Cheng Tianli, Gu Zhongping, Song Danni, Liu Sisi, Tong Xiaoling, Wu Xue, Lin Zhifeng, Hong Wei
Thoracic Medicine Department 1, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, China.
Department of Thoracic Surgery, The Second Affiliated Hospital, Air Force Military Medical University, Xi'an, China.
J Cancer. 2021 Jan 1;12(3):644-651. doi: 10.7150/jca.49391. eCollection 2021.
Alterations in exon 14 (ex14) and its flanking intronic regions have been identified in a variety of cancers. Patients with ex14 alterations often benefit from MET inhibitors such as crizotinib. Given the unique mutation profiles of Chinese lung cancer patients, it is necessary to investigate the prevalence of ex14 alterations in a large cohort of cancer patients. Cases carrying ex14 alterations were screened from 26,391 Chinese cancer patients by next-generation sequencing (NGS), and the clinicopathologic and molecular characteristics were reviewed. Compared to Western population (~3%), the frequency of ex14 alterations is much lower in Chinese cancer patients (0.7%, n=184) and lung cancer patients (1.1%, n=175). Seventy-eight distinct ex14 alterations, including several novel alteration types were detected. Concurrent copy gain and non-exon14 mutations were also found. copy gain (11%) and mutations (8%), (5%) and (5%), appeared in a mutually exclusive pattern. Female patients contain much less mutations than male patients (65% vs. 24%, FDR = 0.01). Co-amplification of and , and were identified, which indicated cell cycle dysregulation and alteration are important co-occurring features in patients with ex 14 alteration. Of 9 tissue specimens having PD-L1 immunohistochemistry (IHC) results, 5 of them (55.5%) were found PD-L1 positive, which is comparable to other types of tumor. In 14 crizotinib-treated patients, the median progression free survival (mPFS) was 7 months. Upon resistance to crizotinib, two patients acquired secondary mutations in and one patient acquired p.K601E that can be a novel resistance mechanism. Chinese cancer patients have a relatively lower frequency of ex14 alterations compared to Western patients. Patients with ex14 alterations showed distinct molecular characteristics and the representative case study showed responses to MET tyrosine kinase inhibitor (TKI).
外显子14（ex14）及其侧翼内含子区域的改变已在多种癌症中被发现。患有ex14改变的患者通常受益于MET抑制剂，如克唑替尼。鉴于中国肺癌患者独特的突变谱，有必要在一大群癌症患者中调查ex14改变的发生率。通过下一代测序（NGS）从26391名中国癌症患者中筛选出携带ex14改变的病例，并回顾其临床病理和分子特征。与西方人群（约3%）相比，中国癌症患者（0.7%，n = 184）和肺癌患者（1.1%，n = 175）中ex14改变的频率要低得多。检测到78种不同的ex14改变，包括几种新的改变类型。还发现了同时存在的拷贝数增加和非外显子14突变。拷贝数增加（11%）和突变（8%）、（5%）和（5%）以互斥模式出现。女性患者的突变比男性患者少得多（65%对24%，FDR = 0.01）。鉴定出和、和的共扩增，这表明细胞周期失调和改变是ex14改变患者中重要的共同发生特征。在9个有PD-L1免疫组织化学（IHC）结果的组织标本中，其中5个（55.5%）被发现PD-L1呈阳性，这与其他类型的肿瘤相当。在14名接受克唑替尼治疗的患者中，中位无进展生存期（mPFS）为7个月。在对克唑替尼耐药后，两名患者在中获得继发突变，一名患者获得p.K601E，这可能是一种新的耐药机制。与西方患者相比，中国癌症患者中ex14改变的频率相对较低。患有ex14改变的患者表现出独特的分子特征，代表性病例研究显示对MET酪氨酸激酶抑制剂（TKI）有反应。
