Oncogenic Activating Mutations Are Associated with Local Copy Gain

Modrek, Barmak; Ge, Lianying; Pandita, Ajay; Lin, Eva; Mohan, Sankar; Yue, Peng; Guerrero, Steve; Lin, William M.; Pham, Thinh Q.; Modrušan, Zora; Seshagiri, Somasekar; Stern, Howard M.; Waring, Paul; Garraway, Levi A.; Chant, John; Stokoe, David; Cavet, Guy

doi:10.1158/1541-7786.mcr-08-0532

Cited by 61 publications

(77 citation statements)

References 33 publications

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“…One patient with an EPAS1 mutation also had copy number gain of the EPAS1 locus. The combination of activating mutations and copy number gain has previously been reported for EPAS1 (Comino-Mendez et al 2013), as well as for other oncogenes (Modrek et al 2009). …”

Section: Discussionmentioning

confidence: 59%

Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma

Welander¹,

Andreasson²,

Brauckhoff³

et al. 2014

Endocrine-Related Cancer

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Pheochromocytomas are neuroendocrine tumors arising from the adrenal medulla. While heritable mutations are frequently described, less is known about the genetics of sporadic pheochromocytoma. Mutations in genes involved in the cellular hypoxia response have been identified in tumors, and recently EPAS1, encoding HIF2a, has been revealed to be a new gene involved in the pathogenesis of pheochromocytoma and abdominal paraganglioma. The aim of this study was to further characterize EPAS1 alterations in non-familial pheochromocytomas. Tumor DNA from 42 adrenal pheochromocytoma cases with apparently sporadic presentation, without known hereditary mutations in predisposing genes, were analyzed for mutations in EPAS1 by sequencing of exons 9 and 12, which contain the two hydroxylation sites involved in HIF2a degradation, and also exon 2. In addition, the copy number at the EPAS1 locus as well as transcriptome-wide gene expression were studied by DNA and RNA microarray analyses, respectively. We identified six missense EPAS1 mutations, three in exon 9 and three in exon 12, in five of 42 pheochromocytomas (12%). The mutations were both somatic and constitutional, and had no overlap in 11 cases (26%) with somatic mutations in NF1 or RET. One sample had two different EPAS1 mutations, shown by cloning to occur in cis, possibly indicating a novel mechanism of HIF2a stabilization through inactivation of both hydroxylation sites. One of the tumors with an EPAS1 mutation also had a gain in DNA copy number at the EPAS1 locus. All EPAS1-mutated tumors displayed a pseudo-hypoxic gene expression pattern, indicating an oncogenic role of the identified mutations.

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Section: Discussionmentioning

confidence: 59%

Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma

Welander¹,

Andreasson²,

Brauckhoff³

et al. 2014

Endocrine-Related Cancer

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“…7,10 Recently, it was shown that reactivation of p53 in a KRAS G12D mouse model of non-small-cell lung carcinoma lead to tumor regression only in tumors with KRAS signal elevated through the amplification of the mutant allele and loss of wild-type allele. 17,18 In this larger series of KRAS-mutated lung adenocarcinomas, we confirm and expand the finding that KRAS MASI correlates with worse clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

“…Second, in a subgroup analysis, the presence of KRAS MASI maintained its adverse prog- The quantitative nature of the direct sequencing and its reliability in assessing allelic imbalance was previously shown both on cell lines and in clinical tumor samples. 7,10,19 In addition to sequencing electropherogram and FISH, previous studies of KRAS allelic imbalance in lung adenocarcinomas used such methods as qPCR and SNP ( Table 2). The number of clinical samples was lower, and the ethnicity of studied patients was distinct from the present study.…”

Section: Discussionmentioning

confidence: 99%

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KRAS mutant allele-specific imbalance in lung adenocarcinoma

et al. 2011

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The significance of KRAS mutant allele-specific imbalance (MASI) in lung adenocarcinomas is unknown. KRAS MASI was defined as predominance of the mutant allele over the wild-type allele. We assessed the frequency of KRAS MASI by comparing peak heights of mutant and wild-type alleles on sequencing electropherograms and by KRAS fluorescence in situ hybridization (FISH). A review of sequencing electropherograms of 207 KRAS-mutated lung adenocarcinomas demonstrated 23 (11%) cases with the mutant allele peak higher than the wild-type allele peak and 15 (7%) cases with the mutant allele peak equal to the wild-type allele peak. Of 17 cases with the mutant allele peak higher or equal to the wild-type allele peak, 8 (47%) showed KRAS amplification by FISH. KRAS FISH analysis of 36 KRAS-mutated lung adenocarcinomas with the mutant allele peak lower than the wild-type allele peak, 21 KRAS and EGFR wild-type and 16 EGFR-mutated adenocarcinomas showed no KRAS amplification. KRAS MASI was associated with selective amplification of the KRAS mutant allele (Po0.001). Patients with KRAS MASI showed worse overall survival. The cumulative proportion surviving at 17 months for KRAS MASI group was 35% compared with 84.1% for patients with KRAS mutant allele peak lower than wild-type allele peak (P ¼ 0.012). The adverse prognostic significance of KRAS MASI was independent of clinical stage and was maintained among stage I patients. The detection of KRAS MASI in lung adenocarcinomas by sequencing electropherograms may identify patients with more aggressive disease.

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“…The identification of events driving distinct tumor phenotypes requires interrogation of multiple omics dimensions on appropriate, well-annotated tumor specimens, and the interpretation of these molecular data in a biologically and clinically meaningful way (Hood et al 2004;Gondek et al 2007;Yamamoto et al 2007;Cancer Genome Atlas Research Network 2008;Dunbar et al 2008;Gandhi et al 2009;Modrek et al 2009;Segditsas et al 2009;Soh et al 2009;Wang et al 2010;Vidal et al 2011). Using a multi-omics systems-based approach to the analysis of patient cancer samples will enhance our understanding of cancer biology and accelerate the translation of omics research.…”

Section: A Multidimensional Approach To Cancer Omicsmentioning

confidence: 99%

Translating cancer ‘omics’ to improved outcomes: Figure 1.

Vucic¹,

Thu²,

Robison³

et al. 2012

Genome Res.

107

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The genomics era has yielded great advances in the understanding of cancer biology. At the same time, the immense complexity of the cancer genome has been revealed, as well as a striking heterogeneity at the whole-genome (or omics) level that exists between even histologically similar tumors. The vast accrual and public availability of multi-omics databases with associated clinical annotation including tumor histology, patient response, and outcome are a rich resource that has the potential to lead to rapid translation of high-throughput omics to improved overall survival. We focus on the unique advantages of a multidimensional approach to genomic analysis in this new high-throughput omics age and discuss the implications of the changing cancer demographic to translational omics research.

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Oncogenic Activating Mutations Are Associated with Local Copy Gain

Cited by 61 publications

References 33 publications

Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma

Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma

KRAS mutant allele-specific imbalance in lung adenocarcinoma

Translating cancer ‘omics’ to improved outcomes: Figure 1.

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