PGx397 whole genome sequencing of lapatinib concurrent ALT/TBL elevation and extreme ALT elevation cases

Trial description: Previous work has identified a robust and confirmed association of the MHC Class II locus, that is described by carriage of HLA-DRB1*07:01 and DQA1*02:01 alleles, and lapatinib-induced hepatotoxicity. The present analysis seeks to extend this work to identify additional genetic markers that may improve the predictive performance of the HLA alleles as markers of hepatotoxicity risk. The experiment performed included whole genome sequencing of 26 expert-adjudicated possible Hy’s Law cases (n=20) or extreme elevated alanine aminotransferase (ALT) (>10x ULN) cases (n=6), and 19 matched controls, all selected from lapatinib clinical trials. DNA from these 45 subjects were subjected to whole genome re-sequencing, using the Illumina HiSeq platform with paired-end reads of 90bp at BGI, to 30-fold depth or greater. There are two key objectives to this study. First, to refine the previously identified signal in the MHC region by looking for an association with an underlying variant in the MHC region differentiating HLA risk allele carriers that develop hepatotoxicity from those who do not. Second, to identify additional genetic markers associated with lapatinib-induced hepatotoxicity elsewhere in the genome.