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High mutational concordance between primary colorectal tumors and associated pulmonary metastases.


  • 影响因子:2.88
  • DOI:10.1002/jso.25871
  • 作者列表:"Corsini EM","Datar SS","Mitchell KG","Zhou N","Hofstetter WL","Mehran RJ","Rajaram R","Rice DC","Roth JA","Sepesi B","Swisher SG","Vaporciyan AA","Walsh GL","Blackmon SH","Loree JM","Morris VK","Antonoff MB
  • 发表时间:2020-05-01

BACKGROUND AND OBJECTIVES:Precision medicine has altered the management of colorectal cancer (CRC). However, the concordance of mutational findings between primary CRC tumors and associated pulmonary metastases (PM) is not well-described. This study aims to determine the concordance of genomic profiles between primary CRC and PM. METHODS:Patients treated for colorectal PM at a single institution from 2000 to 2017 were identified. Mutational concordance was defined as either both wild-type or both mutant alleles in lung and colorectal lesion; genes with opposing mutational profiles were reported as discordant. RESULTS:Thirty-eight patients met inclusion criteria, among whom KRAS, BRAF, NRAS, MET, RET, and PIK3CA were examined for concordance. High concordance was demonstrated among all evaluated genes, ranging from 86% (KRAS) to 100% concordance (NRAS, RET, and MET). De novo KRAS mutations were detected in the PM of 4 from 35 (11%) patients, 3 of whom had previously received anti-epidermal growth factor receptor (EGFR) therapy. Evaluation of Cohen's κ statistic demonstrated moderate to perfect correlation among evaluated genes. CONCLUSIONS:Because high intertumoral genomic homogeneity exists, it may be reasonable to use primary CRC mutational profiles to guide prognostication and targeted therapy for PM. However, the possibility of de novo KRAS-mutant PM should be considered, particularly among patients previously treated with anti-EGFR therapy.


背景和目的: 精准医学已经改变了结直肠癌 (CRC) 的管理。然而,原发性CRC肿瘤和相关肺转移 (PM) 之间的突变结果的一致性没有得到很好的描述。本研究旨在确定原发性CRC和PM之间的基因组谱的一致性。 方法: 确定 2000 年至 2017 年在单一机构接受结直肠PM治疗的患者。突变一致性被定义为肺和结直肠病变中的野生型或两个突变等位基因; 具有相反突变谱的基因被报告为不一致的。 结果: 38 例患者符合纳入标准,其中KRAS、BRAF、NRAS、met、RET和PIK3CA检查一致性。在所有评估的基因中表现出高一致性,范围从 86% (KRAS) 到 100% 一致性 (NRAS、RET和MET)。在来自 35 名 (11%) 患者的 4 名患者的PM中检测到从头KRAS突变,其中 3 名先前接受过抗表皮生长因子受体 (EGFR) 治疗。Cohen的 κ 统计量的评估证明了所评估的基因之间的中度至完全相关性。 结论: 由于存在高肿瘤间基因组同质性,因此使用原发性CRC突变谱来指导PM的预后和靶向治疗可能是合理的。然而,应该考虑新生KRAS突变PM的可能性,特别是在先前接受抗EGFR治疗的患者中。



作者列表:["Mammana M","Zuin A","Serra E","Bellini A","Rea F"]

METHODS::Pulmonary artery sling is a rare congenital anomaly of the origin and course of the left pulmonary artery. Patients with this condition typically present with respiratory failure in young infancy, and asymptomatic cases are uncommon. We describe the case of an adult patient with a lung adenocarcinoma of the right upper lobe, extending into the hilum and superior mediastinum, and with a previously unknown pulmonary artery sling anomaly. The local invasiveness of the tumor and the peculiar vascular anatomy contributed to a unique surgical scenario, wherein multiple reconstructive procedures were required.

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作者列表:["Hata A","Nakajima T","Matsusaka K","Fukuyo M","Morimoto J","Yamamoto T","Sakairi Y","Rahmutulla B","Ota S","Wada H","Suzuki H","Matsubara H","Yoshino I","Kaneda A"]

METHODS::Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.

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作者列表:["Zhang L","Yang Y","Chai L","Bu H","Yang Y","Huang H","Ran J","Zhu Y","Li L","Chen F","Li W"]

METHODS::The role of Fyn-related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK-KO-H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial-mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK-KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U-13 C flux assay revealed that FRK-KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.

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