Fig. 5: Heterogeneous drug responses of synchronous colorectal tumors depend on site-specific tumor heterogeneity.

See also Supplementary Fig. 6. a Multifocal organoids displayed heterogeneous drug responses in accordance with various branch mutations. Universal mutations detected in all multifocal organoids accounted for similar responses among subregional clones (marked with red lines, poor response; blue lines, good response). Branch mutations that were partially observed among subregional clones were related to heterogeneous drug responses (marked with plane figures). Previously known driver genes that are listed in the CGC were highlighted in orange and those related to drug responses were indicated in blue. b According to the clonal association identified in drug responses, tumor sites C, F, and the rest of the derived models were designated as clone 1(orange) and clone 2(blue) respectively. Transcripts (n = 759), methylated promoter sites (n = 328), and AUC values of 25 chemical compounds separating subregional clones derived from sites C and F from the rest were integrated. Multivariate values including mRNA expression, methylation, and drug response were normalized by Weight Standardization and ranged from −2(blue) to 2(red). Only the top 10% variables (n = 114) were selected to confirm the significant correlation between multiple variants. Parameters that highly separate sites A, B, D, and E from sites C and F are clustered on the left side. c The positive and negative correlation between parameters is displayed with circos plot. (red, positive correlation; blue, negative correlation). Two-component connecting 3 variables were selected by the cutoff of correlation coefficient values over 0.8. In accordance with the drug responses, derivatives from sites A, B, D, and E were designated as clone 1. The rest was labeled as clone 2. d Two components separating sites A, B, D, and E from sites C and F. Their parameters accounted for the different clonality. In accordance with the drug responses, derivatives from sites A, B, D, and E were designated as clone 1. The rest was labeled as clone 2.