Sequence analysis of<i><scp>RAS</scp></i>and<i><scp>RAF</scp></i>mutation hot spots in canine carcinoma

Mochizuki, Hiroyasu; Breen, Matthew

doi:10.1111/vco.12275

Cited by 22 publications

(29 citation statements)

References 54 publications

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“…We further investigated these results using RFLP assays on all allele (see Appendix S1), consistent with a previous report showing low frequency of this oncogenic mutation in this tumour type. 24 The presence of a somatic HRAS p.Q61R mutation in 94% of the CAA tumour samples analysed in this study, combined with pathogenic similarities between CAA and AM, strongly implicate conserved oncogenic molecular mechanisms between canine and human cancers.…”

Section: Polya+mentioning

confidence: 62%

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Ultra‐frequent HRAS p.Q61R somatic mutation in canine acanthomatous ameloblastoma reveals pathogenic similarities with human ameloblastoma

Peralta

McCleary‐Wheeler

Duhamel

et al. 2019

Vet Comparative Oncology

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Ameloblastoma is a locally aggressive odontogenic tumour that occurs in humans and dogs. Most ameloblastomas (AM) in humans harbour mutually‐exclusive driving mutations in BRAF, HRAS, KRAS, NRAS or FGFR2 that activate MAPK signalling, and in SMO that activates Hedgehog signalling. The remarkable clinical and histological similarities between canine acanthomatous ameloblastoma (CAA) and AM suggest they may harbour similar driving mutations. In this study, aimed at characterizing the mutational status of SMO, BRAF, HRAS, KRAS, NRAS and FGFR2 in CAA, we used RNA sequencing, Sanger sequencing and restriction fragment length polymorphism assays to demonstrate that 94% of CAA (n = 16) harbour a somatic HRAS p.Q61R mutation. The similarities in MAPK‐activating mutational profiles between CAA and AM implicate conserved molecular mechanisms of tumorigenesis, thus, qualifying the dog as a potentially useful model of disease. Given the relevance of RAS mutations in the pathogenesis of odontogenic tumours and other types of cancer, the results of this study are of comparative, translational, and veterinary value.

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Section: Polya+mentioning

confidence: 62%

“…All OSCC samples had wild‐type HRAS alleles, except case No. 22 which showed an HRAS p.Q61L allele (see Appendix S1), consistent with a previous report showing low frequency of this oncogenic mutation in this tumour type …”

Section: Clinical Information and Hras Mutation Status Of Dogs Includmentioning

confidence: 87%

Ultra‐frequent HRAS p.Q61R somatic mutation in canine acanthomatous ameloblastoma reveals pathogenic similarities with human ameloblastoma

Peralta

McCleary‐Wheeler

Duhamel

et al. 2019

Vet Comparative Oncology

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“…In canine tumors, the BRAF V588E variant has been identified in canine bladder carcinoma (67%), prostatic carcinoma (80%), pulmonary carcinoma (6%), oral squamous cell carcinoma (11%), melanoma (6%) and melanocytoma (17%), glioma (15%), and peripheral nerve sheath tumors (22%; refs. [34][35][36][37][38]. Previous studies exploring canine melanomas have identified the NRAS Q61R mutation in the Jones cell line (33,39) and indicated that canine melanomas have activating NRAS/KRAS/HRAS mutations in 24% of samples (33).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies exploring canine melanomas have identified the NRAS Q61R mutation in the Jones cell line (33,39) and indicated that canine melanomas have activating NRAS/KRAS/HRAS mutations in 24% of samples (33). Activating KRAS and NRAS mutations have also been identified in 17% of canine pulmonary carcinomas (38), 58% of acute myelogenous leukemia samples, and NRAS mutations were identified in 14% of acute lymphocytic leukemias (40) while KRAS mutations have been identified in 1 of 14 gastric carcinomas (41), and 4 of 5 pancreatic carcinomas (42). We found activating KRAS or NRAS mutations in 2 of the 6 melanoma lines and 5 of the 33 cell lines including two osteosarcoma cell lines and a bladder carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Identifying Candidate Druggable Targets in Canine Cancer Cell Lines Using Whole-Exome Sequencing

Das

Idate

Cronise

et al. 2019

Molecular Cancer Therapeutics

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Cancer cell culture has been a backbone in cancer research, in which analysis of human cell line mutational profiles often correlates with oncogene addiction and drug sensitivity. We have conducted whole-exome sequence analyses on 33 canine cancer cell lines from 10 cancer types to identify somatic variants that contribute to pathogenesis and therapeutic sensitivity. A total of 66,344 somatic variants were identified. Mutational load ranged from 15.79 to 129.37 per Mb, and 13.2% of variants were located in protein-coding regions (PCR) of 5,085 genes. PCR somatic variants were identified in 232 genes listed in the Cancer Gene Census (COSMIC). Cross-referencing variants with human driving mutations on cBioPortal identified 61 variants as candidate cancer drivers in 30 cell lines. The most frequently mutated cancer driver was TP53 (15 mutations in 12 cell lines). No drivers were identified in three cell lines. We identified 501 non-COSMIC genes with PCR variants that functionally annotate with COSMIC genes. These genes frequently mapped to the KEGG MAPK and PI3K-AKT pathways. We evaluated the cell lines for ERK1/2 and AKT (S473) phosphorylation and sensitivity to the MEK1/2 inhibitor, trametinib. Twelve of the 33 cell lines were trametinibsensitive (IC 50 < 32 nmol/L), all 12 exhibited constitutive or serum-activated ERK1/2 phosphorylation, and 8 carried MAPK pathway cancer driver variants: NF1(2), BRAF(3), N/KRAS(3). This functionally annotated database of canine cell line variants will inform hypothesis-driven preclinical research to support the use of companion animals in clinical trials to test novel combination therapies.

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“…Die BRAF-Mutation c.1784T>A war in 54,5 % (12) bis 85 % der Übergangszell-und Prostatakarzinome (16)(17)(18), aber nur selten in melanozytären Tumoren, Nervenscheidentumoren, Gliomen und einzelnen anderen Karzinomen des Hundes nachweisbar (16). In den untersuchten hämatopoetischen Tumoren oder Sarkomen wurde die Mutation nicht gefunden (16). Im Gegensatz zum Hund kommt die Mutation des BRAF-Gens beim humanen ÜZCa nur selten (1 %) vor.…”

Section: Introductionunclassified

Diagnostische Aussagekraft der BRAF-Mutation V595E in Urinproben, Ausstrichen und Bioptaten beim kaninen Übergangszellkarzinom

Aupperle‐Lellbach¹,

Grassinger²,

Hohloch³

et al. 2018

Tierarztl Prax Ausg K

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Zusammenfassung Gegenstand und Ziel: Übergangszellkarzinome (ÜZCa) sind die häufigsten malignen Tumoren der harnableitenden Wege beim Hund. In früheren Studien wurde mittels DNA-Sequenzierung in Urinproben, Gefrier- und Paraffinmaterial von Harnblasenbioptaten die Mutation im BRAF-Gen V595E bei bis zu 85 % der kaninen ÜZCa in den Tumorzellen identifiziert. Ziel der eigenen Arbeit war, diese Methode für zytologische Ausstriche zu etablieren und die Prävalenz dieser Mutation im eigenen Kollektiv zu untersuchen. Material und Methoden: Es wurden 43 formalinfixierte Bioptate, 48 Urinproben und/oder 31 zytologische Ausstriche von 66 Hunden mit ÜZCa (n = 33), Harnblasenpolypen (n = 7), Zystitis (n = 23) oder ohne Harnblasenerkrankung (n = 3) analysiert. Die DNA-Isolierung erfolgte mit kommerziell erhältlichen Testkits. Das Exon 15 wurde mittels Sanger-Sequenzierung auf das Vorliegen der BRAF-Mutation c.1784T>A untersucht. Ergebnisse: Aus 39/43 Paraffinproben, 38/48 Urinproben und 16/18 zellreichen Ausstrichen ließ sich eine ausreichende Menge auswertbarer DNA isolieren. Bei 10/13 zellarmen Ausstrichen reichte die DNA für eine aussagefähige PCR nicht aus. In allen Fällen, in denen verschiedene Materialien vorlagen, stimmten die Ergebnisse der BRAF-Genanalyse in den Paraffin-, Urin- und/oder Zytologieproben des jeweiligen Hundes überein, sofern sich DNA isolieren ließ. Bei 22/31 Hunden (70,9 %) mit einem ÜZCa wurde die Mutation festgestellt, während sie bei keinem Hund mit Zystitis, Polypen oder ohne Harnblasenveränderung gefunden wurde. Schlussfolgerung und klinische Relevanz: Die Untersuchung auf Vorliegen einer BRAF-Variante stellt ein gutes neues Verfahren dar, mit dem sich in Zweifelsfällen die Verdachtsdiagnose eines ÜZCa häufig absichern lässt. Für die Methode eignen sich alle nichtinvasiv gewonnenen, zellreichen Materialien wie Ausstriche von Urinsediment oder Ansaugbioptate sowie formalinfixierte Bioptate. Aber nur der positive Befund ist beweisend. Hinsichtlich der prognostischen und therapeutischen Relevanz sowie der Möglichkeiten einer Frühdiagnostik von ÜZCa mittels der BRAF-Mutationsanalyse bedarf es weiterer Untersuchungen.

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Sequence analysis ofRASandRAFmutation hot spots in canine carcinoma

Cited by 22 publications

References 54 publications

Ultra‐frequent HRAS p.Q61R somatic mutation in canine acanthomatous ameloblastoma reveals pathogenic similarities with human ameloblastoma

Ultra‐frequent HRAS p.Q61R somatic mutation in canine acanthomatous ameloblastoma reveals pathogenic similarities with human ameloblastoma

Identifying Candidate Druggable Targets in Canine Cancer Cell Lines Using Whole-Exome Sequencing

Diagnostische Aussagekraft der BRAF-Mutation V595E in Urinproben, Ausstrichen und Bioptaten beim kaninen Übergangszellkarzinom

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