Uzunoglu Faik G, Dethlefsen Ebba, Hanssen Annkathrin, Wrage Michaela, Deutsch Lena, Harms-Effenberger Katharina, Vashist Yogesh K, Reeh Matthias, Sauter Guido, Simon Ronald, Bockhorn Maximillian, Pantel Klaus, Izbicki Jakob R, Wikman Harriet
Department of General, Visceral and Thoracic Surgery, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
Institute of Tumour Biology, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
PLoS One. 2014 Dec 11;9(12):e113315. doi: 10.1371/journal.pone.0113315. eCollection 2014.
This study was performed to assess the prognostic relevance of genomic aberrations at chromosome 4q in NSCLC patients. We have previously identified copy number changes at 4q12-q32 to be significantly associated with the early hematogenous dissemination of non-small cell lung cancer (NSCLC), and now aim to narrow down potential hot-spots within this 107 Mb spanning region. Using eight microsatellite markers at position 4q12-35, allelic imbalance (AI) analyses were performed on a preliminary study cohort (n = 86). Positions indicating clinicopathological and prognostic associations in AI analyses were further validated in a larger study cohort using fluorescence in situ hybridization (FISH) in 209 NSCLC patients. Losses at positions 4q21.23 and 4q22.1 were shown to be associated with advanced clinicopathological characteristics as well as with shortened disease free (DFS) and overall survival (OS) (DFS: P = 0.019; OS: P = 0.002). Multivariate analyses identified the losses of 4q21.23-22.1 to be an independent prognostic marker for both DFS and OS in NSCLC (HR 1.64-2.20, all P<0.04), and especially in squamous cell lung cancer (P<0.05). A case report study of a lung cancer patient further revealed a loss of 4q21.23 in disseminated tumor cells (DTCs). Neither gains at the latter positions, nor genomic aberrations at 4q12, 4q31.2 and 4q35.1, indicated a prognostic relevance. In conclusion, our data indicate that loss at 4q21.23-22.1 in NSCLC is of prognostic relevance in NSCLC patients and thus, includes potential new tumor suppressor genes with clinical relevance.
本研究旨在评估非小细胞肺癌（NSCLC）患者4号染色体长臂（4q）基因组畸变的预后相关性。我们之前已确定4q12-q32区域的拷贝数变化与非小细胞肺癌早期血行播散显著相关，现在旨在缩小这个跨度达107 Mb区域内的潜在热点。使用位于4q12-35的8个微卫星标记，对一个初步研究队列（n = 86）进行了等位基因失衡（AI）分析。在AI分析中显示出与临床病理及预后相关的位置，在一个更大的研究队列中，对209例NSCLC患者使用荧光原位杂交（FISH）进行了进一步验证。结果显示，4q21.23和4q22.1位置的缺失与晚期临床病理特征以及无病生存期（DFS）和总生存期（OS）缩短相关（DFS：P = 0.019；OS：P = 0.002）。多变量分析确定4q21.23-22.1的缺失是NSCLC患者DFS和OS的独立预后标志物（风险比1.64-2.20，所有P<0.04），尤其在肺鳞状细胞癌中（P<0.05）。一项肺癌患者的病例报告研究进一步揭示，在播散肿瘤细胞（DTCs）中存在4q21.23缺失。在这些位置的增益，以及4q12、4q31.2和4q35.1的基因组畸变，均未显示出预后相关性。总之，我们的数据表明，NSCLC患者中4q21.23-22.1的缺失具有预后相关性，因此，其中包含具有临床相关性的潜在新肿瘤抑制基因。
