Genomic and clinical characteristics of exon14 alterations in a large cohort of Chinese cancer patients revealed distinct features and a novel resistance mechanism for crizotinib.

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).