scholarly journals Genomic Analysis Identifies Rare ALK Positive Cases In The TCGA Database

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S148-S148
Author(s):  
A R Patil ◽  
D S Dabrowski ◽  
J Cotelingam ◽  
D Veillon ◽  
M Ong ◽  
...  
Keyword(s):  
Prevalence Rate ◽  
Genomic Analysis ◽  
Asian Population ◽  
The Cancer Genome Atlas ◽  
Driver Mutations ◽  
Lower Prevalence ◽  
Salivary Duct ◽  
Kinase Gene ◽  
Anaplastic Lymphoma ◽  
Alk Positive

Abstract Introduction/Objective The anaplastic lymphoma kinase (ALK) gene is a receptor tyrosine kinase gene located in the 2p23.2 region. Normally, dimerization of ALK receptor by binding to its ligand activates the ALK receptor by autophosphorylation of c-termius and activates downstream PI3K, MAPK and JAK3 pathways. The ALK gene is abnormally hyperactivated by fusion of the 3’ half containing the kinase domain with 5’ portion of other genes, resulting in the ligand independent dimerization and activation of the ALK receptor. The tumors harboring these translocations are termed as ALK-positive tumors and can be treated with ALK inhibitors. Methods We analyzed the status of clinically relevant ALK fusion driver mutations in 230 different cancer studies, containing tumors from 79222 different individuals, in The Cancer Genome Atlas database (TCGA) using the cbioportal web browser. Results We observed that, as expected ALK-positive mutations are predominantly present in NSCLC, with EML4- ALK being the most common. In addition, we were able to identify ALK positive mutations in colorectal carcinomas, papillary thyroid carcinomas, papillary renal cell carcinomas, sarcomas and invasive ductal carcinomas of the breast. Most important, our analysis identified extremely rare ALK positive cases in salivary duct carcinomas, urothelial carcinomas, cutaneous melanomas and prostatic adenocarcinomas. Conclusion Our analysis identified ALK positive cases were predominant in adenocarcinoma of lung with EML4-ALK being the most common ALK positive mutation, which is also consistent with the literature. However, the ALK positive mutations were at a lower prevalence rate than that described in the literature. We attribute the lower prevalence rate to underrepresentation of the Asian population in the TCGA database. In addition, we identified extremely rare ALK positive cases in salivary duct carcinomas, melanomas and prostate cancers, thus highlighting the need for testing for these mutations in these cancers.

Potentially actionable kinase fusions in inflammatory myofibroblastic tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10513-10513 ◽  
Author(s):  
Christine Marie Lovly ◽  
Doron Lipson ◽  
Geoff Otto ◽  
Tina Brennan ◽  
Sabita Sankar ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Driver Mutations ◽  
Kinase Gene ◽  
Anaplastic Lymphoma ◽  
Formalin Fixed Paraffin ◽  
Mesenchymal Neoplasm ◽  
Formalin Fixed Paraffin Embedded ◽  
Alk Positive ◽  
Next Generation Sequencing Ngs

10513 Background: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm that harbors anaplastic lymphoma kinase (ALK) gene rearrangements in approximately 50% of cases. ALK inhibitors have been validated as an effective therapeutic approach in this subset of IMTs. The goal of this study was to characterize a series of IMTs using both immunohistochemistry (IHC) and next generation sequencing (NGS). Methods: 30 formalin-fixed, paraffin-embedded IMT specimens from 28 patients were evaluated by IHC for ALK expression using standard techniques. DNA was extracted and sequenced using a targeted capture-based NGS assay for 3769 exons of 236 cancer-related genes and 47 introns of 19 commonly rearranged genes, including 8 tyrosine kinases in a CLIA laboratory (Foundation Medicine). Selected specimens were also evaluated for ALK fusions by fluorescence in-situ hybridization (FISH). Results: 20 samples were ALK positive and 10 samples were ALK negative by IHC. Targeted NGS was successfully performed in 16/20 ALK positive and 10/10 ALK negative cases. Among the 16 ALK positive cases analyzed by NGS, 12 harbored ALK fusions with various 5’ gene fusion partners, including LMNA, TPM3, TPM4, SEC31A, TFG, RANBP2, and CLTC. The remaining 4 were also negative by FISH suggesting a different mechanism of ALK overexpression. Among the 10 ALK negative cases, 2 harbored ALK fusions (EML4-ALK, TPM3-ALK). In the other 8 ALK negative samples, 2 contained distinct ROS1 fusions (YWHAE-ROS1, TFG-ROS1) and 1 contained a PDGFRβ fusion (NAB2-PDGFRβ), none of which have been described in IMT samples to date. Overall, kinase gene fusions were identified in 18/26 (69%) evaluable samples. Conclusions: This study represents the most comprehensive NGS analysis of IMTs. 12/12(100%) ALK IHC and FISH positive cases contained ALK fusions, while 5/8 (63%) of distinct ALK IHC negative cases harbored kinase fusions, involving ALK, ROS1, or PDGFRβ. Since these fusions are all targetable with existing kinase inhibitors (i.e. crizotinib, dasatinib), this study suggests that IMTs should be routinely profiled for kinase fusions and not just by ALK IHC. Efforts are ongoing to identify “driver mutations” in the fusion-negative specimens.

scholarly journals ALK-Positive Squamous Cell Carcinoma Dramatically Responded to Alectinib

2018 ◽  
Vol 2018 ◽  
pp. 1-3
Author(s):  
Ray Sagawa ◽  
Takehiko Ohba ◽  
Eisaku Ito ◽  
Susumu Isogai
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lower Lobe ◽  
Smoking History ◽  
Driver Mutations ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Alk Positive ◽  
Loss Of Appetite

Anaplastic lymphoma kinase (ALK) rearrangement is usually observed in patients with adenocarcinoma. Herein, we report a case of squamous cell carcinoma (SCC) with ALK rearrangement treated with alectinib. The patient was a 73-year-old woman without a smoking history. She consulted us with nonproductive cough and loss of appetite. Computed tomography scan revealed a mass in the left lower lobe of the lung. According to the pathological examinations, we diagnosed the tumor as SCC. Because the patient had never smoked, we searched for driver mutations and found that the tumor harbored ALK rearrangement. We began treatment with alectinib, and the tumor remarkably reduced in volume. No severe adverse events were observed. Although there are only few reports of SCC with ALK rearrangement, this case implies that clinicians should consider searching for driver mutations in patients with SCC when there are atypical findings or characteristics.

The Simulated Random Assignment of Missense Mutations Throughout a Gene of Interest Can Determine Whether Missense Mutations Found in That Gene in a Population of Tumor Genomes Are Non-Randomly Distributed v1

2021 ◽  
Author(s):  
Richard L Cullum ◽  
David J Riese II
Keyword(s):  
Tumor Progression ◽  
Tumor Cells ◽  
Random Distribution ◽  
Selective Advantage ◽  
The Cancer Genome Atlas ◽  
Driver Mutations ◽  
Missense Mutations ◽  
Random Assignment ◽  
Kinase Gene ◽  
Tcga Dataset

Human malignancies result from the accumulation of genetic and epigenetic changes to normal cells. In many malignancies, gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes drive tumorigenesis and tumor progression. The identification of tumor driver mutations and the genes that host such mutations is critical for the molecular staging and targeted therapy of malignancies. Since tumor driver mutations cause tumorigenesis or tumor progression, the proliferation of tumor cells selects for these mutations. Thus, in a gene that hosts tumor driver mutations, there will be a non-random distribution of mutations across the gene, as mutations that provide a selective advantage for the tumor cells will predominate over mutations that do not provide a selective advantage for the tumor cells. Consider a particular gene in a population of tumor genomes; the total number of coincident missense mutations in that gene, defined here as two or more missense mutations that affect a particular codon, will be greater than the total number of coincident missense mutations that arise through random assignment of missense mutations across the gene. Consequently, here we use the R Statistical Computing environment to simulate the random assignment of missense mutations across a user-specified gene. The number of randomly assigned missense mutations is defined by the user and should be equal to the total number of missense mutations observed in the desired gene in the collection of tumor genomes of interest. Based on the simulated random assignment of missense mutations, the R code then determines the total number of simulated coincident and non-coincident mutations. This simulation is repeated a user-defined number of times, and the average number of simulated coincident and non-coincident mutations is calculated from the set of simulations. The R code then uses a Chi-square test to determine whether the observed number of coincident mutations (in the gene of interest in a collection of tumor genomes) significantly exceeds the average number of simulated coincident mutations. A positive result indicates that the gene hosts a non-random distribution of missense mutations and suggests that the gene hosts tumor driver mutations. We have used this R code to analyze mutations in the ERBB4 receptor tyrosine kinase gene that are found in The Cancer Genome Atlas (TCGA) dataset. Our analysis indicates that the number of coincident mutations observed in ERBB4 in the TCGA dataset is statistically greater than the number of coincident mutations that arise from the simulated random assignment of missense mutations across the ERBB4 gene. This finding indicates that the distribution of missense mutations in ERBB4 in the TCGA dataset is non-random.

scholarly journals EML4-ALK positive lung adenocarcinoma with skeletal muscle metastasis in the right calf which was treatable with lorlatinib after resistance to treatment with alectinib

2021 ◽  
Vol 14 (4) ◽  
pp. e240295
Author(s):  
Hironari Matsuda ◽  
Munechika Hara ◽  
Shin-Ichiro Iwakami ◽  
Kazuhisa Takahashi
Keyword(s):  
Skeletal Muscle ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Stable Condition ◽  
Japanese Woman ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Resistance To Treatment ◽  
Alk Positive ◽  
The Right

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.

scholarly journals Increased Tenascin C, Osteopontin and HSP90 Levels in Plasmatic Small Extracellular Vesicles of Pediatric ALK-Positive Anaplastic Large Cell Lymphoma: New Prognostic Biomarkers?

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 253
Author(s):  
Federica Lovisa ◽  
Anna Garbin ◽  
Sara Crotti ◽  
Piero Di Battista ◽  
Ilaria Gallingani ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Enrichment Analysis ◽  
Heat Shock Protein 90 ◽  
Large Cell ◽  
Tenascin C ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma ◽  
Alk Positive

Over the past 15 years, several biological and pathological characteristics proved their significance in pediatric anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) prognostic stratification. However, the identification of new non-invasive disease biomarkers, relying on the most important disease mechanisms, is still necessary. In recent years, plasmatic circulating small extracellular vesicles (S-EVs) gathered great importance both as stable biomarker carriers and active players in tumorigenesis. In the present work, we performed a comprehensive study on the proteomic composition of plasmatic S-EVs of pediatric ALCL patients compared to healthy donors (HDs). By using a mass spectrometry-based proteomics approach, we identified 50 proteins significantly overrepresented in S-EVs of ALCL patients. Gene Ontology enrichment analysis disclosed cellular components and molecular functions connected with S-EV origin and vesicular trafficking, whereas cell adhesion, glycosaminoglycan metabolic process, extracellular matrix organization, collagen fibril organization and acute phase response were the most enriched biological processes. Of importance, consistently with the presence of nucleophosmin (NPM)-ALK fusion protein in ALCL cells, a topological enrichment analysis based on Reactome- and Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived networks highlighted a dramatic increase in proteins of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in ALCL S-EVs, which included heat shock protein 90-kDa isoform alpha 1 (HSP90AA1), osteopontin (SPP1/OPN) and tenascin C (TNC). These results were validated by Western blotting analysis on a panel of ALCL and HD cases. Further research is warranted to better define the role of these S-EV proteins as diagnostic and, possibly, prognostic parameters at diagnosis and for ALCL disease monitoring.

scholarly journals Systematic Review and Network Meta-Analysis of Anaplastic Lymphoma Kinase (ALK) Inhibitors for Treatment-Naïve ALK-Positive Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1966
Author(s):  
Cheng-Hao Chuang ◽  
Hsiao-Ling Chen ◽  
Hsiu-Mei Chang ◽  
Yu-Chen Tsai ◽  
Kuan-Li Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Anaplastic Lymphoma Kinase ◽  
Low Dose ◽  
Meta Analysis ◽  
Phase Iii ◽  
Pairwise Comparisons ◽  
Anaplastic Lymphoma ◽  
Treatment Naïve ◽  
Alk Positive

Several anaplastic lymphoma kinase inhibitors (ALKIs) have demonstrated excellent efficacy on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and also better adverse effect (AE) profiles compared to cytotoxic chemotherapy in advanced stage anaplastic lymphoma kinase (ALK) rearrangement-positive non-small cell lung cancer (NSCLC) in phase III randomized clinical trials (RCTs). We conducted this systematic review and network meta-analysis to provide a ranking of ALKIs for treatment-naïve ALK-positive patients in terms of PFS, ORR, and AEs. In addition, a sub-group analysis of treatment benefits in patients with baseline brain metastasis was also conducted. Contrast-based analysis was performed for multiple treatment comparisons with the restricted maximum likelihood approach. Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being the best (Prbest) reference. All next-generation ALKIs were superior to crizotinib in PFS but lorlatinib and brigatinib had increased AEs. The probability of lorlatinib being ranked first among all treatment arms was highest (SUCRA = 93.3%, Prbest = 71.8%), although there were no significant differences in pairwise comparisons with high- (600 mg twice daily) and low- (300 mg twice daily) dose alectinib. In subgroup analysis of patients with baseline brain metastasis, low-dose alectinib had the best PFS (SUCRA = 87.3%, Prbest = 74.9%). Lorlatinib was associated with the best ranking for ORR (SUCRA = 90.3%, Prbest = 71.3%), although there were no significant differences in pairwise comparisons with the other ALKIs. In addition, low-dose alectinib had the best safety performance (SUCRA = 99.4%, Prbest = 97.9%). Lorlatinib and low-dose alectinib had the best PFS and ORR in the overall population and baseline brain metastasis subgroup, respectively. Low-dose alectinib had the lowest AE risk among the available ALKIs. Further head-to-head large-scale phase III RCTs are needed to verify our conclusions.

Complete response after ceritinib treatment in non-small cell lung cancer in an elderly patient

2020 ◽  
Vol 26 (8) ◽  
pp. 2031-2033
Author(s):  
Nilay Sengul Samanci ◽  
Emir Celik ◽  
Burak Akovalı ◽  
Sait Sager ◽  
Fuat Hulusi Demirelli
Keyword(s):  
Lung Cancer ◽  
Elderly Patient ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Complete Response ◽  
Small Cell ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Stage 4 ◽  
Alk Positive

Introduction Ceritinib is a selective second-generation ALK inhibitor that is highly sensitive to echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) molecule. Case report In this paper, we report a 68-year-old female that was diagnosed with stage 4 ALK-positive non-small cell lung cancer (NSCLC). Management and outcome: She was treated with crizotinib first-line, cisplatin and gemcitabine as second-line. And for third-line, ceritinib was started. She had complete response over 3.5 years under ceritinib treatment. And she is still receiving ceritinib with no adverse event. Discussion Cases achieving complete response with ceritinib treatment are rare. In this paper, we aimed to emphasize the complete response in stage 4 NSCLC in an elderly patient.

scholarly journals Actionable Gene Alterations in an Asian Population With Triple-Negative Breast Cancer

2018 ◽  
pp. 1-13 ◽  
Author(s):  
Masayuki Nagahashi ◽  
YiWei Ling ◽  
Tetsu Hayashida ◽  
Yuko Kitagawa ◽  
Manabu Futamura ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Ethnic Diversity ◽  
Triple Negative ◽  
Asian Population ◽  
Japanese Patients ◽  
The United States ◽  
The Cancer Genome Atlas ◽  
Cancer Genes ◽  
Asian Patients

Purpose It has been suggested that the biologic characteristics of breast cancer may differ among different geographic or ethnic populations. Indeed, triple-negative breast cancer (TNBC), the most lethal breast cancer subgroup, has been reported to occur at a higher incidence in Japan than in the United States. However, most genomic studies of these tumors are from Western countries, and the genomic landscape of TNBC in an Asian population has not been thoroughly investigated. Here, we sought to elucidate the geographic and ethnic diversity of breast cancer by examining actionable driver alterations in TNBC tumors from Japanese patients and comparing them with The Cancer Genome Atlas (TCGA) database, which gathers data primarily from non-Asian patients. Materials and Methods We performed comprehensive genomic profiling, including an analysis of 435 known cancer genes, among Japanese patients with TNBC (n = 53) and compared the results with independent data obtained from TCGA (n = 123). Results Driver alterations were identified in 51 (96%) of 53 Japanese patients. Although the overall alteration spectrum among Japanese patients was similar to that of TCGA, we found significant differences in the frequencies of alterations in MYC and PTK2. We identified three patients (5.7%) with a high tumor mutational burden, although no microsatellite instability was observed in any of the Japanese patients. Importantly, pathway analysis revealed that 66.0% (35 of 53) of Japanese patients, as well as 66.7% (82 of 123) of TCGA cohort, had alterations in at least one actionable gene targetable by US Food and Drug Administration–approved drug. Conclusion Our study identified actionable driver alterations in Japanese patients with TNBC, revealing new opportunities for targeted therapies in Asian patients.

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