Sheikine Yuri, Pavlick Dean, Klempner Samuel J, Trabucco Sally E, Chung Jon H, Rosenzweig Mark, Wang Kai, Velcheti Vamsidhar, Frampton Garrett M, Peled Nir, Murray Molly, Chae Young Kwang, Albacker Lee A, Gay Laurie, Husain Hatim, Suh James H, Millis Sherri Z, Reddy Venkataprasanth P, Elvin Julia A, Hartmaier Ryan J, Dowlati Afshin, Stephens Phil, Ross Jeffrey S, Bivona Trever G, Miller Vincent A, Ganesan Shridar, Schrock Alexa B, Ou Sai-Hong Ignatius, Ali Siraj M
, Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ.
JCO Precis Oncol. 2018 Apr 19;2. doi: 10.1200/PO.17.00172. eCollection 2018.
Dabrafenib and trametinib are approved for the management of advanced non-small-cell lung cancers (NSCLCs) that harbor V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 B alterations in lung cancer.
A total of 23,396 patients with lung cancer provided data to assay with comprehensive genomic profiling. Data were reviewed for predicted pathogenic base substitutions, short insertions and deletions, copy number changes, and rearrangements.
Adenocarcinomas represented 65% of the occurrences; NSCLC not otherwise specified (NOS), 15%; squamous cell carcinoma, 12%; and small-cell lung carcinoma, 5%. was altered in 4.5% (1,048 of 23,396) of all tumors; 37.4% (n = 397) were V600E, 38% were non-V600E activating mutations, and 18% were inactivating. Rearrangements were observed at a frequency of 4.3% and consisted of N-terminal deletions (NTDs; 0.75%), kinase domain duplications (KDDs; 0.75%), and fusions (2.8%). The fusions involved three recurrent fusion partners: , and . V600E was associated with co-occurrence of alterations, but other alterations were not and were instead associated with , , and alterations ( < .05). Potential mechanisms of acquired resistance to V600E inhibition are demonstrated.
This series characterized the frequent occurrence (4.4%) of alterations in lung cancers. Recurrent alterations in NSCLC adenocarcinoma are comparable to the frequency of other NSCLC oncogenic drivers, such as , and exceed that of or . This work supports a broad profiling approach in lung cancers and suggests that non-V600E BR alterations represent a subgroup of lung cancers in which targeted therapy should be considered.
达拉非尼和曲美替尼被批准用于治疗携带V600E突变的晚期非小细胞肺癌（NSCLC）。小规模研究和泛癌分析已将非V600改变确定为治疗靶点。我们试图研究一个大型基因组数据集，以全面表征肺癌中的非V600 B改变。
共有23396例肺癌患者提供了数据以进行全面基因组分析。对数据进行了审查，以确定预测的致病性碱基替换、短插入和缺失、拷贝数变化以及重排。
腺癌占病例的65%；非特殊类型NSCLC（NOS）占15%；鳞状细胞癌占12%；小细胞肺癌占5%。所有肿瘤中有4.5%（23396例中的1048例）发生了改变；37.4%（n = 397）为V600E，38%为非V600E激活突变，18%为失活突变。重排的发生率为4.3%，包括N端缺失（NTDs；0.75%）、激酶结构域重复（KDDs；0.75%）和融合（2.8%）。融合涉及三个常见的融合伙伴：、和。V600E与改变的共发生相关，但其他改变则不然，而是与、和改变相关（P <.05）。证明了对V600E抑制获得性耐药的潜在机制。
本系列研究表明肺癌中改变的发生率较高（4.4%）。NSCLC腺癌中常见的改变频率与其他NSCLC致癌驱动因素（如）相当，且超过了或的频率。这项工作支持对肺癌进行广泛的分析方法，并表明非V600E BR改变代表了肺癌的一个亚组，其中应考虑靶向治疗。
