FGFR3, HRAS, KRAS, NRAS and PIK3CA Mutations in Bladder Cancer and Their Potential as Biomarkers for Surveillance and Therapy

Kompier, Lucie C.; Lurkin, Irene; Aa, Madelon N.M. van der; Rhijn, Bas W.G. van; Kwast, Theodorus H. van der; Zwarthoff, Ellen C.

doi:10.1371/journal.pone.0013821

Cited by 275 publications

(236 citation statements)

References 82 publications

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“…62 FGFR3 and PIK3CA mutations are present in a subset of invasive urothelial cancers, 63,64 and we found PIK3CA mutations in 14% of PCMR colorectal cancers.…”

Section: Discussionmentioning

confidence: 53%

Multiplex Mutation Screening by Mass Spectrometry

Beadling

Heinrich

Warrick

et al. 2011

The Journal of Molecular Diagnostics

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There is an immediate and critical need for a rapid, broad-based genotyping method that can evaluate multiple mutations simultaneously in clinical cancer specimens and identify patients most likely to benefit from targeted agents now in use or in late-stage clinical development. We have implemented a prospective genotyping approach to characterize the frequency and spectrum of mutations amenable to drug targeting present in urothelial, colorectal, endometrioid, and thyroid carcinomas and in melanoma. Cancer patients were enrolled in a Personalized Cancer Medicine Registry that houses both clinical information and genotyping data, and mutation screening was performed using a multiplexed assay panel with mass spectrometry-based analysis to detect 390 mutations across 30 cancer genes. Formalin fixed, paraffin-embedded specimens were evaluated from 820 Registry patients. The genes most frequently mutated across multiple cancer types were BRAF, PIK3CA, KRAS, and NRAS. Less common mutations were also observed in AKT1, CTNNB1, FGFR2, FGFR3, GNAQ, HRAS, and MAP2K1. Notably, 48 of 77 PIK3CA-mutant cases (62%) harbored at least one additional mutation in another gene, most often KRAS. Among melanomas, only 54 of 73 BRAF mutations (74%) were the V600E substitution. These findings demonstrate the diversity and complexity of mutations in druggable targets among the different cancer types and underscore the need for a broadspectrum, prospective genotyping approach to personalized cancer medicine. The identification of somatic mutations that cause aberrant activation of intracellular signaling pathways has transformed the diagnosis and treatment of cancer. Mutations in specific genes define distinct subtypes of cancer, and provide invaluable markers for disease diagnosis and prognosis. Many of the mutated proteins also represent targets for novel therapeutic agents that are more specific, more efficacious, and less toxic than broad-based chemotherapeutic regimens.1-5 Indeed, matching the right drug to the right cancer genotype is a proven model for improving treatment and outcome in patients with chronic myelogenous leukemia (CML), nonsmall-cell lung carcinoma (NSCLC), gastrointestinal stromal tumor (GIST), colorectal carcinoma, and, most recently, malignant melanoma. 2,5-16The major successes from this therapeutic approach have been in diseases in which there is limited molecular heterogeneity, with all or most cases having a drug-sensitive mutation. Prime examples include BCR-ABL in CML 9 and KIT in GIST. 3,7 There is increasing evidence that many common cancers similarly harbor potentially druggable targets, albeit at relatively lower frequencies. For example, subsets of NSCLC have oncogenic mutations in EGFR, KRAS, BRAF, PIK3CA, or HER2 or a translocation involving the ALK gene. [17][18][19] In the more molecularly heterogeneous cancers, mutations in proteins other than the intended therapeutic target can profoundly affect response to therapy. Thus, in the case of EGFR inhibitor therapy in lung and colon cancer, KRAS and B...

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“…62 FGFR3 and PIK3CA mutations are present in a subset of invasive urothelial cancers, 63,64 and we found PIK3CA mutations in 14% of PCMR colorectal cancers.…”

Section: Discussionmentioning

confidence: 53%

Multiplex Mutation Screening by Mass Spectrometry

Beadling

Heinrich

Warrick

et al. 2011

The Journal of Molecular Diagnostics

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“…We determined the frequencies of A→T transversion events at the second nucleotide of the HRAS codon 61 ( 5′ CAG) and at the first nucleotide of the FGFR3 codon 373 ( 5′ AGT), nonsynonymous mutations that activate these oncogenes in urothelial tumors (17,18). These frequencies (Table S2) were compared with those for urothelial carcinomas in the COS-MIC database (http://www.sanger.ac.uk/genetics/CGP/cosmic).…”

Section: Resultsmentioning

confidence: 99%

Aristolochic acid-associated urothelial cancer in Taiwan

Chen

Dickman

Moriya³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

356

391

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Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53 mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of 5′ AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.upper urinary tract carcinoma | traditional Chinese medicine | transitional cell carcinoma | DNA damage | herbal medicine

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“…This is consistent with several genetic profiling studies. FGFR and RAS mutations are mutually exclusive in bladder cancer and endometrial cancer (26,27); in contrast, FGFR mutations are frequently associated with mutations in the PI3K/AKT pathway (26,27). Conversely, when an FGFR-altered cancer also carries a KRAS mutation, FGFR inhibitors are ineffective (28), suggesting that FGFR and RAS likely activate the same pathway.…”

Section: Discussionmentioning

confidence: 99%

ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor

Nakanishi¹,

Mizuno²,

Sase³

et al. 2015

Molecular Cancer Therapeutics

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Drugs that target specific gene alterations have proven beneficial in the treatment of cancer. Because cancer cells have multiple resistance mechanisms, it is important to understand the downstream pathways of the target genes and monitor the pharmacodynamic markers associated with therapeutic efficacy. We performed a transcriptome analysis to characterize the response of various cancer cell lines to a selective fibroblast growth factor receptor (FGFR) inhibitor (CH5183284/Debio 1347), a mitogen-activated protein kinase kinase (MEK) inhibitor, or a phosphoinositide 3-kinase (PI3K) inhibitor. FGFR and MEK inhibition produced similar expression patterns, and the extracellular signal-regulated kinase (ERK) gene signature was altered in several FGFR inhibitor-sensitive cell lines. Consistent with these findings, CH5183284/Debio 1347 suppressed phospho-ERK in every tested FGFR inhibitor-sensitive cell line. Because the mitogen-activated protein kinase (MAPK) pathway functions downstream of FGFR, we searched for a pharmacodynamic marker of FGFR inhibitor efficacy in a collection of cell lines with the ERK signature and identified dual-specificity phosphatase 6 (DUSP6) as a candidate marker. Although a MEK inhibitor suppressed the MAPK pathway, most FGFR inhibitor-sensitive cell lines are insensitive to MEK inhibitors and we found potent feedback activation of several pathways via FGFR. We therefore suggest that FGFR inhibitors exert their effect by suppressing ERK signaling without feedback activation. In addition, DUSP6 may be a pharmacodynamic marker of FGFR inhibitor efficacy in FGFR-addicted cancers.

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FGFR3, HRAS, KRAS, NRAS and PIK3CA Mutations in Bladder Cancer and Their Potential as Biomarkers for Surveillance and Therapy

Cited by 275 publications

References 82 publications

Multiplex Mutation Screening by Mass Spectrometry

Multiplex Mutation Screening by Mass Spectrometry

Aristolochic acid-associated urothelial cancer in Taiwan

ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor

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