ANKRD26-RET - A novel gene fusion involving RET in papillary thyroid carcinoma

Staubitz, Julia I.; Musholt, Thomas J.; Schad, Arno; Springer, Erik; Lang, Hauke; Rajalingam, Krishnaraj; Roth, Wilfried; Hartmann, Nils

doi:10.1016/j.cancergen.2019.07.002

Cited by 11 publications

(16 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, ligand-induced multisubunit receptor complex formation, which is normally mediated by extracellular interactions, is required for efficient activation of RET signaling (Morandi et al, 2010;Shaw et al, 2013;Mulligan, 2014;Salvatore et al, 2021). Since the RET piece of the Ankrd26-RET fusion solely represents the intracellular kinase domain of RET (Staubitz et al, 2019), also this important aspect in RET functions is disrupted in the RET fragment included in the Ankrd26-RET fusion product found in papillary thyroid carcinoma patients. Our results show that the papillary thyroid carcinoma-associated Ankrd26-RET fusion obviously does have both of these capabilities.…”

Section: Discussionmentioning

confidence: 99%

“…Fusion of the membrane-binding and self-association-competent part of Ankrd26 with the kinase domain of RET, as found in papillary thyroid carcinoma patients (Staubitz et al, 2019), thus leads to a fusion protein with a massively increased autophosphorylation of RET.…”

Section: Fusion Declined Correspondingly (Fig 5l)mentioning

confidence: 95%

“…Human Ankrd26 1-1405 and RET were fused by complementing Ankrd26 1-1405 with RET using the internal AgeI site of the RET-encoding DNA sequence to yield a fusion protein with an amino acid sequence identical to the Ankrd-RET fusion identified in papillary thyroid carcinoma patients (Staubitz et al, 2019). For primers see Table S1.…”

Section: Dna Constructsmentioning

confidence: 99%

See 2 more Smart Citations

Ankrd26 is critical for cell differentiation and cancer-linked mutations affect its key properties

Metzner

et al. 2021

Preprint

View full text Add to dashboard Cite

Derailed signaling originating from the plasma membrane is associated with many types of cancer. Mutations in ANKRD26 have been linked to different human cancers and to thrombocytopenia. These mutations include an N-terminal truncation associated with acute myeloid leukemia (AML). We conducted an initial characterization of Ankrd26's protein properties and unveil that an N-terminal amphipathic structure of Ankrd26 lacking in the AML-associated mutant is critical for membrane binding and for Ankrd26's ability to bend membranes by partial membrane insertion. Another Ankrd26 mutation linked to papillary thyroid carcinoma includes truncation and fusion with the kinase domain of the protooncogene RET. Our characterization of Ankrd26 properties reveals that the Ankrd26 part in the Ankrd26-RET fusion mutant is able to anchor the RET kinase domain to the plasma membrane and to mediate self-association - a function we demonstrate to be mediated by Ankrd26's coiled coil domain. Ankrd26-RET fusion led to a massive increase in RET autophosphorylation, i.e. to aberrant RET signaling. Understanding the molecular mechanistic properties of Ankrd26 thus provides important insights into Ankrd26-associated pathomechanisms in human cancer patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Fusion Declined Correspondingly (Fig 5l)mentioning

confidence: 95%

See 1 more Smart Citation

Ankrd26 is critical for cell differentiation and cancer-linked mutations affect its key properties

Metzner

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…PTC contributes to almost 80% of thyroid cancers and RET fusions are the most commonly detected gene fusions in PTCs 15 . More than 20 RET fusions have been reported in PTCs, of which the most common are the RET/PTC1 and RET/PTC3 fusions [27][28][29] . Recent studies have also identified RET fusions in lung and colon adenocarcinoma, breast cancer as well in MTCs, a more aggressive form of thyroid cancer 30,31 .…”

Section: Discussionmentioning

confidence: 99%

Proteogenomics analysis unveils a TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas

et al. 2020

Self Cite

View full text Add to dashboard Cite

Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy. By RNAseq analysis, we identify a RET rearrangement in the tumour material of a patient who does not harbour any known RAS or BRAF mutations. This new gene fusion involves exons 1-4 from the 5′ end of the Trk fused Gene (TFG) fused to the 3′ end of RET tyrosine kinase leading to a TFG-RET fusion which transforms immortalized human thyroid cells in a kinasedependent manner. TFG-RET oligomerises in a PB1 domain-dependent manner and oligomerisation of TFG-RET is required for oncogenic transformation. Quantitative proteomic analysis reveals the upregulation of E3 Ubiquitin ligase HUWE1 and DUBs like USP9X and UBP7 in both tumor and metastatic lesions, which is further confirmed in additional patients. Expression of TFG-RET leads to the upregulation of HUWE1 and inhibition of HUWE1 significantly reduces RET-mediated oncogenesis.

show abstract

“…The RET gene, a gene name derived from ''rearranged during transfection,'' is mutated in approximately 80% of medullary thyroid cancer, and fusions have been detected in papillary thyroid carcinoma, NSCLC, and a range of other tumor types at lower frequencies. [43][44][45][46] The overall detection rate of RET fusions in NSCLC is 1% to 2% but fusions are enriched in nonsmokers lacking other known driver mutations. 47,48 RET fusions define a new therapeutic target in this subset of lung cancers, especially with the availability of selective RET inhibitor selpercatinib, which demonstrated durable response and increased progression-free survival.…”

Section: Rearranged During Transfection Fusions and Mutationsmentioning

confidence: 99%

Pan-Cancer Biomarkers: Changing the Landscape of Molecular Testing

Yao

Arcila

Ladanyi

et al. 2020

Archives of Pathology &Amp; Laboratory Medicine

View full text Add to dashboard Cite

Context.— The increasing use of large panel next-generation sequencing technologies in clinical settings has facilitated the identification of pan-cancer biomarkers, which can be diagnostic, prognostic, predictive, or most importantly, actionable. Objective.— To discuss recently approved and emerging pan-cancer and multihistology biomarkers as well as testing methodologies. Data Sources.— The US Food and Drug Administration approval documents, National Comprehensive Cancer Network guidelines, literature, and author's own publications. Conclusions.— Since 2017, the US Food and Drug Administration has approved genotype-directed therapies for pan-cancer biomarkers, including microsatellite instability, neurotrophic receptor kinases fusions, and high-tumor mutation burden. Both the importance and rarity of these biomarkers have increased the prevalence of genomic profiling across solid malignancies. As an integral part of the management team of patients with advanced cancer, pathologists need to be aware of these emerging biomarkers, the therapies for which they determine eligibility, and the strengths and pitfalls of the available clinical assays.

show abstract

ANKRD26-RET - A novel gene fusion involving RET in papillary thyroid carcinoma

Cited by 11 publications

References 66 publications

Ankrd26 is critical for cell differentiation and cancer-linked mutations affect its key properties

Ankrd26 is critical for cell differentiation and cancer-linked mutations affect its key properties

Proteogenomics analysis unveils a TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas

Pan-Cancer Biomarkers: Changing the Landscape of Molecular Testing

Contact Info

Product

Resources

About