Abstract
Among chemotherapeutic agents, paclitaxel has shown great efficacy against breast cancer. Prediction of paclitaxel response may improve patient outcomes. Here we show, using exome sequencing, that in comparison with pre-treatment biopsies, two TEKT4 germline variations are enriched in post-treatment tumours. We find TEKT4 variations in ~ 10% of an independent cohort of 84 pairs of samples. Tektin4 (encoded by TEKT4) associates closely with tubulin in doublet microtubules and helps stabilize these structures. These two TEKT4 germline variations in a high cis linkage are biologically relevant, as the ectopic expression of variant TEKT4 deregulates the microtubule stability, antagonizes the paclitaxel-induced stabilizing effect of microtubules and increases paclitaxel resistance. Furthermore, TEKT4 germline variations are associated with reduced disease-free survival and overall survival compared with wild-type TEKT4 in patients undergoing paclitaxel-based chemotherapy. Taken together, we reveal a potential mechanism of resistance to paclitaxel through the acquisition of germline variations in breast cancer.