Whole‐genome Sequencing of an Aggressive BRAF Wild‐type Papillary Thyroid Cancer Identified EML4–ALK Translocation as a Therapeutic Target

Demeure, Michael J.; Aziz, Meraj; Rosenberg, Richard K.; Gurley, Steven D.; Bussey, Kimberly J.; Carpten, John D.

doi:10.1007/s00268-014-2485-3

Cited by 54 publications

(40 citation statements)

References 35 publications

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“…This information has helped identify common mutational signatures in cancer types and subtypes (3)(4)(5). However, application of systematic patient-specific sequencing data to guide personalized cancer treatment has been limited in practice (6)(7)(8). The key challenge is functional understanding of the individual genetic lesions in the given phenotypic context and its translation into actionable strategies for targeted treatment.…”

mentioning

confidence: 99%

Discovery and functional characterization of a neomorphic PTEN mutation

Costa

Leitner

Sos

et al. 2015

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

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Although a variety of genetic alterations have been found across cancer types, the identification and functional characterization of candidate driver genetic lesions in an individual patient and their translation into clinically actionable strategies remain major hurdles. Here, we use whole genome sequencing of a prostate cancer tumor, computational analyses, and experimental validation to identify and predict novel oncogenic activity arising from a point mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor protein.We demonstrate that this mutation (p.A126G) produces an enzymatic gain-of-function in PTEN, shifting its function from a phosphoinositide (PI) 3-phosphatase to a phosphoinositide (PI) 5-phosphatase. Using cellular assays, we demonstrate that this gain-of-function activity shifts cellular phosphoinositide levels, hyperactivates the PI3K/ Akt cell proliferation pathway, and exhibits increased cell migration beyond canonical PTEN loss-of-function mutants. These findings suggest that mutationally modified PTEN can actively contribute to welldefined hallmarks of cancer. Lastly, we demonstrate that these effects can be substantially mitigated through chemical PI3K inhibitors. These results demonstrate a new dysfunction paradigm for PTEN cancer biology and suggest a potential framework for the translation of genomic data into actionable clinical strategies for targeted patient therapy.functional genomics | PTEN | tumor suppressor

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mentioning

confidence: 99%

Discovery and functional characterization of a neomorphic PTEN mutation

Costa

Leitner

Sos

et al. 2015

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

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“…This STRN-ALK fusion results in constitutive activity of ALK kinase and induction of thyroid cell proliferation and tumorigenesis [47]. In addition to STRN-ALK gene fusions, the echinoderm microtubule-associated protein-like 4 ( EML4 ) gene has been reported as another gene fusion with ALK [48]. This fusion is more commonly described in lung cancer and results in constitutive ALK activation leading to cell proliferation and tumorigenesis [48].…”

Section: The Genetic Landscape Of Anaplastic Thyroid Cancermentioning

confidence: 99%

“…In addition to STRN-ALK gene fusions, the echinoderm microtubule-associated protein-like 4 ( EML4 ) gene has been reported as another gene fusion with ALK [48]. This fusion is more commonly described in lung cancer and results in constitutive ALK activation leading to cell proliferation and tumorigenesis [48]. EML4-ALK has also been found to be a potent oncogenic activator in cell lines and genetically engineered mouse models [49].…”

Section: The Genetic Landscape Of Anaplastic Thyroid Cancermentioning

confidence: 99%

Genomically Driven Precision Medicine to Improve Outcomes in Anaplastic Thyroid Cancer

Pinto

Black

Patel

et al. 2014

Journal of Oncology

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Thyroid cancer is an endocrine malignancy with an incidence rate that has been increasing steadily over the past 30 years. While well-differentiated subtypes have a favorable prognosis when treated with surgical resection and radioiodine, undifferentiated subtypes, such as anaplastic thyroid cancer (ATC), are far more aggressive and have a poor prognosis. Conventional therapies (surgical resection, radiation, chemotherapy, and radioiodine) have been utilized for treatment of ATC, yet these treatments have not significantly improved the overall mortality rate. As cancer is a genetic disease, genetic alterations such as mutations, fusions, activation of oncogenes, and silencing of tumor suppressors contribute to its aggressiveness. With the use of next-generation sequencing and the Cancer Genome Atlas, mutation-directed therapy is recognized as the upcoming standard of care. In this review, we highlight the known genetic landscape of ATC and the need for a comprehensive genetic characterization of this disease in order to identify additional therapeutic targets to improve patient outcomes.

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“…More recently, rearrangements of anaplastic lymphoma kinase (ALK) that lead to both ectopic expression and constitutive activation of the ALK fusion protein were reported in DTC and anaplastic carcinoma , Kelly et al 2014. Treatment with clinically available ALK inhibitors, such as crizotinib and TAE684, yielded in vitro antitumor efficacy (Kelly et al 2014) and produced clinical improvement in anecdotal cases (Demeure et al 2014.…”

Section: Introductionmentioning

confidence: 99%

Standard immunohistochemistry efficiently screens for anaplastic lymphoma kinase rearrangements in differentiated thyroid cancer

Park¹,

Kim²,

Lee³

et al. 2015

Endocrine-Related Cancer

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The anaplastic lymphoma kinase (ALK) gene is frequently rearranged in various types of cancer and is highly responsive to targeted therapeutics. We developed a system to detect rearrangement of ALK in a large group of Korean thyroid cancer patients. We screened 474 malignant or benign thyroid tumor cases to identify ALK fusions. Expression and translocation of the ALK gene were analyzed by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and digital multiplexed gene expression (DMGE) analysis in formalinfixed paraffin-embedded tissues. Four cases of rearrangement of ALK were detected by IHC, and these cases were validated with FISH on 189 samples. On the other hand, DMGE analysis using Nanostring detected three out of four IHC-positive cases. Two rearrangements of ALK were striatin (STRN)-ALK fusions, which were identified by 5 0 RACE analysis. Rearrangements of ALK were found exclusively in v-raf murine sarcoma viral oncogene homolog B (BRAF) WT papillary carcinomas. Given the wide availability and accuracy of IHC for detecting ectopic expression of ALK in the thyroid, we suggest that IHC-based screening can be a practical method for identifying patients with ALK rearrangements in differentiated thyroid cancer.

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Whole‐genome Sequencing of an Aggressive BRAF Wild‐type Papillary Thyroid Cancer Identified EML4–ALK Translocation as a Therapeutic Target

Cited by 54 publications

References 35 publications

Discovery and functional characterization of a neomorphic PTEN mutation

Discovery and functional characterization of a neomorphic PTEN mutation

Genomically Driven Precision Medicine to Improve Outcomes in Anaplastic Thyroid Cancer

Standard immunohistochemistry efficiently screens for anaplastic lymphoma kinase rearrangements in differentiated thyroid cancer

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