scholarly journals Identification of novel variant of EML4-ALK fusion gene in NSCLC: Potential benefits of the RT-PCR method.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e12007-e12007
Author(s):  
Martin Karl Herbert Maus ◽  
Craig Stephens ◽  
Gary Zeger ◽  
Peter Philipp Grimminger ◽  
Eric Huang ◽  
...  
Keyword(s):  
Fusion Gene ◽  
Progression Free Survival ◽  
Rt Pcr ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
New Variant ◽  
Short Period ◽  
Two Samples ◽  
Novel Variant ◽  
Transforming Gene

e12007 Background: The discovery of the transforming fusion gene of the anaplastic lymphoma kinase (ALK) with the echinoderm microtubule-associated protein like 4 (EML4) as an oncogene in 2007 has led to its validation as a clinical target in NSCLC patients in a short period of time. The inhibition of the anaplastic lymphoma receptor tyrosine kinase has demonstrated to prolong progression-free survival compared to the standard of care chemotherapy in patients with advanced NSCLC that are ALK positive. However, the clinical implications of the 15 different variants of the EML4-ALK transforming gene described so far are currently not defined. Here we present a novel variant of the EML4-ALK fusion gene which we named variant 3c. Methods: RNA extracted from formalin fixed paraffin embedded (FFPE) specimens from patients with advanced and metastatic NSCLC was amplified, using primers and probes designed to detect specific EML4-ALK fusion gene fragments. Gel electrophoresis showed a different band for the new variant 3c compared to the known bands of positive cell lines for variant 3a and 3b. These findings were further investigated by dye-terminator Sequencing and FISH. Results: The novel variant, detected in two NSCLC specimens, is longer than v3a and shorter than v3b, representing an 18 base pair insertion of intron 19 of ALK between exon 6 of EML4 and exon 20 of ALK. All of the two samples showed exactly the same sequencing result. One of the samples was negative for FISH break apart testing and the other one showed a positive result, defined by ≥ 15% split nuclei as indicative of an ALK rearrangement. Conclusions: Compared to FISH technology, RT-PCR enables the detection of different isoforms of the EML4-ALK transforming gene, which can be validated by sequencing. Only one out of two samples that were positive for the new variant by RT-PCR could be confirmed by FISH. The clinical significance of the different variants, notably to resistance and response to ALK-Inhibitors and the concordance and sensitivity of FISH and RT-PCR should be subject to further investigations.

Concomitant Presence of EGFR and ALK Fusion Gene Mutation in Adenocarcinoma of Lung: A Case Report and Review of the Literature

2017 ◽  
Vol 31 (2) ◽  
pp. 244-248
Author(s):  
Nishitha Thumallapally ◽  
Hana Yu ◽  
Mohammad Farhan ◽  
Uroosa Ibrahim ◽  
Maricel Odiami
Keyword(s):  
Molecular Mechanisms ◽  
Fusion Gene ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Adenocarcinoma Of Lung ◽  
Practical Guidelines ◽  
Oncogenic Driver

Empirical evidence has long suggested that oncogenic driver mutations in non-small-cell lung cancer are mutually independent. However, recent studies reported in pertinent literature reveal that concomitant epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangement can occur in a subset of patients with NSCLC. In order to shed further light on this issue, we report a case of adenocarcinoma of lung harboring both EGFR mutation in exon 21 (L861Q) and ALK rearrangement. This allows us to speculate on likely molecular mechanisms underlying this uncommon phenomenon, while also offering some practical guidelines on the therapeutic options that could benefit patients diagnosed with this dual-positive tumor.

scholarly journals Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors

2021 ◽  
pp. 756-766
Author(s):  
Yuki Takeyasu ◽  
Hitomi S. Okuma ◽  
Yuki Kojima ◽  
Tadaaki Nishikawa ◽  
Maki Tanioka ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Alk Rearrangement ◽  
Free Survival ◽  
Anaplastic Lymphoma ◽  
Treatment Interruptions ◽  
Alk Positive

PURPOSE Anaplastic lymphoma kinase ( ALK) rearrangement is a well-known driver oncogene in non–small-cell lung cancer and has also been identified in other types of tumors. However, there is limited evidence on the clinical response to ALK tyrosine kinase inhibitors (TKIs), such as alectinib and crizotinib, in rare tumors with ALK fusion. We evaluated the therapeutic effect of ALK-TKIs in rare ALK-rearranged tumors. PATIENTS AND METHODS Between April 2012 and April 2019, clinical outcomes and characteristics of patients with ALK-rearranged nonlung solid tumors who received ALK-TKIs (alectinib and/or crizotinib) outside of clinical trials were reviewed. Expression and/or rearrangement of ALK was evaluated by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. The tumor response was assessed according to RECIST (version 1.1). Progression-free survival was estimated from initial ALK-TKI initiation until progression. RESULTS We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare ALK fusions, namely, CTNNA1-ALK and ITSN2-ALK, were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib. CONCLUSION This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with ALK-rearranged nonlung solid tumors.

scholarly journals What are the Uncommon Anaplastic Lymphoma Kinase (ALK) Fusions in Non-Small Cell Lung Cancer?

2019 ◽  
Vol 6 ◽  
Author(s):  
Hind El Yacoubi ◽  
Mohamed Sow ◽  
Hassan Errihani
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Anaplastic Lymphoma Kinase ◽  
Fusion Gene ◽  
Small Cell ◽  
Small Cell Lung ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Cancer Pathogenesis

The lung cancer carcinogenesis is increasingly related to genetic disorders that lead to use specific targeted therapies which improve clinical outcome and survival. Gene fusion is one of the mechanisms of lung cancer pathogenesis besides gene mutation. The oncogenic echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene was the first described in non small cell lung cancer (NSCLC) and it’s the most frequent ALK rearrangement which occurs in approximately 5% of NSCLC. The development of sequencing technology has allowed the discovery of other ALK partners that cause an ALK fusion in NSCLC. They are still less known, however. The aim of this revue is to report the novel ALK fusions in NSCLC described in the literature and their particular characteristics. We will present the kinesin family member 5B (KIF5B) - ALK fusion, the huntingtin interacting protein 1 (HIP 1)- ALK fusion, and other uncommon ALK fusions.  

scholarly journals Anaplastic lymphoma kinase (ALK)-rearranged pulmonary pleomorphic carcinoma successfully treated with crizotinib

2018 ◽  
Vol 46 (8) ◽  
pp. 3491-3497 ◽  
Author(s):  
Liping Lin ◽  
Fuxi Huang ◽  
Fang Chen ◽  
Yan He ◽  
Jiazhu Hu ◽  
...  
Keyword(s):  
Anaplastic Lymphoma Kinase ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Pleomorphic Carcinoma ◽  
Conventional Chemotherapy ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Cell Components ◽  
Resected Tissue ◽  
Epidermal Growth

Pulmonary pleomorphic carcinoma (PPC) is rare, and the response of patients to conventional chemotherapy is very poor. Here we present a patient with anaplastic lymphoma kinase (ALK)-rearranged advanced PPC treated with crizotinib. Computed tomography revealed a mass in the left upper lung of a nonsmoking 60-year-old woman. Pathological findings using resected tissue were consistent with PPC stage 1A, T1bN0M0. Although the patient received adjuvant radiotherapy, the disease relapsed, quickly progressed, and remained PPC according to analysis of biopsied tissue. Although negative for epidermal growth factor receptor mutations, ALK rearrangements were detected in adenocarcinoma and spindle-cell components. The patient received crizotinib therapy and achieved a partial response for 7 months. This case indicates that patients with PPC, particularly those with adenocarcinoma, may harbor an epithelial component with the ALK rearrangement. Although the progression-free survival of patients treated with crizotinib is limited, they may obtain more benefit compared with conventional chemotherapy.

scholarly journals Transcripts of the npm-alk fusion gene in anaplastic large cell lymphoma, Hodgkin's disease, and reactive lymphoid lesions

Blood ◽  
1995 ◽  
Vol 86 (9) ◽  
pp. 3517-3521 ◽  
Author(s):  
PG Elmberger ◽  
MD Lozano ◽  
DD Weisenburger ◽  
W Sanger ◽  
WC Chan
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Hodgkin's Disease ◽  
Fusion Gene ◽  
Cell Lymphoma ◽  
Cytogenetic Study ◽  
Hodgkin’S Disease ◽  
Large Cell ◽  
Rt Pcr ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma

Anaplastic large cell lymphoma (ALCL) and Hodgkin's disease (HD) have some pathologic and immunohistochemical similarities, and a histogenetic relationship between them has been suggested by some investigators. By cytogenetic study, the t(2;5)(p23;q35) translocation appears to be unique for ALCL. The breakpoints of the t(2;5)(p23;q35) have recently been cloned and are reported to involve a novel tyrosine kinase gene, anaplastic lymphoma kinase (alk), on chromosome 2 and the nucleophosmin gene (npm) on chromosome 5. Therefore, we studied the frequency of npm-alk translocation in ALCL using a reverse transcriptase-polymerase chain reaction (RT-PCR) assay. We also studied HD and a variety of reactive lymphoid lesions since there is contradictory information in the literature on the occurrence of the npm-alk rearrangement in HD. We detected npm-alk hybrid mRNA in 8 of 22 cases of ALCL (36%), but none of the 21 cases of HD or the 11 cases with reactive lesions contained amplifiable template. All positive ALCL had the T or indeterminate phenotype and occurred in young adults or children. There was very good correlation between a cytogenetically detectable t(2;5) and a positive signal by RT-PCR. Our results indicate a selective but relatively infrequent association between the t(2;5) and ALCL of T or indeterminate phenotype, not shared with HD or reactive hyperplasia.

scholarly journals Nanostring-based screening for tyrosine kinase fusions in inflammatory myofibroblastic tumors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Taisei Kurihara ◽  
Yoshiyuki Suehara ◽  
Keisuke Akaike ◽  
Takuo Hayashi ◽  
Shinji Kohsaka ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Rna Sequencing ◽  
Fusion Gene ◽  
Rt Pcr ◽  
Anaplastic Lymphoma ◽  
Inflammatory Myofibroblastic Tumors ◽  
Polymerase Chain ◽  
Lymphoplasmacytic Infiltration ◽  
Tyrosine Receptor Kinase

Abstract Gene expression imbalances were measured for tyrosine kinase (TK) genes using Nanostring in 19 samples of inflammatory myofibroblastic tumor (IMT). All cases were immunohistochemically stained with anaplastic lymphoma kinase (ALK) and pan-tropomyosin-related-kinase (pan-Trk) antibodies. Five cases with imbalanced ALK expression, reported with Nanostring, were tested using fluorescence in situ hybridization (FISH); two cases with imbalanced neurotrophic tyrosine receptor kinase 3 (NTRK3) expression were tested using reverse transcription-polymerase chain reaction (RT-PCR). One case with imbalanced expression for ROS proto-oncogene 1 (ROS1) was tested using RNA sequencing and RT-PCR. TK fusions were detected in all cases with imbalanced TK expression. RNA sequencing detected a FN1–ROS1 fusion gene in an adult IMT case. IMT with ALK rearrangement showed myofibroblast-dominant features. IMT with ETV6–NTRK3 fusion showed prominent lymphoplasmacytic infiltration with scattered myofibroblasts. Pan-Trk IHC revealed only scattered positively stained cells in IMT with ETV6–NTRK3 fusion gene. ROS1-positive IMT showed myofibroblast-dominant features.

scholarly journals Molecular Characterization and Clinical Impact ofTMPRSS2-ERGRearrangement on Prostate Cancer: Comparison between FISH and RT-PCR

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
A. Fernández-Serra ◽  
L. Rubio ◽  
A. Calatrava ◽  
J. Rubio-Briones ◽  
R. Salgado ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Fusion Gene ◽  
Digital Rectal Examination ◽  
Progression Free Survival ◽  
Tissue Microarrays ◽  
Clinicopathological Parameters ◽  
Protease Gene ◽  
Rt Pcr ◽  
Gene Status ◽  
Transmembrane Serine Protease

Prostate cancer (PCa) is a very heterogeneous disease, and there are constraints in its current diagnosis. Serum PSA levels, digital rectal examination (DRE), and histopathologic analysis often drive to overdiagnosis and overtreatment. Since 2005, the presence of the genetic rearrangement between transmembrane-serine protease gene (TMPRSS2) and the erythroblast transformation-specific (ETS) memberERG(v-ets erythroblastosis virus E26 oncogene homolog avian) has been demonstrated in almost half of PCa cases. Both FISH and RT-PCR are useful tools for detecting these rearrangements, but very few comparatives between both techniques have been published. In this study, we included FFPE tumors from 294 PCa patients treated with radical prostatectomy with more than 5 years of followup. We constructed a total of 20 tissue microarrays in order to perform break-apart and tricolor probe FISH approaches that were compared with RT-PCR, showing a concordance of 80.6% (P<0.001). The presence ofTMPRSS2-ERGrearrangement was observed in 56.6% of cases. No association betweenTMPRSS2-ERGstatus and clinicopathological parameters nor biochemical progression and clinical progression free survival was found. In conclusion, this study demonstrates that both FISH and RT-PCR are useful tools in the assessment of theTMPRSS2-ERGfusion gene status in PCa patients and that this genetic feature per se lacks prognostic value.

scholarly journals HGG-24. HIGH-GRADE GLIOMA WITH A NOVEL FUSION GENE OF VCL-ALK

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii348-iii348
Author(s):  
Shunsuke Yamamoto ◽  
Yuhki Koga ◽  
Hiroaki Ono ◽  
Hiroshi Asai ◽  
Kyutaro Ono ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Fusion Gene ◽  
Occipital Lobe ◽  
High Grade Glioma ◽  
Communicating Hydrocephalus ◽  
Histopathological Diagnosis ◽  
Positive Staining ◽  
High Grade ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma

Abstract A previously healthy 2-year-old boy presented with status epilepticus following intermittent vomiting. Computed tomography scan showed a 7cm mass on the left occipital lobe with midline shift, inferior cerebellar herniation, and diffuse cerebral edema. The extensive dissemination to bilateral cerebral hemispheres, brain stem, and optic nerve was also observed. He underwent brain biopsy from the lesion on his left occipital lobe. The histopathological diagnosis determined the diffuse or epithelial proliferation of astrocytic tumor cells with high mitotic rate, positive for p53 and glial fibrillary acidic protein positive staining consistent with high-grade glioma. The progressive tumor led to communicating hydrocephalus, that was favorably controlled by cerebrospinal fluid shunting. The data from the FoundationOne CDx cancer genome profile disclosed a novel VCL- anaplastic lymphoma kinase (ALK) fusion in the tumor cells of the patient. ALK rearrangement was determined to be positive for the tumor cells assessed by fluorescence in situ hybridization. Only 4 pediatric cases of glioma with ALK-rearrangement have ever been reported. All of them received subtotal or gross total resections and then survived with or without chemotherapy. This is the first case of glioma harboring VCL as a novel partner of ALK fusion gene. After the favorable response to the first-line chemotherapy, subsequent irradiation therapy has now been scheduled. The molecular classification of high-grade glioma may help to expand the targeted therapy for unresectable advanced brain tumor.

scholarly journals Pathological cytomorphologic features and the percentage of ALK FISH-positive cells predict pulmonary adenocarcinoma prognosis: a prospective cohort study

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Fenge Jiang ◽  
Congcong Wang ◽  
Ping Yang ◽  
Ping Sun ◽  
Jiannan Liu
Keyword(s):  
Overall Survival ◽  
Progression Free Survival ◽  
Signet Ring Cell ◽  
Pulmonary Adenocarcinoma ◽  
Cell Group ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Signet Ring ◽  
Ring Cell ◽  
Alk Positive

Abstract Background We conducted a study to explore the relationship between pathological cytomorphologic features and the percentage of anaplastic lymphoma kinase (ALK)-positive cells to better predict pulmonary adenocarcinoma prognosis with crizotinib treatment. Patients and methods We investigated 60 cases of patients with ALK-positive advanced or metastatic non-small cell lung cancer (NSCLC). Immunohistochemistry was performed to screen for ALK rearrangement. Fluorescence in situ hybridization (FISH) was used to detect the percentage of ALK-positive cells. The primary objectives of the study were the progression-free survival (PFS), the 3-year overall survival, and the 3-year overall survival (OS) rates. The secondary objectives of the study were the disease control rate (DCR) and the overall response rate (ORR). Results We compared the pathological cytomorphologic features of 60 cases of ALK-positive pulmonary adenocarcinoma, of which 21 cases were ALK-positive with signet ring cell cytomorphologic characteristics. There were statistical differences in the ORR (p = 0.019), DCR (p = 0.032), and PFS (p = 0.047) between the signet ring cell group and group without signet ring cells. Of these, 37 cases were ALK-positive with EML4 (echinoderm microtubule associated protein like 4)-ALK high percentage of positivity group. These cases benefited more from crizotinib treatment in the ORR (p = 0.046) and achieved a longer PFS (p = 0.036) compared to those with EML4-ALK low percentage of positivity group. Conclusions Signet ring cell cytomorphologic characteristics of pulmonary adenocarcinoma are associated with the percentage of ALK-positive cells. Signet ring cell cytomorphologic characteristics and the percentage of ALK-positive cells might predict the prognosis of pulmonary adenocarcinoma with crizotinib treatment. Trial registration The study was approved by the Institutional Review Board (Medical Ethics Committee of Yantai Yuhuangding Hospital). The registration number is NO.2016[193].

The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia

Blood ◽  
2007 ◽  
Vol 110 (12) ◽  
pp. 4073-4076 ◽  
Author(s):  
Alberto Catalano ◽  
Mark A. Dawson ◽  
Karthiga Somana ◽  
Stephen Opat ◽  
Anthony Schwarer ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Fusion Gene ◽  
Splice Variants ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Promyelocytic Leukemia ◽  
Regulatory Subunit ◽  
Type I ◽  
Rt Pcr ◽  
New Variant

Abstract We report the molecular and cytogenetic characterization of a novel variant of acute promyelocytic leukemia (APL). The bone marrow showed 88% hypergranular promyelocytes, and the karyotype was 47,XY,+22 [5]/46,XY[30]. Fluorescence in situ hybridization (FISH) indicated disruption and deletion of the 5′-end of the RARA gene. Treatment with all-trans retinoic acid, idarubicin, and arsenic trioxide induced cytogenetic complete remission without morphologic evidence of residual leukemia. The diagnostic marrow was negative for PML-RARA transcripts by reverse transcription–polymerase chain reaction (RT-PCR), but an atypical product was observed. Sequencing showed partial homology to the PRKAR1A gene, encoding the regulatory subunit type I-α of cyclic adenosine monophosphate–dependent protein kinase. RT-PCR using specific primers for PRKAR1A and RARA amplified 2 transcript splice variants of a PRKAR1A-RARA fusion gene, and PRKAR1A and RARA FISH probes confirmed the fusion. This novel PRKAR1A-RARA gene rearrangement is the fifth variant APL in which the RARA partner gene has been identified and the second known rearrangement of PRKAR1A in a malignant disease. This trial was registered at www.actr.org.au with the Australian Clinical Trials Registry as number 12605000070639.

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