Gene Summary

Gene:ALK; ALK receptor tyrosine kinase
Aliases: CD246, NBLST3
Summary:This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:ALK tyrosine kinase receptor
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: ALK (cancer-related)

Shao K, Wang Y, Xue Q, et al.
Clinicopathological features and prognosis of ciliated muconodular papillary tumor.
J Cardiothorac Surg. 2019; 14(1):143 [PubMed] Free Access to Full Article Related Publications
BACKGROUNDS: The pulmonary ciliated muconodular papillary tumor (CMPT) is a very rare tumor with only several case reports in published literatures, and its clinicopathological features, standard treatment methods and prognosis has not been well defined.
METHODS: Two cases of CMPT diagnosed and treated in our hospital and 39 cases reported in the published literature were analyzed retrospectively.
RESULTS: The cohort of 41 CMPT patients comprised of 20 males and 21 females, aged 9-84 years. The diameter of the primary tumor was 0.3-4.5 cm. Most of these lesions were subsolid nodules, as observed on computed tomography and easily misdiagnosed as early lung adenocarcinoma. Tumors of 26 patients were stained by immunohistochemistry method, which revealed that CK7, CEA, and TTF-1 were positive and CK20 was negative in most patients. The results of gene alternation demonstrated mutations in EGFR, KRAS, and BRAF and ALK rearrangements in CMPT. All the patients underwent surgical treatment and did not receive postoperative adjuvant therapy. The follow-up duration was 0-120 months, and no case of tumor recurrence was found until the final follow-up.
CONCLUSIONS: The incidence of CMPT was low and rate of image misdiagnosis high. Immunohistochemistry is helpful for accurate diagnosis of CMPT. Sub-lobectomy may be proper and adjuvant treatment should be avoided since the disease is now prone to benign lesions. Furthermore, since the biological behavior of this tumor is not yet fully elucidated, additional case data are essential for accurate conclusions.

Ito M, Miyata Y, Hirano S, et al.
Synchronicity of genetic variants between primary sites and metastatic lymph nodes, and prognostic impact in nodal metastatic lung adenocarcinoma.
J Cancer Res Clin Oncol. 2019; 145(9):2325-2333 [PubMed] Related Publications
PURPOSE: Nodal positive lung adenocarcinoma includes wide range of survival. Several methods for the classification of nodal-positive lung cancer have been proposed. However, classification considering the impact of targetable genetic variants are lacking. The possibility of genetic variants for the better stratification of nodal positive lung adenocarcinoma was estimated.
METHODS: Mutations of 36 genes between primary sites and metastatic lymph nodes (LNs) were compared using next-generation sequencing. Subsequently, mutations in EGFR and BRAF, rearrangements in ALK and ROS1 were evaluated in 69 resected pN1-2M0 adenocarcinoma cases. Recurrence-free survival (RFS), post-recurrence survival (PRS), and overall survival (OS) were evaluated with respect to targetable variants and tyrosine kinase inhibitor (TKI) therapy after recurrence.
RESULTS: About 90% of variants were shared and allele frequencies were similar between primary and metastatic sites. In 69 pN1-2M0 cases, EGFR/ALK were positive in primary sites of 39 cases and same EGFR/ALK variants were confirmed in metastatic LNs of 96.7% tissue-available cases. Multivariate analyses indicated positive EGFR/ALK status was associated with worse RFS (HR 2.366; 95% CI 1.244-4.500; P = 0.009), and PRS was prolonged in cases receiving TKI therapy (no post-recurrence TKI therapies, HR 3.740; 95% CI 1.449-9.650; P = 0.006). OS did not differ with respect to targetable variants or TKI therapy.
CONCLUSIONS: Cases harbouring targetable genetic variants had a higher risk of recurrence, but PRS was prolonged by TKI therapy. Classification according to the targetable genetic status provides a basis for predicting recurrence and determining treatment strategies after recurrence.

Cao Y, Zhu W, Chen W, et al.
Prognostic Value of BIRC5 in Lung Adenocarcinoma Lacking EGFR, KRAS, and ALK Mutations by Integrated Bioinformatics Analysis.
Dis Markers. 2019; 2019:5451290 [PubMed] Free Access to Full Article Related Publications
Objective: This study was aimed at investigating the prognostic significance of Baculoviral IAP repeat containing 5 (BIRC5) in lung adenocarcinoma (LAD) lacking EGFR, KRAS, and ALK mutations (triple-negative (TN) adenocarcinomas).
Methods: The gene expression profiles were obtained from Gene Expression Omnibus (GEO). The identification of the differentially expressed genes (DEGs) was performed by GeneSpring GX. Gene set enrichment analysis (GSEA) was used to execute gene ontology function and pathway enrichment analysis. The protein interaction network was constructed by Cytoscape. The hub genes were extracted by MCODE and cytoHubba plugin from the network. Then, using BIRC5 as a candidate, the prognostic value in LAD and TN adenocarcinomas was verified by the Kaplan-Meier plotter and The Cancer Genome Atlas (TCGA) database, respectively. Finally, the mechanism of BIRC5 was predicted by a coexpressed network and enrichment analysis.
Results: A total of 38 upregulated genes and 121 downregulated genes were identified. 9 hub genes were extracted. Among them, the mRNA expression of 5 genes, namely, BIRC5, MCM4, CDC20, KIAA0101, and TRIP13, were significantly upregulated among TN adenocarcinomas (all
Conclusion: Overexpressed in tumors, BIRC5 is associated with unfavorable overall survival in TN adenocarcinomas. BIRC5 is a potential predictor and therapeutic target in TN adenocarcinomas.

Pastor ER, Mousa SA
Current management of neuroblastoma and future direction.
Crit Rev Oncol Hematol. 2019; 138:38-43 [PubMed] Related Publications
Neuroblastoma is the most common solid extracranial tumor in pediatrics and can regress spontaneously or grow and metastasize with resistance to multiple therapeutic approaches. The prognosis and approach to treatment depends on the tumor presentation and whether it expresses certain drivers such as MYCN, ALK, and TrkB. Expression or mutation of these genes and kinases correlates with high-risk and poor prognosis. Multiple therapeutic approaches are being used to target MYCN, ALK, and TrkB, as well as GD2, a surface antigen present on the surface of neuroblastoma tumor cells. This review discusses the nature of these targets and several current therapies for neuroblastoma. A focus is placed on recent therapeutic developments including targeted delivery of chemotherapy, novel radiation therapy, and immunotherapy.

Fuchs S, Naderi J, Meggetto F
Non-Coding RNA Networks in ALK-Positive Anaplastic-Large Cell Lymphoma.
Int J Mol Sci. 2019; 20(9) [PubMed] Free Access to Full Article Related Publications
Non-coding RNAs (ncRNAs) are essential regulators of gene expression. In recent years, it has become more and more evident that the different classes of ncRNAs, such as micro RNAs, long non-coding RNAs and circular RNAs are organized in tightly controlled networks. It has been suggested that deregulation of these networks can lead to disease. Several studies show a contribution of these so-called competing-endogenous RNA networks in various cancer entities. In this review, we highlight the involvement of ncRNA networks in anaplastic-large cell lymphoma (ALCL), a T-cell neoplasia. A majority of ALCL cases harbor the molecular hallmark of this disease, a fusion of the anaplastic lymphoma kinase (ALK) gene with the nucleophosmin (NPM, NPM1) gene leading to a permanently active kinase that promotes the malignant phenotype. We have focused especially on ncRNAs that are regulated by the

Liang W, Guo M, Pan Z, et al.
Association between certain non-small cell lung cancer driver mutations and predictive markers for chemotherapy or programmed death-ligand 1 inhibition.
Cancer Sci. 2019; 110(6):2014-2021 [PubMed] Free Access to Full Article Related Publications
This study aimed to analyze the association between driver mutations and predictive markers for some anti-tumor agents in non-small cell lung cancer (NSCLC). A cohort of 785 Chinese patients with NSCLC who underwent resection from March 2016 to November 2017 in the First Affiliated Hospital of Guangzhou Medical University was investigated. The specimens were subjected to hybridization capture and sequence of 8 important NSCLC-related driver genes. In addition, the slides were tested for PD-L1, excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthase (TS) and β-tubulin III by immunohistochemical staining. A total of 498 (63.4%) patients had at least 1 driver gene alteration. Wild-type, EGFR rare mutation (mut), ALK fusion (fus), RAS mut, RET fus and MET mut had relatively higher proportions of lower ERCC1 expression. EGFR 19del, EGFR L858R, EGFR rare mut, ALK fus, HER2 mut, ROS1 fus and MET mut were more likely to have TS low expression. Wild-type, EGFR L858R, EGFR rare mut and BRAF mut were associated with lower β-tubulin III expression. In addition, wild-type, RAS mut, ROS1 fus, BRAF and MET mut had higher proportion of PD-L1 high expression. As a pilot validation, 21 wild-type patients with advanced NSCLC showed better depth of response and response rate to taxanes compared with pemetrexed/gemcitabine (31.2%/60.0% vs 26.6%/45.5%). Our study may aid in selecting the optimal salvage regimen after targeted therapy failure, or the chemo-regimen where targeted therapy has not been a routine option. Further validation is warranted.

Wang Y, Yu L, Fang N, Sun B
[Genetic mutations among Chinese patients with non-small cell lung cancer and targeted therapy].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2019; 36(5):424-428 [PubMed] Related Publications
OBJECTIVE: To provide mutational analysis and targeted therapy for Chinese patients with non-small cell lung cancer (NSCLCs).
METHODS: Mutation of 13 genes including EGFR, ALK, KRAS were detected among 102 patients with NSCLCs by next-generation sequencing, and the correlation between mutations and clinical characteristics and response to targeted therapy was analyzed.
RESULTS: In total 42 EGFR mutations (40.8%), 3 ALK fusions (3.9%), 6 KRAS mutations (5.8%), 3 PIK3CA mutations and amplifications (2.9%), 1 MET exon 14-skipping (1%) and 1 RET fusion (1%) were detected. The occurrence of mutations have varied with sample types and pathological types. Seventeen out of 20 EGFR tyrosine kinase inhibitor (TKI)-treated patients with EGFR mutations have shown remission.
CONCLUSION: The mutational frequency of NSCLCs among Chinese patients slightly differed from the western populations, in particular the frequency of ALK fusion. The mutations have well correlated with clinical response to targeted therapy.

Politi A, Tsiambas E, Mastronikolis NS, et al.
Combined EGFR/ALK Expression Analysis in Laryngeal Squamous Cell Carcinoma.
In Vivo. 2019 May-Jun; 33(3):815-819 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: Epidermal growth factor receptor (EGFR) acts as an oncogene in malignancies. Our aim was to examine the role of combined EGFR/ anaplastic lymphoma kinase (ALK) expression as molecular markers in laryngeal squamous cell carcinoma (LSCC) patients.
MATERIALS AND METHODS: Fifty (n=50) tissue sections derived from twenty-five (n=25) primary LSCCs were analyzed by immunohistochemistry (IHC).
RESULTS: EGFR overexpression was observed in 17/25 (68%) cases. Concerning ALK, 23/25 (92%) demonstrated low expression. EGFR expression was associated with grade (p=0.049), whereas ALK expression was correlated with stage (p=0.048). ALK overexpression was detected at advanced-stage EGFR-positive cases. A biphasic EGFR protein expression pattern was observed in five (n=5) LSCC cases, whereas ALK expression was stable in all cases.
CONCLUSION: EGFR overexpression is frequently observed in LSCC combined with low ALK expression. LSCC patients with EGFR/ALK protein overexpression should be eligible for targeted therapeutic strategies.

Sakai K, Ohira T, Matsubayashi J, et al.
Performance of Oncomine Fusion Transcript kit for formalin-fixed, paraffin-embedded lung cancer specimens.
Cancer Sci. 2019; 110(6):2044-2049 [PubMed] Free Access to Full Article Related Publications
Gene fusions play an important role in the carcinogenesis of lung adenocarcinoma. The recent association of four oncogenic driver genes, ALK, ROS1, RET, and NTRK1, as lung tumor predictive biomarkers has increased the need for precision medicine. We used formalin-fixed, paraffin-embedded tissue samples of non-small cell lung cancer from 150 EGFR mutation-negative cases and 10 fusion status-known cases and compared the performance of the Oncomine Dx Fusion Transcript Test (ODxFT) with FISH break-apart for the detection of ALK, RET, and ROS1 fusion genes. RNA was extracted from the paraffin-embedded tissue samples with or without macrodissection under hematoxylin and eosin staining, and the ALK fusion gene was independently determined using these assays. Fusion detection analyses were successfully carried out using ODxFT in 150 cases, with only one invalid case. ALK fusion genes were detected at a frequency of 7.3% (11/150) in the lung cancer specimens. Concordance rate between the ODxFT and ALK-FISH analyses was 99.3% (148/149). Sensitivity and specificity were 91.7% and 99.3%, respectively. All the samples with a known fusion status were accurately matched between the two assays. Our results show a high concordance rate between the ODxFT and ALK-FISH analyses. ODxFT was thus validated as an effective method for detecting clinically significant ALK fusion genes in paraffin-embedded tissue samples.

Singal G, Miller PG, Agarwala V, et al.
Association of Patient Characteristics and Tumor Genomics With Clinical Outcomes Among Patients With Non-Small Cell Lung Cancer Using a Clinicogenomic Database.
JAMA. 2019; 321(14):1391-1399 [PubMed] Article available free on PMC after 09/10/2019 Related Publications
Importance: Data sets linking comprehensive genomic profiling (CGP) to clinical outcomes may accelerate precision medicine.
Objective: To assess whether a database that combines EHR-derived clinical data with CGP can identify and extend associations in non-small cell lung cancer (NSCLC).
Design, Setting, and Participants: Clinical data from EHRs were linked with CGP results for 28 998 patients from 275 US oncology practices. Among 4064 patients with NSCLC, exploratory associations between tumor genomics and patient characteristics with clinical outcomes were conducted, with data obtained between January 1, 2011, and January 1, 2018.
Exposures: Tumor CGP, including presence of a driver alteration (a pathogenic or likely pathogenic alteration in a gene shown to drive tumor growth); tumor mutation burden (TMB), defined as the number of mutations per megabase; and clinical characteristics gathered from EHRs.
Main Outcomes and Measures: Overall survival (OS), time receiving therapy, maximal therapy response (as documented by the treating physician in the EHR), and clinical benefit rate (fraction of patients with stable disease, partial response, or complete response) to therapy.
Results: Among 4064 patients with NSCLC (median age, 66.0 years; 51.9% female), 3183 (78.3%) had a history of smoking, 3153 (77.6%) had nonsquamous cancer, and 871 (21.4%) had an alteration in EGFR, ALK, or ROS1 (701 [17.2%] with EGFR, 128 [3.1%] with ALK, and 42 [1.0%] with ROS1 alterations). There were 1946 deaths in 7 years. For patients with a driver alteration, improved OS was observed among those treated with (n = 575) vs not treated with (n = 560) targeted therapies (median, 18.6 months [95% CI, 15.2-21.7] vs 11.4 months [95% CI, 9.7-12.5] from advanced diagnosis; P < .001). TMB (in mutations/Mb) was significantly higher among smokers vs nonsmokers (8.7 [IQR, 4.4-14.8] vs 2.6 [IQR, 1.7-5.2]; P < .001) and significantly lower among patients with vs without an alteration in EGFR (3.5 [IQR, 1.76-6.1] vs 7.8 [IQR, 3.5-13.9]; P < .001), ALK (2.1 [IQR, 0.9-4.0] vs 7.0 [IQR, 3.5-13.0]; P < .001), RET (4.6 [IQR, 1.7-8.7] vs 7.0 [IQR, 2.6-13.0]; P = .004), or ROS1 (4.0 [IQR, 1.2-9.6] vs 7.0 [IQR, 2.6-13.0]; P = .03). In patients treated with anti-PD-1/PD-L1 therapies (n = 1290, 31.7%), TMB of 20 or more was significantly associated with improved OS from therapy initiation (16.8 months [95% CI, 11.6-24.9] vs 8.5 months [95% CI, 7.6-9.7]; P < .001), longer time receiving therapy (7.8 months [95% CI, 5.5-11.1] vs 3.3 months [95% CI, 2.8-3.7]; P < .001), and increased clinical benefit rate (80.7% vs 56.7%; P < .001) vs TMB less than 20.
Conclusions and Relevance: Among patients with NSCLC included in a longitudinal database of clinical data linked to CGP results from routine care, exploratory analyses replicated previously described associations between clinical and genomic characteristics, between driver mutations and response to targeted therapy, and between TMB and response to immunotherapy. These findings demonstrate the feasibility of creating a clinicogenomic database derived from routine clinical experience and provide support for further research and discovery evaluating this approach in oncology.

Mok TSK, Wu YL, Kudaba I, et al.
Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
Lancet. 2019; 393(10183):1819-1830 [PubMed] Related Publications
BACKGROUND: First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.
METHODS: This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at, number NCT02220894.
FINDINGS: From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.
INTERPRETATION: The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.
FUNDING: Merck Sharp & Dohme.

Si HP, Wang Z, Fan QH, et al.
[Dedifferentiated liposarcoma with inflammatory myofibroblastic tumor-like features: a clinicopathological analysis of five cases].
Zhonghua Bing Li Xue Za Zhi. 2019; 48(4):282-287 [PubMed] Related Publications

Fang F, Qiao XB, Yang L, et al.
[Diagnosis of lung biopsy employing the 2015 WHO criteria and detection of related oncogenic driver mutations].
Zhonghua Bing Li Xue Za Zhi. 2019; 48(4):270-275 [PubMed] Related Publications

Gerbe A, Alame M, Dereure O, et al.
Systemic, primary cutaneous, and breast implant-associated ALK-negative anaplastic large-cell lymphomas present similar biologic features despite distinct clinical behavior.
Virchows Arch. 2019; 475(2):163-174 [PubMed] Related Publications
Despite distinct clinical presentation and outcome, systemic, primary cutaneous, and breast implant-associated anaplastic large cell lymphomas (S-, PC-, BI-ALCL) ALK-negative (ALK-) show similar histopathological features including the presence of the "hallmark" cells with horseshoe-shaped nuclei and CD30 protein expression. The purpose was to better characterize these three entities using immunohistochemistry and FISH (Fluorescent in situ hybridization) to identify biomarkers differently expressed and that might be involved in their pathogenesis. Twenty-two S-ALCL ALK-, 13 PC-ALCL, and 2 BI-ALCL were included. Cases were tested for P53, P63, MUM1, MYC, GATA3, p-STAT3, PD1, and PDL1 protein expression and DUP22, TP53, TP63, MYC, and PDL1 chromosomal aberrations. As expected, S-ALCL ALK- patients had adverse outcome compare to PC and BI-ALCL. No difference was observed between the three groups concerning protein expression except for MUM1 that was significantly more frequently expressed in S-ALCL ALK- compared to PC-ALCL. In particular, constitutive activation of the STAT3 pathway and PDL1/PD1 immune-checkpoint expression was present in the three entities. TP53 deletion and PDL1 gene amplification were the commonest cytogenetic alterations and were present in the three entities. None of the studied biological parameters was associated with prognosis. Despite distinct clinical behavior, S-ALCL ALK-, PC-ALCL, and BI-ALCL share similar biological features. Larger series should be investigated with the current approach to determine more precisely the activity and the prognostic value of these biomarkers and pathways in each group.

Szpechcinski A, Florczuk M, Duk K, et al.
The expression of circulating miR-504 in plasma is associated with EGFR mutation status in non-small-cell lung carcinoma patients.
Cell Mol Life Sci. 2019; 76(18):3641-3656 [PubMed] Article available free on PMC after 09/10/2019 Related Publications
MicroRNAs (miRNAs), key regulators of gene expression at the post-transcriptional level, are grossly misregulated in some human cancers, including non-small-cell lung carcinoma (NSCLC). The aberrant expression of specific miRNAs results in the abnormal regulation of key components of signalling pathways in tumour cells. MiRNA levels and the activity of the gene targets, including oncogenes and tumour suppressors, produce feedback that changes miRNA expression levels and indicates the cell's genetic activity. In this study, we measured the expression of five circulating miRNAs (miR-195, miR-504, miR-122, miR-10b and miR-21) and evaluated their association with EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) mutation status in 66 NSCLC patients. Moreover, we examined the discriminative power of circulating miRNAs for EGFR mutant-positive and -negative NSCLC patients using two different data normalisation approaches. We extracted total RNA from the plasma of 66 non-squamous NSCLC patients (31 of whom had tumours with EGFR mutations) and measured circulating miRNA levels using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The miRNA expression levels were normalised using two endogenous controls: miR-191 and miR-16. We found significant associations between the expression of circulating miR-504 and EGFR-activating mutations in NSCLC patients regardless of the normalisation approach used (p = 0.0072 and 0.0236 for miR-16 and miR-191 normalisation, respectively). The greatest discriminative power of circulating miR-504 was observed in patients with EGFR exon 19 deletions versus wild-type EGFR normalised to miR-191 (area under the curve (AUC) = 0.81, p < 0.0001). Interestingly, circulating miR-504 levels were significantly reduced in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated subgroup compared to EGFR-mutated patients (p < 0.0030) and those with EGFR/KRAS wild-type tumours (p < 0.0359). Our study demonstrated the feasibility and potential diagnostic value of plasma miR-504 expression analysis to distinguish between EGFR-mutated and wild-type NSCLC patients. However, quality control and normalisation strategies are very important and have a major impact on the outcomes of circulating miRNA analyses.

Furugaki K, Mochizuki M, Kohno M, et al.
Expression of C-terminal ALK, RET, or ROS1 in lung cancer cells with or without fusion.
BMC Cancer. 2019; 19(1):301 [PubMed] Article available free on PMC after 09/10/2019 Related Publications
BACKGROUND: Genetic alterations, including mutation of epidermal growth factor receptor or v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog and fusion of anaplastic lymphoma kinase (ALK), RET proto-oncogene (RET), or v-ros UR2 sarcoma virus oncogene homolog 1 (ROS1), occur in non-small cell lung cancers, and these oncogenic drivers are important biomarkers for targeted therapies. A useful technique to screen for these fusions is the detection of native carboxy-terminal (C-terminal) protein by immunohistochemistry; however, the effects of other genetic alterations on C-terminal expression is not fully understood. In this study, we evaluated whether C-terminal expression is specifically elevated by fusion with or without typical genetic alterations of lung cancer.
METHODS: In 37 human lung cancer cell lines and four tissue specimens, protein and mRNA levels were measured by capillary western blotting and reverse transcription-PCR, respectively.
RESULTS: Compared with the median of all 37 cell lines, mRNA levels at the C-terminus of all five of the fusion-positive cell lines tested (three ALK, one RET, and one ROS1) were elevated at least 2000-, 300-, or 2000-fold, respectively, and high C-terminal protein expression was detected. In an ALK fusion-positive tissue specimen, the mRNA and protein levels of C-terminal ALK were also markedly elevated. Meanwhile, in one of 36 RET fusion-negative cell lines, RET mRNA levels at the C-terminus were elevated at least 500-fold compared with the median of all 37 cell lines, and high C-terminal protein expression was detected despite the absence of RET fusion.
CONCLUSIONS: This study of 37 cell lines and four tissue specimens shows the detection of C-terminal ALK or ROS1 proteins could be a comprehensive method to determine ALK or ROS1 fusion, whereas not only the detection of C-terminal RET protein but also other methods would be needed to determine RET fusion.

Zhang Y, Zhang Y, Li M, et al.
Combination of SB431542, CHIR99021 and PD0325901 has a synergic effect on abrogating valproic acid‑induced epithelial‑mesenchymal transition and stemness in HeLa, 5637 and SCC‑15 cells.
Oncol Rep. 2019; 41(6):3545-3554 [PubMed] Related Publications
Epithelial‑mesenchymal transition (EMT) plays an important role in cancer progression, metastasis and drug resistance, and recent studies have revealed that neoplastic epithelial cells regain the stem cell state through EMT. Single‑agent targeted cancer therapy frequently fails due to acquired drug resistance. Therefore, multi‑agent targeted therapy exhibits advantages in fighting cancer cells. In the present study, small molecule inhibitors SB431542 (ALK inhibitor), CHIR99021 (GSK3 pathway inhibitor), PD0325901 (MEK/ERK inhibitor) and valproic acid (VPA; HDAC inhibitor) were applied individually or in combination to HeLa uterine cervix carcinoma cells, 5637 bladder cancer cells and SCC‑15 squamous cell carcinoma cells to clarify their potential effects on cancer cells. Cell morphological alterations, pluripotency and EMT‑related gene expression, cell growth rate, cell migration, signal transduction, cell cycle arrest, CD24‑/CD44+ cell percentage, and in vivo tumor clump formation were evaluated. The results of the present study revealed that VPA treatment induced EMT morphology, upregulated the expression of pluripotency and EMT‑related genes, promoted migration and increased CD24‑/CD44+ cell percentage in all three cell lines. PD0325901, SB431542 and CHIR99021 in combination could significantly inhibit cell growth, suppress expression of pluripotency and EMT‑related genes, curb cell migration, cause cell cycle arrest, decrease CD24‑/CD44+ cell percentage in cell spheres, and delay in vivo cell clump formation of cancer cells. These data indicated that VPA may serve as an EMT and cancer stem cell‑promoting agent that may be useful in establishing a screening system for potential anticancer stem cell drugs. The combined inhibition of MEK/ERK, ALK and GSK3 was revealed to be an effective measure for eliminating cancer stem cells.

Jankovic R, J Goncalves H, Cavic M, et al.
LungCARD - Report on worldwide research and clinical practices related to lung cancer.
J BUON. 2019 Jan-Feb; 24(1):11-19 [PubMed] Related Publications
PURPOSE: The management of advanced lung cancer has evolved tremendously over the past two decades. Increasing understanding of the molecular changes that drive tumor progression has transformed the treatment of this disease. Nevertheless, various countries differ in the degree of implementation of genetic tests and the availability of innovative drugs. The LungCARD consortium created a questionnaire to collect information about the local research and clinical practices related to lung cancer diagnosis and therapy.
METHODS: A survey composed of 37 questions related to specific lung cancer pharmacogenomics and therapy, was distributed among 18 countries.
RESULTS: All together 36 responses were gathered, answered mainly by clinicians. The majority attends 50-200 cancer cases per month, 20-50% of all cancer cases are lung cancer patients, and more than 80% are with non-small-cell lung cancer (NSCLC). Targeted therapy is applied to 50% on average of all NSCLC patients. Forty five percent of participating medical oncologists are treating their patients with immunotherapy. More than 90% of the respondents are guided by results of genetic tests in introducing targeted treatment. As expected, the majority orders EGFR gene testing (85%), followed by ALK (58%) and KRAS testing (32%). Almost all (96%) agreed that more biomarkers should be included in routine genetic testing (ROS1, anti-PDL1, KRAS, MET, HER2, BRAF...), and that blood test is useful in pharmacogenomic testing.
CONCLUSION: There is a great variation between countries with respect to all discussed topics. However, the majority recognized a necessity of introducing next generation sequencing (NGS)-based diagnostics and potential of testing from blood. The biggest problem in the treatment of NSCLC is still an access to innovative drugs.

Cao B, Liu Y, Yin W, et al.
[A Single Center, Retrospective Analysis of Prognosis in Non-small Cell Lung Cancer Patients with Peritoneal Carcinomatosis].
Zhongguo Fei Ai Za Zhi. 2019; 22(3):143-150 [PubMed] Article available free on PMC after 09/10/2019 Related Publications
BACKGROUND: Peritoneal carcinomatosis is a rare clinical event in lung cancer and the prognosis is very poor. There are limited data on what factors predict peritoneal progression and affect the outcome. The aim of this study is to investigate investigate the factors associated with peritoneal carcinomatosis.
METHODS: The patients with non-small cell lung cancer (NSCLC) from the Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital were eligible for retrospective analysis between August 2010 and August 2018. Clinical factors such as age, gender, histology, pleural effusion and gene mutations with epidermal growth factor receptor/anaplastic lymphoma kinase/ROS proto-oncogene 1 receptor tyrosine kinase (EGFR/ALK/ROS1) were analyzed. Overall survival (OS) was calculated by the Kaplan-Meier method.
RESULTS: 1.44% (12/836) patients in this study developed peritoneal carcinomatosis and 12 patients with adenocarcinoma had metachronous NSCLC diagnosis and PC. Malignant pleural effusion rates at baseline and at PC diagnosis were separately 50% (6/12) and 100.0% (12/12). Among the 12 patients, 9 patients harbored EGFR/ALK/ROS1 mutation. The outcome of patients with EGFR/ALK/ROS1 mutation was significantly better than that of patients without EGFR/ALK/ROS1 mutation, the mOS1 and mOS2 were separately 26.0 months and 6.0 months versus 10.0 months and 1.5 months (P<0.05). The mOS2 of patients with aggressive treatment after PC diagnosis was 6.0 months, significantly better than 1.0 month of patients with best supportive care (P<0.05). The mOS2 of the patients with angiogenesis inhibitors based-treatment after PC diagnosis was 8.5 months, significantly longer than that of patients with other treatments (P<0.05).
CONCLUSIONS: Adenocarcinoma and malignant pleural effusion are highly associated with peritoneal carcinomatosis in patients with advanced NSCLC. Aggressive treatment for lung cancer with PC is encouraged when possible. More patients with PC may benefit from the treatment strategies with angiogenesis inhibitors. Further prospective trials are urgently needed.

Li P, Li B, Shi Y, et al.
[Association between the HER2 Gene Status and the Efficacy of First-line Pemetrexed Combined with Platinum Chemotherapy in Patients with Advanced Lung 
Zhongguo Fei Ai Za Zhi. 2019; 22(3):137-142 [PubMed] Article available free on PMC after 09/10/2019 Related Publications
BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is one of the driver genes of non-small cell lung cancer (NSCLC). Several studies have shown that the efficacy of pemetrexed in HER2-mutant NSCLC is controversial. The aim of this study is to investigate the efficacy of pemetrexed combined with platinum chemotherapy in patients with HER2-mutant and HER2 wild-type lung adenocarcinoma.
METHODS: The clinical data of 106 cases of EGFR, ALK, ROS-1, KRAS, BRAF, RET and MET-negative patients with advanced lung adenocarcinoma patients who diagnosed by histopathology in the First Affiliated Hospital of Zhengzhou University were retrospectively reviewed. The relationships between HER2 gene status, clinical characteristics and response and progression-free survival (PFS) were analyzed.
RESULTS: All of the 106 patients' HER2 status were determined. HER2 mutations occurred in 32 cases (30.2%), no mutations in 74 cases (69.8%). HER2 mutations were common in young, non-smoking and female patients. All patients received first-line pemetrexed and platinum-based chemotherapy. The objective response rate (ORR) and disease control rate (DCR) of patients with HER2-mutant lung adenocarcinoma were significantly higher than those without HER2 mutations (40.6% vs 14.9%, χ²=8.464, P=0.004; 93.8% vs 68.9%, χ²=6.327, P=0.012), and the difference was statistically significant. According to univariate analysis, the PFS was significantly associated with the brain metastases, maintenance chemotherapy and HER2 gene status (P<0.05), but not with age, gender, smoking history, oligometastases, liver metastases and type of platinum (P>0.05). Cox multivariate analysis indicated that HER2 mutation was an independent positive prognostic factor of PFS (P=0.038).
CONCLUSIONS: HER2-mutant lung adenocarcinoma patients with first-line pemetrexed combined with platinum chemotherapy have greater clinical benefit than HER2 wild-type patients.

Chen M, Xu Y, Zhao J, et al.
Concurrent Driver Gene Mutations as Negative Predictive Factors in Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer.
EBioMedicine. 2019; 42:304-310 [PubMed] Article available free on PMC after 09/10/2019 Related Publications
BACKGROUND: Tyrosine kinase inhibitors (TKIs) are clinically effective in non-small cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) oncogene mutations. Genetic factors, other than EGFR sensitive mutations, that allow prognosis of TKI treatment remain undefined.
METHODS: We retrospectively screened 423 consecutive patients with advanced NSCLC and EGFR 19del or 21L858R mutations. A total of 71 patients whose progression-free survivals (PFS) were shorter than 6 months or longer than 24 months were included and stratified into separate groups. Genetic background discrepancy was analysed in the two groups using next generation sequencing (NGS).
FINDINGS: Sensitive EGFR mutations of 19del or 21L858R were detected by NGS in all patients; the 21L858R mutation was the major type. The most frequent accompanying somatic mutations were TP53, RB1, MAP2K. ALK fusion, MET amplification, and BRAF V600E were found only in the short PFS group. Concurrent pretreament T790 M mutation was found in both groups, but was proportionally higher in the short PFS group. In the short PFS group, patients had significantly more driver gene mutations than in long PFS group (P = 0·018). The numbers of concomitant somatic mutations, EGFR pathway-related mutations, and tumor mutation burden (TMB) were not significantly different between the two groups.
INTERPRETATION: Co-occuring driver gene mutations were negative predictive factors of TKI therapy in EGFR-mutated patients. This study highlights the importance of exploring co-occuring genomic alterations before initiation of EGFR-TKIs.

Rosas G, Ruiz R, Araujo JM, et al.
ALK rearrangements: Biology, detection and opportunities of therapy in non-small cell lung cancer.
Crit Rev Oncol Hematol. 2019; 136:48-55 [PubMed] Related Publications
The ALK receptor tyrosine kinase (ALK) gene encodes a transmembrane protein rearranged in 2-7% of non-small cell lung cancer (NSCLC) cases. This gene has become the second most studied therapeutic target after EGFR due to the implied therapeutic opportunities. While the diagnostic of ALK rearrangements is well established, small molecules targeting ALK are in constant evolution because tumor cells eventually will develop mechanisms of resistance. In this review we describe the biology of the ALK gene, alterations, epidemiology, diagnostic tests as well as strategies of treatment.

Ji X, Che N, Lin R, et al.
Efficient ten-gene analysis of NSCLC tissue samples by next-generation sequencing.
Pathol Res Pract. 2019; 215(5):1066-1070 [PubMed] Related Publications
In the era of personalized medicine, lung cancer is a typical disease which can be treated strategically based on the patient's histological and molecular diagnosis. Immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), Sanger sequencing and real-time PCR are techniques commonly used in clinical laboratories. Many patients are required to use several of the above technologies to get a complete diagnosis, which is expensive and timeconsuming. Next generation of sequencing (NGS) has the advantage to simultaneously analyze multigene mutations. The average cost for each patient is affordable if each run contains a certain number of samples. In this study, we tested a 10-gene, 32-mutation detection NGS method, which was used to test 195 samples from non-small cell lung cancer (NSCLC). Sanger sequencing and Amplification-refractory Mutation System (AMRS) PCR were employed to verify Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) results. This NGS method was partially proved to have a higher sensitivity to detect mutations with low abundance than Sanger sequencing and even ARMS PCR. Using genomic DNA to detect gene fusions may have some disadvantages to miss low abundance or large fragment fusions. As compared to using a few different technologies to analyze multigene mutations, small NGS analysis panel is a clinically applicable, efficient and affordable choice for NSCLC patients.

Ni J, Li G, Yang X, et al.
Optimal timing and clinical value of radiotherapy in advanced ALK-rearranged non-small cell lung cancer with or without baseline brain metastases: implications from pattern of failure analyses.
Radiat Oncol. 2019; 14(1):44 [PubMed] Article available free on PMC after 09/10/2019 Related Publications
BACKGROUND: Despite development of several next-generation tyrosine kinase inhibitors (TKIs), crizotinib remains one of the first-line treatment options for advanced ALK-positive NSCLC and is widely used in situations where next-generation TKIs aren't yet approved or economically inaccessible. However, the pattern of failure and clinical value of radiotherapy in metastatic crizotinib-treated ALK-mutant lung cancer, with or without baseline brain metastases (BBM), are largely unknown.
METHODS: Consecutive crizotinib-treated NSCLC patients with adequate imaging and measurable disease were retrospectively enrolled. Disease progression in original sites (primary/metastatic), new sites, or both, are classified as original failure (OF), distant failure (DF) and ODF, respectively. Progression free survival, from crizotinib initiation to the first disease progression, and from that to the second disease progression, were calculated as PFS1 and PFS2.
RESULTS: Ninety-three patients were identified. With a median follow up of 22.0 (range, 2.0-72.0) months, 52 patients had crizotinib-treatment failure. The frequencies of OF, ODF, and DF, were 50.0, 26.9, and 23.1%, respectively. Histology, primary tumor size and presence of BBM, were independently associated with OF, using competing risks analyses. The brain was the most common site of initial disease progression. Patients with BBM had a significant higher possibility developing multiple-progressive lesions in the brain (p = 0.002). Importantly, four of the ten patients who had baseline oligo-metastatic cranial disease but didn't receive upfront brain radiation, developed multiple-progressive disease in the brain. Brain radiation before crizotinib could alter the disease failure patterns and improve PFS1 among patients with BBM (p = 0.006). Extracranial radiation was efficient in controlling symptoms but it was not associated with PFS1 (p = 0.223), and the majority of patients were eligible for salvage radiotherapy upon disease progression to crizotinib. By the time of data cut-off, 28 patients had second disease progression, with a median PFS2 of 7.0 (95% CI 5.4-8.6) months and salvage radiotherapy significantly prolonged PFS2 (p = 0.003). Additionally, patients receiving any radiotherapy during their treatment course had a significant longer overall survival (p = 0.048).
CONCLUSIONS: Among patients with baseline oligo-metastatic brain lesions which are suitable for stereotactic radiosurgery, upfront brain radiotherapy provides considerable clinical benefits. While, extracranial radiation may be deferred in asymptomatic patients with multiple-metastatic lesions.

Newman S, Fan L, Pribnow A, et al.
Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas.
Nat Med. 2019; 25(4):597-602 [PubMed] Related Publications
Spitzoid melanoma is a specific morphologic variant of melanoma that most commonly affects children and adolescents, and ranges on the spectrum of malignancy from low grade to overtly malignant. These tumors are generally driven by fusions of ALK, RET, NTRK1/3, MET, ROS1 and BRAF

Wang F, Diao XY, Zhang X, et al.
Identification of genetic alterations associated with primary resistance to EGFR-TKIs in advanced non-small-cell lung cancer patients with EGFR sensitive mutations.
Cancer Commun (Lond). 2019; 39(1):7 [PubMed] Article available free on PMC after 09/10/2019 Related Publications
BACKGROUND: Identification of activated epidermal growth factor receptor (EGFR) mutations and application of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have greatly changed the therapeutic strategies of non-small-cell lung cancer (NSCLC). However, the long-term efficacy of EGFR-TKI therapy is limited due to the development of drug resistance. The aim of this study was to investigate the correlation between the aberrant alterations of 8 driver genes and the primary resistance to EGFR-TKIs in advanced NSCLC patients with activated EGFR mutations.
METHODS: We retrospectively reviewed the clinical data from 416 patients with stage III/IV or recurrent NSCLC who received an initial EGFR-TKI treatment, from April 2004 and March 2011, at the Sun Yat-sen University Cancer Center. Several genetic alterations associated with the efficacy of EGFR-TKIs, including the alterations in BIM, ALK, KRAS, PIK3CA, PTEN, MET, IGF1R, and ROS1, were detected by the routine clinical technologies. The progression-free survival (PFS) and overall survival (OS) were compared between different groups using Kaplan-Meier survival analysis with the log-rank test. A Cox regression model was used to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (95% CIs) associated with the PFS and OS.
RESULTS: Among the investigated patients, 169 NSCLC patients harbored EGFR-sensitive mutations. EGFR-mutant patients having PTEN deletion had a shorter PFS and OS than those with intact PTEN (P = 0.003 for PFS, and P = 0.034 for OS). In the combined molecular analysis of EGFR signaling pathway and resistance genes, we found that EGFR-mutant patients coexisted with aberrant alterations in EGFR signaling pathway and those having resistant genes had a statistically poorer PFS than those without such alterations (P < 0.001). A Cox proportional regression model determined that PTEN deletion (HR = 4.29,95% CI = 1.72-10.70) and low PTEN expression (HR = 1.96, 95% CI = 1.22-3.13), MET FISH + (HR = 2.83,95% CI = 1.37-5.86) were independent predictors for PFS in patients with EGFR-TKI treatment after adjustment for multiple factor.
CONCLUSIONS: We determined that the coexistence of genetic alterations in cancer genes may explain primary resistance to EGFR-TKIs.

Shin HJ, Kho BG, Kim MS, et al.
Co-alteration of EGFR mutation and ALK rearrangement in non-small cell lung cancer: Case series.
Medicine (Baltimore). 2019; 98(9):e14699 [PubMed] Related Publications
RATIONALE: Current guidelines for advanced non-small cell lung cancer (NSCLC) recommend the use of targeted agents for specific driver genes after confirming genetic alterations. Although epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement are usually mutually exclusive, EGFR and ALK co-alterations have been reported increasingly in cases of NSCLC. However, the optimal treatment for these cases has not been established.
PATIENT CONCERNS: This case series describes three patients diagnosed with advanced non-squamous NSCLC who harbored EGFR and ALK co-alterations. The complaints for each case are as follows: 57-year-old woman with coughing and dyspnea in case 1, 32-year-old man with diplopia in case 2 and 77-year-old woman with chest discomfort in case 3.
DIAGNOSES: Three never-smokers were diagnosed pathologically with stage IV adenocarcinoma of the lung. Subsequent molecular studies revealed the EGFR L858R mutation gene and ALK rearrangement, which were proven by real-time polymerase chain reaction and fluorescence in situ hybridization, respectively.
INTERVENTIONS: All 3 patients received first-line therapy with EGFR-tyrosine kinase inhibitors (TKIs). Cases 1 and 2 were treated with ALK-TKIs as second-line therapy and received additional EGFR-TKIs as third- and fourth-line regimens.
OUTCOMES: The patients achieved partial responses to EGFR-TKIs according to radiologic findings. However, second-line ALK-TKI therapy was ineffective in cases 1 and 2.
LESSONS: Cases of NSCLC with concomitant EGFR mutation and ALK rearrangement are rare, and the selection of an optimal targeted therapy is challenging. Here, EGFR-TKI appeared to yield better outcomes than ALK-TKI in patients with NSCLC who harbored EGFR/ALK co-alterations.

Akamine T, Toyokawa G, Tagawa T, et al.
Lorlatinib for the treatment of patients with non-small cell lung cancer.
Drugs Today (Barc). 2019; 55(2):107-116 [PubMed] Related Publications
Lorlatinib is a novel third-generation tyrosine kinase inhibitor (TKI) which targets anaplastic lymphoma kinase (ALK) as well as receptor tyrosine kinase c-ros oncogene 1 (ROS1). A critical limitation of conventional ALK/ROS TKIs is their association with acquired resistance mutations (particularly ALK G1202R and ROS1 G2032R) in the ALK or ROS1 gene, although these are not the only resistance mechanisms. Another limitation of this class of drugs is their inadequate efficacy against central nervous system metastasis, likely attributable to the blood-brain barrier (BBB). Therefore, lorlatinib was developed to overcome these limitations by being more potent, selective and permeable to the BBB than previous-generation ALK/ROS1 TKIs and subsequently received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) in April 2017. In September 2018, Japan became the first country where lorlatinib received approval for treating patients with ALK-rearranged non-small cell lung cancer. Eventually, the FDA approved lorlatinib (Lorbrena; Pfizer) in November 2018. Lorlatinib use is expected to increase in importance, owing to its promising efficacy in clinical trials.

Cheng X, Yin H, Fu J, et al.
Aggregate analysis based on TCGA: TTN missense mutation correlates with favorable prognosis in lung squamous cell carcinoma.
J Cancer Res Clin Oncol. 2019; 145(4):1027-1035 [PubMed] Related Publications
PURPOSE: Lung cancer prevalence with its high mortality rate is a trending topic globally. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. The human gene TTN encoding for TITIN protein is known as major mutation gene in many types of tumor including NSCLC. However, it is still controversial that TTN is a cancer-associated candidate considering tumor heterogeneity and complex genetic structure. In-depth researches on correlation between TTN mutation and NSCLC are still limited and discussable.
METHODS: Related somatic mutation profiles and attached clinical data were from The Cancer Genome Atlas (TCGA) lung project. Clinical relevance analysis of TTN mutation was evaluated using univariate analysis and a binary logistic regressive model. Survival analysis and screening of independent prognostic factors in mutation types were conducted by Cox proportional hazards models and Kaplan-Meier methods.
RESULTS: Available data covering lung adenocarcinoma (n = 517) and lung squamous cell carcinoma (n = 492) were analyzed. TTN genetic mutations exhibited significant association with lung squamous cell carcinoma. Patients with lung squamous cell carcinoma possessed favorable overall survival benefits from TTN mutant type and both favorable overall survival and disease-free survival benefits from TTN/TP53 double mutation. For patients with lung squamous cell carcinoma, about 85% of subjects with TTN mutation harbored missense variations, which was an independent indicator of good prognosis.
CONCLUSIONS: Missense mutation of TTN may act as a beneficial role in lung squamous cell carcinoma, but not in lung adenocarcinoma.

Umapathy G, Mendoza-Garcia P, Hallberg B, Palmer RH
Targeting anaplastic lymphoma kinase in neuroblastoma.
APMIS. 2019; 127(5):288-302 [PubMed] Related Publications
Over the last decade, anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase (RTK), has been identified as a fusion partner in a diverse variety of translocation events resulting in oncogenic signaling in many different cancer types. In tumors where the full-length ALK RTK itself is mutated, such as neuroblastoma, the picture regarding the role of ALK as an oncogenic driver is less clear. Neuroblastoma is a complex and heterogeneous tumor that arises from the neural crest derived peripheral nervous system. Although high-risk neuroblastoma is rare, it often relapses and becomes refractory to treatment. Thus, neuroblastoma accounts for 10-15% of all childhood cancer deaths. Since most cases are in children under the age of 2, understanding the role and regulation of ALK during neural crest development is an important goal in addressing neuroblastoma tumorigenesis. An impressive array of tyrosine kinase inhibitors (TKIs) that act to inhibit ALK have been FDA approved for use in ALK-driven cancers. ALK TKIs bind differently within the ATP-binding pocket of the ALK kinase domain and have been associated with different resistance mutations within ALK itself that arise in response to therapeutic use, particularly in ALK-fusion positive non-small cell lung cancer (NSCLC). This patient population has highlighted the importance of considering the relevant ALK TKI to be used for a given ALK mutant variant. In this review, we discuss ALK in neuroblastoma, as well as the use of ALK TKIs and other strategies to inhibit tumor growth. Current efforts combining novel approaches and increasing our understanding of the oncogenic role of ALK in neuroblastoma are aimed at improving the efficacy of ALK TKIs as precision medicine options in the clinic.

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