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Shanghai, China

Wang R.,Fudan University | Pan Y.,Fudan University | Li C.,Fudan University | Hu H.,Fudan University | And 11 more authors.
Clinical Cancer Research | Year: 2012

Purpose: Approximately 3% to 7% of non-small cell lung cancers (NSCLC) harbor an ALK fusion gene, thus defining a tumor group that may be responsive to targeted therapy. The breakpoint in ALK consistently occurs at exon 20 and EML4 or other fusion partners, thus driving a strong expression of ALK kinase domain and resulting in an unbalanced expression in 5′ and 3′ portions of ALK transcripts. We have developed a rapid and accurate method by simultaneously detecting the expression in 5′ and 3′ portions of ALK mRNA. Experimental Design: Quantitative real-time reverse transcriptase PCR (qRT-PCR) was used to examine expression levels of the 5′ and 3′ portions of ALK transcripts in177 NSCLCs, in which EGFR, KRAS, HER2, and BRAF mutations were absent. If unbalanced ALK mRNA expression was seen, ALK rearrangement was assumed to exist. ALK FISH was used to confirm the accuracy of qRT-PCR. RT-PCR and 5′ RACE coupling sequencing identified the fusion variants. Results: Real-time RT-PCR showed excellent sensitivity and specificity (100% and 100%, respectively) for detection of ALK rearrangements in resected specimens. In addition, six novel ALK fusion variants were identified, including one KIF5B-ALK (E17;A20) and five EML4-ALK variants (E6a;A19, E6a/b ins 18;A20, E17b ins 39;A20, E10a/b, E13;A20, and E17 ins 65;A20). Conclusions: Real-time RT-PCR is a rapid and accurate method for diagnosing ALK-rearranged lung cancers. Coupling of 5′ RACE to this method should further facilitate rapid identification of novel ALK fusion genes. ©2012 AACR. Source

Wang R.,Fudan University | Pan Y.,Fudan University | Li C.,Fudan University | Zhang H.,Fudan University | And 13 more authors.
Journal of Thoracic Oncology | Year: 2014

INTRODUCTION:: Genotyping for driver mutations is now routinely used to guide clinical care of patients with lung cancer. Adenosquamous lung carcinoma (AdSqLC) is a subtype of cancer that contains both adenocarcinoma and squamous cell carcinoma. However, the incidence, clinicopathologic characteristics, and prognostic implications of major driver mutations in AdSqLCs are not well established. METHODS:: Seventy-six resected AdSqLCs and 646 lung adenocarcinomas were screened for known genetic alterations involving EGFR, ERBB2, KRAS, BRAF, PIK3CA, AKT1, RET, and ALK. Tumors showing acinar, lepidic, micropapillary, or papillary growth in glandular component were classified as classical AdSqLC. RESULTS:: Of the 76 AdSqLCs, 43 (56.6%) harbored known mutant kinases, including 24 (31.6%) with EGFR mutations, eight (10.5%) with KRAS mutations, two (2.6%) with AKT1 (2.6%) mutations, one (1.3%) with ERBB2 insertion mutation, one (1.3%) with PIK3CA mutation, four (5.3%) with ALK fusions, and three (4%) with KIF5B-RET fusions. No mutation was found in BRAF. The mutational profiles and clinicopathologic characteristics of classical AdSqLC were strikingly similar to that of poorly differentiated adenocarcinoma. However, AdSqLCs with solid growth pattern in glandular component had high frequency of ALK or RET fusions and low EGFR mutation rate. CONCLUSIONS:: To our knowledge, this is the first comprehensive study investigating major oncogenic driver mutations in a large cohort of AdSqLC patients in a Chinese population. The findings suggest that it will be clinically valuable to investigate the growth pattern of glandular component in AdSqLCs. Copyright © 2014 by the International Association for the Study of Lung Cancer. Source

Li B.,Fudan University | Chen H.,Fudan University | Xiang J.,Fudan University | Zhang Y.,Fudan University | And 3 more authors.
Journal of Thoracic and Cardiovascular Surgery | Year: 2013

Objective Endoscopic treatment of superficial esophageal carcinoma has been increasingly conducted around the world. Because no lymph nodes are removed in such a procedure, the risk of lymph node metastases (LNMs) should be clearly understood. The aim of the present study was to accurately clarify the pattern of lymphatic spread in patients with superficial esophageal squamous cell carcinoma and analyze the factors potentially related to LNMs. Methods The pattern of lymphatic spread was studied in 189 patients who had undergone radical lymphadenectomy from 2006 to 2011. The risk factors associated with LNMs were determined by multivariate logistic regression analysis. According to the depth of tumor invasion, mucosal tumors were classified as M1, M2, and M3 and submucosal tumors as SM1, SM2, and SM3. Results A total of 4252 lymph nodes were resected (average, 23 ± 9; range, 12-68). LNMs occurred in 49 patients (25.9%). The frequency of LNMs was 4.3% in those with mucosal and 33.1% in those with submucosal cancer. LNMs were found in 0%, 0%, 11.8%, 24.0%, 20.5%, and 43.8% of the M1, M2, M3, SM1, SM2, and SM3 cancer, respectively. For submucosal cancer, SM3 cancer (P =.006) and lymphovascular invasion (P =.001) were significant independent risk factors for LNMs. Paratracheal nodes were the most frequently involved. "Skip" metastases occurred in 20 of 49 patients (40.8%). Conclusions Endoscopic treatment can be attempted when the tumor is limited to the lamina propria mucosa. However, 2-field radical lymphadenectomy with careful upper mediastinal lymph node resection should be conducted for submucosal squamous cell carcinoma. Copyright © 2013 by The American Association for Thoracic Surgery. Source

Zhao X.,Fudan University | Wang X.,Fudan University | Wu W.,Fudan University | Wu W.,University of California at San Diego | And 12 more authors.
Cancer | Year: 2012

BACKGROUND: Matrix metalloproteinase-2 (MMP-2) is well known for its critical role in cell survival and cancer development. It also plays an important role in hematopoietic recovery after chemotherapy-induced myelosuppression. In this study, the authors investigated the association of MMP-2 polymorphisms with treatment efficacy and the occurrence of severe toxicity in patients with nonsmall cell lung cancer (NSCLC) who were receiving first-line, platinum-based chemotherapy. METHODS: A pharmacogenetic association study was performed in 663 Chinese patients who had inoperable stage III/IV NSCLC and were receiving first-line, platinum-based regimens. Information about objective response, progression-free survival, overall survival, grade 3 or 4 gastrointestinal toxicity (nausea/vomiting), and hematologic toxicity (neutropenia, anemia, thrombocytopenia) was available. Sixteen tag single nucleotide polymorphisms (SNPs) of MMP-2 were assessed. RESULTS: In 7 polymorphisms, significant associations were observed with the incidence of grade 3 or 4 neutropenia. The variant homozygotes of reference SNP rs12934241 exhibited the most significant effect on the risk of neutropenia, leading to an incidence rate that increased from 12.3% (for the C/C genotype) to 50% (for the T/T genotype; odds ratio, 8.33; P = 8.8 × 10 -5). Stratified analyses indicated that rs12934241 exhibited a much stronger influence in the cisplatin-gemcitabine regimen subgroup than subgroups that received other regimens (P interaction =.003). Further haplotype analyses produced results that were consistent with results from single-SNP analyses. However, no significant association was observed between MMP-2 polymorphisms and treatment efficacy, including response rate, clinical benefit, progression-free survival, and overall survival. CONCLUSIONS: To the authors' knowledge, this study provides the first evidence for a predictive role of MMP-2 polymorphisms in the variability of severe chemotherapy-related neutropenia among Chinese patients with platinum-treated, advanced NSCLC. © 2011 American Cancer Society. Source

Wang R.,Fudan University | Hu H.,Fudan University | Pan Y.,Fudan University | Li Y.,Fudan University | And 16 more authors.
Journal of Clinical Oncology | Year: 2012

Purpose The RET fusion gene has been recently described in a subset of non-small-cell lung cancers (NSCLCs). Because we have limited knowledge about these tumors, this study was aimed at determining the clinicopathologic characteristics of patients with NSCLC harboring the RET fusion gene. Patients and Methods We examined the RET fusion gene in 936 patients with surgically resected NSCLC using a reverse transcriptase polymerase chain reaction (PCR) plus quantitative real-time PCR strategy, with validation using immunohistochemical and fluorescent in situ hybridization assays. A subset of 633 lung adenocarcinomas was also studied for EGFR, KRAS, HER2, and BRAF mutations, as well as ALK rearrangements. Patient characteristics, including age, sex, smoking history, stage, grade, International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of subtypes of lung adenocarcinoma, and relapse-free survival, were collected. Results Of 936 patients with NSCLC, the RET fusion gene was exclusively detected in 13 patients (11 of 633 patients with adenocarcinomas and two of 24 patients with adenosquamous cell carcinomas). Of the 13 patients, nine patients had KIF5B-RET, three patients had CCDC6-RET, and one patient had a novel NCOA4-RET fusion. Patients with lung adenocarcinomas with RET fusion gene had more poorly differentiated tumors (63.6%; P = .029 for RET v ALK, P = .007 for RET v EGFR), with a tendency to be younger (≤ 60 years; 72.7%) and never-smokers (81.8%) and to have solid subtype (63.6%) and a smaller tumor (≤ 3 cm) with N2 disease (54.4%). The median relapse-free survival was 20.9 months. Conclusion RET fusion occurs in 1.4% of NSCLCs and 1.7% of lung adenocarcinomas and has identifiable clinicopathologic characteristics, warranting further clinical consideration and targeted therapy investigation. © 2012 by American Society of Clinical Oncology. Source

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