lobeline Some limitations to our study should be noted First
Some limitations to our study should be noted. First, the sample size of our study was limited. As DDR2 mutations are rare in lung SCC, it is possible that the power of our study was insufficient to detect potential associated factors. Second, a significant proportion of the 271 sequenced patients had to be withdrawn from the data collection to avoid missing information. Consequently, potential selection bias could have influenced our findings. Third, this study was monocentric, and reproducibility of the molecular results could not be assessed on multiple genomic platforms. Fourth, we cannot definitively confirmed the non-germinal status of one of the new p.P492S DDR2 variant described in this cohort, as samples with healthy tissue were not available for this patient.
Conclusion In conclusion, DDR2 mutations were detected in 4% of cases in our lung SCC cohort. Our study identified 10 new DDR2 mutations that have not been described to date, including a unique DDR2 splice mutant and shows that DDR2-mutated tumors can exhibit other driver gene alterations. No clinical characteristics or survival difference was detected between DDR2-mutant and DDR2-WT lung SCC, and no clinical factors were significantly associated with DDR2 mutation. A better understanding of DDR2 biology and its mutants will be critical for developing future dedicated therapy in molecularly selected DDR2-driven tumors.
Introduction Discoidin domain receptors (DDR1 and DDR2) are widely expressed receptor tyrosine kinases that regulate a variety of cellular processes including cell adhesion, differentiation, proliferation and lobeline , collagen fibrillogenesis , , , and remodeling of the extracellular matrix . Collagen(s) is the only known ligand for DDRs . Both the collagen binding domains of the receptors , , ,  and their binding site on the collagen triple helix , , ,  have been elucidated in recent years. In addition, it has been established that DDRs exist as constitutive homodimers on the cell membrane prior to collagen binding and receptor activation , , . DDRs undergo slow and sustained receptor activation upon ligand binding. However, the reasons for the delayed kinetics of DDR phosphorylation upon ligand binding remain poorly defined. Receptor clustering or higher order receptor oligomerization has been postulated by us ,  and others , , ,  as important modulators of both DDR–collagen interaction and receptor phosphorylation. Various domains of DDR1 have been shown to be important for receptor clustering and its oligomeric status. It is now understood that (i) dimerization  and higher-order oligomerization ,  of the DDR1 extracellular domain (ECD) enhance its binding to collagen; (ii) DDR1 exists as non-covalent homodimer on the cell surface, which is mediated by critical residues within its ECD  and transmembrane domain (TMD) ; (iii) both full-length and kinase-dead DDR1 expressed on the cell surface undergo clustering upon collagen binding , , , , ; and (iv) clustering of DDR1 post-ligand binding is mediated in part by its ECD  and by its intracellular domain (ICD) , . DDR1 clustering has been postulated to be a mechanism required for receptor activation based on our earlier microscopy-based studies , , X-ray crystallographic insights by Carafoli et al.  and recent cell-based studies . In this regard, mutation of an N-glycosylation site in the DDR1 ECD (which results in a higher population of dimers) has been shown to induce ligand-independent activation of DDR1 . In another study, a function-blocking monoclonal antibody, which binds to DDR1 ECD and inhibits collagen-induced receptor phosphorylation , also inhibited DDR1 clustering . Thus, understanding the structural constrains and molecular mechanisms that promote the clustering and/or the oligomeric state of DDR1 could be exploited as a therapeutic avenue to modulate receptor function in diseases involving DDR1 activity.