Fig. 1: Reduced frequency of PI3K pathway mutations in TA-UC.

a, Time course for each patient shows duration of tamoxifen treatment (colored bars) and periods of UC diagnosis (diagn., gray bars); crossed dagger indicates treatment for at least 2 years, but exact duration is unknown. b, Plot of mutational features for TA-UCs from the discovery cohort, ordered by significantly mutated genes. From top to bottom, subpanels depict number (no.) of mutations per megabase (Mb), sample identifiers, significantly mutated genes (bold; red line, Q < 0.1; top, unrestricted hypothesis testing; bottom, restricted hypothesis testing of known UC driver genes) and nonsignificantly mutated cancer genes (PI3K pathway genes are in violet and annotated with a dagger). c, Plot of SCNAs ordered as in b; top, significant SCNAs (red line, Q < 0.25, from GISTIC); bottom, nonsignificant SCNAs in the PI3K pathway (violet and annotated with a dagger). d, Plot of molecular classifications and mutational processes (MSI, microsatellite instability; MSS, microsatellite stable; CIN, chromosomal instability; GS, genomically stable; POLE, polymerase ε), clinical annotations (mix., mixed; carcinosarc., carcinosarcoma; FIGO, International Federation of Gynecology and Obstetrics; NA, not available) and median length of tamoxifen use in years (yrs); samples ordered as in b. e, UC driver genes powered to detect differences (higher or lower) in mutation frequencies between TCGA de novo UC and TA-UC sample sets (P-value threshold for statistical power analysis at <0.05 after Bonferroni correction for the 49 significant driver genes in de novo UC). Genes are colored by pathway; gray line indicates equal frequencies in both cohorts; data points represent number of mutated tumors; error bars reflect Poisson-based s.d. estimate. Significance analysis by two-sided BH-corrected Fisher’s exact test (Q values added for all Q < 0.1 and/or PI3K pathway genes; * and sign denote significance). f, Bar plot of all (top, all mut) and hotspot (hs, bottom) PIK3CA mutations; bars represent mutation frequencies; error bars reflect s.d. from the β-distribution; significance analysis by two-sided Fisher’s exact test; numbers in bars indicate mutated tumor count per group. g, Bar plot of PI3K pathway alterations including SNVs (mut) and SCNAs (gain or deletion (del)); only TCGA tumors with both data types were considered; genes altered by either type were counted once per tumor; bars represent mutation frequencies; error bars reflect s.d. from the β-distribution; significance analysis by two-sided Fisher’s exact test; numbers in bars indicate mutated tumor count per group.