Mutations of <i>BRAF</i> and <i>RAS</i> are rare events in germ cell tumours

Sommerer, Florian; Hengge, Ulrich R.; Markwarth, Annett; Vomschloss, Susanne; Stolzenburg, Jens‐Uwe; Wittekind, Christian; Tannapfel, Andrea

doi:10.1002/ijc.20567

Cited by 55 publications

(49 citation statements)

References 26 publications

(36 reference statements)

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“…Two of these failed to identify any BRAF mutations and the remaining study reported a rate of only 5% among 62 samples. In addition, two of these studies were conducted in Germany (6,7), and the other in an ethnically similar population in the United Kingdom (8). Although these reports either did not include cisplatin-resistant tumors or did not have clinical information available to complement the molecular findings, it is likely based upon our data that BRAF mutations are less common in GCT than suggested by Honecker and colleagues.…”

Section: Discussionmentioning

confidence: 81%

“…However, it is notable that our findings are consistent with the other three series that evaluated GCT for BRAF mutations (Table 6; refs. [6][7][8]. Two of these failed to identify any BRAF mutations and the remaining study reported a rate of only 5% among 62 samples.…”

Section: Discussionmentioning

confidence: 94%

“…However, this finding has not been validated. One study of adult GCT (6) found an incidence of BRAF mutations of only 5% (9% among nonseminomas and 0% among seminomas) and a report of pediatric and adolescent GCT (7) identified no BRAF mutations among 66 patients, including 18 diagnosed at age !13 and 15 with progressive disease after primary therapy. One additional series of 65 testicular GCT and four GCT cell lines also failed to identify any BRAF mutations (8).…”

Section: Introductionmentioning

confidence: 99%

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Presence of Somatic Mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in Cisplatin-Resistant Germ Cell Tumors

Feldman

Iyer

Alstine

et al. 2014

Clinical Cancer Research

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Purpose: A previous study noted frequent B-RAF mutations among European patients with cisplatinresistant but not cisplatin-sensitive germ cell tumors (GCT). We sought to validate this finding by assessing for these mutations among patients with GCT at our center.Experimental Design: Adolescent and adult patients with GCT who received cisplatin-based chemotherapy and had tumor tissue available were eligible for participation. Response to cisplatin was reviewed to determine sensitivity and resistance. Tumor DNA was extracted and subjected to Sequenom analysis to detect hotspot alterations in FGFR3, AKT1, PIK3CA, KRAS, HRAS, NRAS, and BRAF with Sanger sequencing for confirmation. Nine GCT cell lines with varying degrees of cisplatin sensitivity and resistance were also assayed by Sequenom.Results: Seventy (24 cisplatin-sensitive; 46 cisplatin-resistant) of 75 patients had tumors with sufficient quality DNA to perform Sequenom. Nineteen mutations were detected among 16 (23%) patients but no BRAF mutations were identified. Similarly, none of the cell lines harbored BRAF mutations. FGFR3 was the most frequent mutation, identified in 13% of both sensitive and resistant samples. All other mutations were exclusive to resistant cases (3 KRAS, 3 AKT1, 3 PIK3CA, and 1 HRAS).Conclusions: BRAF mutations are rare in American patients with GCT, including those with cisplatin resistance. However, other potentially targetable mutations occur in more than 25% of cisplatin-resistant patients. FGFR3, AKT1, and PIK3CA mutations are all reported for the first time in GCT. Whereas FGFR3 mutations occurred with equal frequency in both sensitive and resistant GCTs, mutations in AKT1 and PIK3CA were observed exclusively in cisplatin-resistant tumors.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Presence of Somatic Mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in Cisplatin-Resistant Germ Cell Tumors

Feldman

Iyer

Alstine

et al. 2014

Clinical Cancer Research

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“…The TERT mutation profile has been associated with other molecular features in several tumor types, in particular an interesting association with BRAF mutation in skin melanomas and thyroid cancer [3,4]. The frequency and clinical impact of BRAF mutations in TGCT is still controversial [25,26]. BRAF mutations were not evaluated in the present study.…”

Section: Discussionmentioning

confidence: 86%

Hotspot TERT promoter mutations are rare events in testicular germ cell tumors

et al. 2015

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The abnormal activation of telomerase, codified by the telomerase reverse transcriptase (TERT) gene, is related to one of cancer hallmarks. Hotspot somatic mutations in the promoter region of TERT, specifically the c.-124:C>T and c.-146:C>T, were recently identified in a range of human cancers and have been associated with a more aggressive behavior. Testicular germ cell tumors frequently exhibit a good prognosis; however, the development of refractory disease is still a clinical challenge. In this study, we aim to evaluate for the first time the presence of the hotspot telomerase reverse transcriptase gene promoter mutations in testicular germ cell tumors. A series of 150 testicular germ cell tumor cases and four germ cell tumor cell lines were evaluated by PCR followed by direct Sanger sequencing and correlated with patient's clinical pathological features. Additionally, we genotyped the telomerase reverse transcriptase gene promoter single nucleotide polymorphism rs2853669 (T>C) located at −245 position. We observed the presence of the TERT promoter mutation in four patients, one exhibited the c.-124:C>T and three the c.-146:C>T. No association between TERT mutation status and clinicopathological features could be identified. The analysis of the rs2853669 showed that variant C was present in 22.8 % of the cases. In conclusion, we showed for the first time that TERT promoter mutations occur in a small subset (~3 %) of testicular germ cell tumors.

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“…The proto-oncogene BRAF has been shown to be mutated in a variety of cancers, including TGCTs. 66 The affected pathway is the MEK-pathway, in which RAS also act. Activating mutations of KRAS and BRAF are mutually exclusive in TGCTs.…”

Section: Other Polymorphismsmentioning

confidence: 99%

Genetic aspects of testicular germ cell tumors

Krausz

Looijenga²

2008

Cell Cycle

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Testicular Germ Cell Tumor (TGCT) is the most common malignant tumor in young Caucasian men with an annual increase of 3-6% in the past 50 years. Data in the literature indicate that both environmental and genetic factors acting on the primordial gonocyte/gonocyte are implicated in the etiopathogenesis of this tumour. Genetic linkage and genome-wide analyses did not reveal a major gene effect so far, implying that multiple loci must contribute to the development of TGCTs. Only one significant genetic risk factor has been reported, the so called "gr/gr" deletion of the Y chromosome which still request further confirmation by independent studies. On the other side, the analysis of somatic genetic changes through mutation and genome imbalance analyses and expression profiling has just began to unravel the complex interaction of multiple pathways involved in TGCTs. This review focuses on genetic factors (both genomic and somatic) involved in the etiology, progression and treatment sensitivity of TGCTs.

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Mutations of BRAF and RAS are rare events in germ cell tumours

Cited by 55 publications

References 26 publications

Presence of Somatic Mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in Cisplatin-Resistant Germ Cell Tumors

Presence of Somatic Mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in Cisplatin-Resistant Germ Cell Tumors

Hotspot TERT promoter mutations are rare events in testicular germ cell tumors

Genetic aspects of testicular germ cell tumors

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