G. Pálmer, Zighereda Ogbah, Judit Matito, Francesco M. Mancuso, Alejandro Navarro, Alex Martinez Marti, Guillem Argilés, Elena Élez, Jordi Rodón, Paolo Nucíforo, Josep Tabernero, Enriqueta Felip,
Tópico(s)Cancer-related Molecular Pathways
Resumoe23235 Background: It is well recognized that mutations in downstream components of the canonical Wnt pathway (e.g. APCand beta-catenin) can contribute to tumorigenesis. Recently, genetic alterations in upstream regulators of the Wnt pathway, such as RNF43 and R-spondins, have also been implicated in tumorigenesis. RNF43 and its homolog ZNRF3 are E3 ubiquitin ligases that promote the degradation of the frizzled family of Wnt receptors. R-spondins, in turn, are secreted proteins that interact with LGR4/5 receptors to promote membrane clearance of RNF43 and ZNRF3. Thereby, R-spondins act as agonists of the pathway. Gene fusions involving R-spondin family members RSPO2 and RSPO3 have been reported to occur in 10% of colon cancer. The gene fusions identified so far promote the acquisition of a strong promoter upstream of the RSPO2 and RSPO3 genes, increasing the levels of transcription. We profiled gene expression of the RSPO1-4 genes in solid tumors and compared to the levels detected in RSPO2/3-fused samples. Methods: We developed a custom codeset with nCounter (Nanostring) technology with probes for the RSPO1-4 genes as well as RSPO2-3 gene fusions. We analyzed FFPE samples from 190 solid tumor of patients that were candidates to clinical trials, as part of our prescreening program. Results: The cohort was composed of colorectal (n = 29), NSCLC (n = 54, adenocarcinoma (ADC) n = 10), breast (n = 21), brain (n = 18), cholangiocarcinoma (n = 17), thyroid (n = 13), bladder (n = 13), urological (n = 5) and a group of rare cancer types. As expected, most samples showed very low expression of any RSPO. However, a subgroup of them presented significantly higher levels of expression. In particular, for RSPO3, 50% of NSCLC ADC (n = 5) and 20% of CRC (n = 6) tumors were particularly positive. Of them, 3 CRC were RSPO3 fused, as confirmed by qRT-PCR. We also detected RSPO4 overexpression only in NSCLC samples (n = 5, 10%). Additional outlier cases of brain, bladder or thyroid tumors show high RSPO expression. Conclusions: These data highlight that a subset of NSCLC shows high expression of different RSPOs, even higher than RSPO3 fusion-positive CRC tumors. Altogether, some lung cancer patients could benefit from targeted anti-WNT treatments, as is the case for CRC.
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