摘要：SummaryGenomic data can facilitate personalized treatment decisions by enabling therapeutic hypotheses in individual patients. Mutual exclusivity has been an empirically useful signal for identifying activating mutations that respond to single agent targeted therapies. However, a low mutation frequency can underpower this signal for rare variants. We develop a resampling based method for the direct pairwise comparison of conditional selection between sets of gene pairs. We apply this method to a transcript variant of anaplastic lymphoma kinase (ALK) in melanoma, termed ALKATIthat was suggested to predict sensitivity to ALK inhibitors and we find that it is not mutually exclusive with key melanoma oncogenes. Furthermore, we find that ALKATIis not likely to be sufficient for cellular transformation or growth, and it does not predict single agent therapeutic dependency. Our work strongly disfavors the role of ALKATIas a targetable oncogenic driver that might be sensitive to single agent ALK treatment.Graphical abstractDisplay OmittedHighlights•A method to test rare genomic findings for their relative conditional selection•ALKATIis not as mutually exclusive with BRAF or NRAS as they are with each other•ALKATIis not likely to be sufficient for cellular transformation or growthin vitro•Expressing activated oncogenic ALK in BRAFV600Emelanoma cells is cytotoxicBiological sciences; Systems biology; Cancer systems biology
