Molecular Typing of Lung Adenocarcinoma on Cytological Samples Using a Multigene Next Generation Sequencing Panel

Scarpa, Aldo; Sikora, Katarzyna; Fassan, Matteo; Rachiglio, Anna Maria; Cappellesso, Rocco; Antonello, Davide; Amato, Eliana; Mafficini, Andrea; Lambiase, Matilde; Esposito, Claudia; Bria, Emilio; Simonato, Francesca; Scardoni, Maria; Turri, Giona; Chilosi, Marco; Tortora, Giampaolo; Fassina, Ambrogio; Normanno, Nicola

doi:10.1371/journal.pone.0080478

Cited by 98 publications

(95 citation statements)

References 42 publications

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“…Aberrant TGF-β signaling is common in human lung cancer, and loss of SMAD4 is thought to play an important role in the inactivation of TGF-β signaling (38,39). However, the frequency of mutation and/or deletion on SMAD4 is relatively low in NSCLC (40,41); therefore, the actual mechanism of aberrant expression of SMAD4 in NSCLC remained unclear. Given the significant up-regulation of miR-224 in NSCLC and the fact that SMAD4 is a direct target of miR-224, it is possible that loss of SMAD4 might be attributable to up-regulated miR-224 expression in NSCLC.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer

Cui

Wang

Sun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, we identify microRNA-224 (miR-224) to be significantly up-regulated in NSCLC tissues, particularly in resected NSCLC metastasis. Increased miR-224 expression promotes cell migration, invasion, and proliferation by directly targeting the tumor suppressors TNFα-induced protein 1 (TNFAIP1) and SMAD4. In concordance with in vitro studies, mouse xenograft studies validated that miR-224 functions as a potent oncogenic miRNA in NSCLC in vivo. Moreover, we found promoter hypomethylation and activated ERK signaling to be involved in the regulation of miR-224 expression in NSCLC. Up-regulated miR-224, thus, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 and TNFAIP1 toward enhanced invasion and growth in NSCLC. Our findings indicate that targeting miR-224 could be effective in the treatment of certain lung cancer patients.ung cancer is the second most common cancer and the leading cause of cancer-related death worldwide. In 2013, there were an estimated 228,190 new cases of lung cancer and 159,480 deaths in the United States. Despite advancements and improvements in surgical and medical treatments, the 5-y survival rate of lung cancer patients remains frustratingly poor (1). Although local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients (2, 3), ∼20% of early-stage patients, however, are developing distant metastasis (4, 5), and

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Section: Discussionmentioning

confidence: 99%

MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer

Cui

Wang

Sun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

133

128

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“…Massive parallel sequencing, also known as next-generation sequencing (NGS) or deep sequencing, is the most sensitive approach to index multiple genes even with only a limited amount of DNA from different sources including FFPE tissues [8,9]. NGS can simultaneously investigate multiple potential molecular targets and represents a potent diagnostic complement to histopathological and immunophenotypic diagnosis.…”

Section: Introductionmentioning

confidence: 99%

High-throughput mutation profiling identifies novel molecular dysregulation in high-grade intraepithelial neoplasia and early gastric cancers

et al. 2013

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Background There is still no widely accepted molecular marker available to distinguish between gastric high-grade intraepithelial neoplasia (HG-IEN) and invasive early gastric cancer (EGC). Methods HG-IEN and EGC lesions coexisting in the same patient were manually microdissected from a series of 15 gastrectomies for EGC; 40 ng DNA was used for multiplex PCR amplification using the Ion AmpliSeq Cancer Panel, which explores the mutational status of hotspot regions in 50 cancer-associated genes. Results Of the 15 EGCs, 12 presented at least one somatic mutation among the 50 investigated genes, and 6 of these showed multiple driver gene somatic mutations. TP53 mutations were observed in 9 cases; APC mutations were identified in 3 cases; and ATM and STK11 were mutated in 2 cases. Seven HG-IEN lesions shared an identical mutational profile with the EGC from the same patient; 13 mutations observed in APC, ATM, FGFR3, PIK3CA, RB1, STK11, and TP53 genes were shared by both HG-IEN and ECG lesions. CDKN2A, IDH2, MET, and RET mutations were observed only in EGC. TP53 deregulation was further investigated in an independent series of 75 biopsies corresponding to all the phenotypic lesions occurring in the EGC carcinogenetic cascade. p53 nuclear immunoreaction progressively increased along with the dedifferentiation of the lesions (P \ 0.001). Overall, 18 of 20 p53-positive lesions showed a TP53 mutated gene. Discussion Our results support the molecular similarity between HG-IEN and EGC and suggest a relevant role for TP53 in the progression to the invasive phenotype and the use of immunohistochemistry as a surrogate to detect TP53 gene mutations.

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“…Though, it has been optimized to work with highly fragmented and degraded FFPE DNA, recent studies have shown that it can be used to analyze mutations in cfDNA (https://www.illumina.com/). The Ion Ampliseq Colon and Lung cancer panel on the Ion Torrent Personal Genome Machine selectively amplifies 90 amplicons that encompass 1825 mutational hotspots of 22 genes related to colon and lung cancer [86][87][88]. It has been clinically validated in a retrospective study of 39 NSCLC samples and 51 colorectal cancer samples [84].…”

Section: Methods Targeting Druggable Mutation and Other Aberrations Imentioning

confidence: 99%

Liquid biopsy - emergence of a new era in personalized cancer care

2018

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The most successful treatment for cancer involves identifying druggable, biological markers for targeted therapy. In the clinical setting, surgical removal of tumors is the only procedure for identifying such targetable molecules. Shed from tumor cells, these markers are also present in circulating blood, albeit in very negligible amounts. Liquid biopsy is a procedure performed on a blood sample to look for such circulating cancer markers cells or pieces of nucleic acid from the tumor. The procedure shows promise in revolutionizing personalized cancer treatments. Here we briefly review the technique, characterization, and its utilization in clinics.

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Molecular Typing of Lung Adenocarcinoma on Cytological Samples Using a Multigene Next Generation Sequencing Panel

Cited by 98 publications

References 42 publications

MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer

MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer

High-throughput mutation profiling identifies novel molecular dysregulation in high-grade intraepithelial neoplasia and early gastric cancers

Liquid biopsy - emergence of a new era in personalized cancer care

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