Fig. 3

Distribution of PSA in histologically defined RCC subtypes. A–C Distributions of assigned proportions of ccRCC (A), pRCC (B), and chRCC (C) to tumors of C3 are shown for distinct, pathologically defined subgroups including 469 ccRCC, 270 pRCC including 159 pRCC T1 and 78 pRCC T2, and 80 chRCC, respectively. Tumors with a maximum PSA value ≥ 95% are colored. Furthermore, ten tumors with the CpG island methylator phenotype (CIMP), a molecular pRCC subtype with a specific methylation profile, are indicated, as well as six metabolically divergent (MD) chRCC. Samples with \({P}_{psa}>0.05\) are marked in gray. Boxes refer to median and interquartile ranges with whiskers extending to a maximum of 1.5 times the interquartile range. D The information content of different subtype classifications was quantified by determining the amount of variance they explained in gene expression data. Expression of 25,208 genes in 623 tumors consisting of 466 ccRCC, 116 pRCC, and 41 chRCC that were repeatedly resampled (with replacement) from 805 cases of C3 was analyzed. Points and error bars indicate the mean together with the 95% value range of the resampling distribution. “Cohort” refers to the TCGA cohorts KIRC (n = 479), KIRP (n = 266), and KICH (n = 60). “Path.cat” comprises ccRCC (n = 466), pRCC (n = 266), and chRCC (n = 73) subgroups. Additionally, the combination of Path.cat and PSA was evaluated. Samples with \({P}_{psa}>0.05\) were not considered here. E, F Relationship between PSA and computational histopathology. The mean pairwise Manhattan distance between 50 randomly selected tiles per tumor tissue slide was used as a measure of histopathological complexity. A circle represents one tissue slide, and multiple slides may be present per tumor. The values in parentheses indicate the number of the slides and associated tumors. Samples with \({P}_{psa}>0.05\) were not considered here. E Histological complexity is displayed in dependence on the ccRCC proportion. Slides from samples classified as either chRCC or with chRCC proportion above 5% were excluded. Colors indicate the pathological classification, and the dashed lines display the mean distance of the respective set of slides. The Pearson correlation coefficient (PCC) was calculated. F Per pathologically defined RCC subgroup (Path.cat), histopathological complexity was compared between tumors with maximum PSA value ≥ 95% (filled circles) and potential heterogeneous tumors with maximum PSA value < 95% (open circles) using the t-test. Boxes refer to median and interquartile ranges with whiskers extending to a maximum of 1.5 times the interquartile range