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  • br Introduction Lung cancer is the


    Introduction Lung cancer is the leading cause of cancer-related death worldwide, accounting for more than 1.5 million deaths in 2012. Non–small-cell lung cancers represent approximately 85% of lung neoplasms; among these, squamous cell carcinomas (SCC) account for approximately 30% of cases. The landscape of thoracic oncology has greatly changed during the past decade with the discovery of tumor driver mutations predicting response to targeted therapies. Recent clinical trials demonstrated an unprecedented improvement in progression-free survival and quality of life, especially in molecularly selected lung adenocarcinoma.3, 4, 5 Lung SCC lacks available molecular targets, and tyrosine kinase inhibitors are mostly ineffective in unselected populations, despite many efforts made to understand the genomics. Among all of the somatic alterations explored to date in lung squamous histology, discoidin domain receptor 2 (DDR2) gene mutations are reported in approximately 3% of cases.8, 9 DDR2 is a tyrosine kinase receptor that belongs to the same family as epidermal growth factor receptor (EGFR). Numerous in vitro studies on various tumoral cell lines demonstrated the important role of DDR2 in the regulation of cellular proliferation, migration, metastasis, and secretion of matrix metalloproteinase. In 2011, Hammerman et al showed that a subset of DDR2 mutants are oncogenic in SCC cell lines in vitro, delivering a strong rational for targeting DDR2 mutations. In addition, 2 patients with DDR2-mutated lung SCC were reported in the literature to experience a dramatic response to dasatinib, a potent SrC inhibitor.8, 12 Altogether, these data establish DDR2 6-O-α-Maltosyl-β-cyclodextrin as a promising molecular target of tyrosine kinase inhibitors in lung SCC. Few studies are available concerning the clinical characteristics of patients harboring DDR2 mutations. The first aim of this study was to describe DDR2 gene mutations in a large monocentric cohort of SCC. Further objectives of the study were to compare the clinical characteristics of DDR2-mutant to DDR2 wild-type (WT) lung SCC and to investigate factors associated with DDR2 mutations.
    Patients and Methods
    Discussion In this study, we provide one of the largest description of DDR2 genetic landscape in lung SCC to date. We identified 11 DDR2 mutations (4%) and report, for the first time, a splicing mutant c.566-1G>C of the DDR2 gene in lung cancer. The following rates of mutation were previously observed: 2% (2/100), 3.2% (9/277), 4.6% (4/86), 1.1% (2/178), and 1.3% (3/178) in the lung SCC cohorts of Lee et al, Hammerman et al, Miao et al, and cBioportal database (TCGA and TCGA provisional), respectively. In contrast, Kenmotsu et al (sequencing limited to p.S768R mutation) and Hashima et al (sequencing of 8 exons of DDR2 gene) failed to identify any DDR2 mutation in their Japanese cohort comprising more than 100 cases. Of note, sequencing coverage of DDR2 gene is very different between these studies and may contribute to such prevalence inconsistency. Some authors have suggested that DDR2 mutations may be related to tobacco exposure. To support this notion, the largest percentage of DDR2 mutations described in this report are transversions, known to be smoking-related. Epidemiologic studies showing that East Asian populations are less susceptible to smoking-related lung cancer might also partially explain these geographic variations. We identified a new DDR2 truncating mutation p.E85X that is predicted to have a major impact on the receptor function. Nevertheless, to date, some discrepancies exist in the literature concerning the oncogenic potential induced by DDR2 aberrant signaling. Functional validations assays are needed to assess the oncogenic properties of this variant. Moreover, DDR2 mutations appear not to be exclusive from other driver gene alterations. This is supported by the observation of co-occurrence of such mutations with a KRAS p.G12D mutation in our cohort. However, known-driver mutations frequencies appear lower in our cohort than expected, compared with TCGA. This could be explained by our methodology based on hotspot exon sequencing, which, contrary to TCGA, does not cover all gene coding-sequences. In their founding publication, Hammerman et al demonstrated that ectopic expression of a subset of DDR2 mutants (p.L63V and p.I638F) in nontumoral cells is able to promote proliferation in vitro in a DDR2-dependent manner. These results were strengthened by in vivo experiments, with a recent publication revealing that inducible DDR2 p.L63V mutation combined with conditional loss of TP53 is oncogenic in a murine model. However, a recent publication showed the presence of DDR2 p.L63V and p.G505S alterations not only in tumor specimens but also in matched normal tissues, suggesting that these variants are inherited. Some of these variants, also identified in our cohort, have already been reported in the National Heart, Lung, and Blood Institute Exome Sequencing Project but misclassified as mutations in the literature. Further research should now investigate to what extent these constitutional DDR2 variants could be associated with lung SCC initiation; similar to the ongoing research on EGFR germline mutations. A better deciphering of DDR2 somatic mutations by deep-sequencing is now critical to better select patients in clinical trials, as new potent and selective DDR2 inhibitors are currently in development.