Identification of atypical ATRNL1 insertion to EML4-ALK fusion gene in NSCLC

Robešová, Blanka; Bajerová, Monika; Hausnerová, Jitka; Skřičková, Jana; Tomíšková, Marcela; Dvořáková, Dana

doi:10.1016/j.lungcan.2015.01.002

Cited by 7 publications

(3 citation statements)

References 6 publications

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“…Related to its candidate tumor suppressor function, the TUSC3 protein localizes to the endoplasmic reticulum and is involved in protein glycosylation, enabling it to inhibit cell proliferation and promote both apoptosis and autophagy [ 37 ]. For the other three newly identified hypermethylated genes, POMT1 is involved in protein glycosylation (as also described above for TUSC3) and has been found to be related to the development of hematological malignancies [ 38 ], a tumor type also enriched in our cell line and TCGA methylation screening; ATRNL1 regulates energy homoeostasis and has been found inserted in the EML4-ALK fusion gene [ 39 ]; and SAMD4A is an RNA-binding protein linked to drug resistance in cancer cells [ 40 ]. Our results pave the way to study the extent to which the putative tumor suppressor functions of these genes are associated with their linear RNA form, circular RNA form, or both.…”

Section: Discussionmentioning

confidence: 99%

Circular RNA CpG island hypermethylation-associated silencing in human cancer

et al. 2018

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Noncoding RNAs (ncRNAs), such as microRNAs and long noncoding RNAs (lncRNAs), participate in cellular transformation. Work done in the last decade has also demonstrated that ncRNAs with growth-inhibitory functions can undergo promoter CpG island hypermethylation-associated silencing in tumorigenesis. Herein, we wondered whether circular RNAs (circRNAs), a type of RNA transcripts lacking 5′-3′ ends and forming closed loops that are gaining relevance in cancer biology, are also a target of epigenetic inactivation in tumors. To tackle this issue, we have used cancer cells genetically deficient for the DNA methyltransferase enzymes in conjuction with circRNA expression microarrays. We have found that the loss of DNA methylation provokes a release of circRNA silencing. In particular, we have identified that promoter CpG island hypermethylation of the genes TUSC3 (tumor suppressor candidate 3), POMT1 (protein O-mannosyltransferase 1), ATRNL1 (attractin-like 1) and SAMD4A (sterile alpha motif domain containing 4A) is linked to the transcriptional downregulation of both linear mRNA and the hosted circRNA. Although some circRNAs regulate the linear transcript, we did not observe changes in TUSC3 mRNA levels upon TUSC3 circ104557 overexpression. Interestingly, we found circRNA-mediated regulation of target miRNAs and an in vivo growth inhibitory effect upon TUSC3 circ104557 transduction. Data mining for 5′-end CpG island methylation of TUSC3, ATRNL1, POMT1 and SAMD4A in cancer cell lines and primary tumors showed that the epigenetic defect was commonly observed among different tumor types in association with the diminished expression of the corresponding transcript. Our findings support a role for circRNA DNA methylation-associated loss in human cancer.

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Section: Discussionmentioning

confidence: 99%

Circular RNA CpG island hypermethylation-associated silencing in human cancer

et al. 2018

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“… 3 , 5 Regarding rare variants, the recently described E6:A18 was intrinsically refractory to crizotinib, 2 while a patient with an uncommon 138 bp in-frame insertion from the ATRNL1 gene in v3 derived benefit from this drug. 6 The partial response we also observed in the patient with the v1insLTBP1 suggests that in-frame, atypical insertions do not affect the sensitivity of the EML4-ALK fusion protein to crizotinib.…”

Section: Discussionmentioning

confidence: 67%

Response to crizotinib in a non-small-cell lung cancer patient harboring an <em>EML4-ALK</em> fusion with an atypical <em>LTBP1</em> insertion

Aguado¹,

Gil

Yeste³

et al. 2018

OTT

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Fusion of the anaplastic lymphoma receptor tyrosine kinase gene (ALK) with the echinoderm microtubule-associated protein 4 gene (EML4) is the second most common actionable alteration in non-small-cell lung cancer, with a frequency of 5%. Here, we present a case of an EML4-ALK-positive patient with an atypical in-frame insertion from the LTBP1 gene in the canonical junction of variant 1. The patient was a 39-year-old never-smoker female diagnosed with Stage IV lung adenocarcinoma. A core biopsy was negative for EGFR and KRAS mutations but positive for ALK immunohistochemistry and fluorescence in situ hybridization. When submitted to nCounter, the sample showed a 3′/5′ imbalance indicative of an ALK rearrangement, but failed to give a positive signal for any of the variants tested. Finally, a band with a molecular weight higher than expected appeared after reverse transcriptase-polymerase chain reaction analysis. When Sanger sequencing was performed, the band revealed an atypical EML4-ALK fusion gene with an in-frame 129 bp insertion. A 115 bp segment of the insertion corresponded to an intronic region of LTBP1, a gene located in the short arm of chromosome 2, between ALK and EML4. The patient received crizotinib and showed a good therapeutic response that is still ongoing after 12 months. Our result suggests that short in-frame insertions of other genes in the EML4-ALK junction do not affect the sensitivity of the EML4-ALK fusion protein to crizotinib.

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“…Rearranged with an oncogenic fusion partner, ALK is found in 2% to 7% of all NSCLC patients, which are usually younger never-smokers suffering from AC with a solid pattern or signet-ring cells [ 65 ]. In rare cases combination with other mutations like EGFR has been described [ 43 , 62 , 66 , 67 , 68 , 69 ]. Nevertheless, tumors harboring ALK translocations are resistant to EGFR -specific TKIs like erlotinib or gefitinib [ 27 , 30 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ].…”

Section: Markers Of Current Diagnostic and Therapeutic Relevancementioning

confidence: 99%

Molecular Pathology and Personalized Medicine: The Dawn of a New Era in Companion Diagnostics—Practical Considerations about Companion Diagnostics for Non-Small-Cell-Lung-Cancer

Plönes

Engel-Riedel

Stoelben

et al. 2016

JPM

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Companion diagnostics (CDx) have become a major tool in molecular pathology and assist in therapy decisions in an increasing number of various cancers. Particularly, the developments in lung cancer have been most impressing in the last decade and consequently lung cancer mutation testing and molecular profiling has become a major business of diagnostic laboratories. However, it has become difficult to decide which biomarkers are currently relevant for therapy decisions, as many of the new biomarkers are not yet approved as therapy targets, remain in the status of clinical studies, or still have not left the experimental phase. The current review is focussed on those markers that do have current therapy implications, practical implications arising from the respective companion diagnostics, and thus is focused on daily practice.

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Identification of atypical ATRNL1 insertion to EML4-ALK fusion gene in NSCLC

Cited by 7 publications

References 6 publications

Circular RNA CpG island hypermethylation-associated silencing in human cancer

Circular RNA CpG island hypermethylation-associated silencing in human cancer

Response to crizotinib in a non-small-cell lung cancer patient harboring an <em>EML4-ALK</em> fusion with an atypical <em>LTBP1</em> insertion

Molecular Pathology and Personalized Medicine: The Dawn of a New Era in Companion Diagnostics—Practical Considerations about Companion Diagnostics for Non-Small-Cell-Lung-Cancer

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