Fig. 5

Contribution of PAH variants to the metabolic process. a Diagram of the phenylalanine hydroxylase (PAH) pathway and profiling of 220 metabolites for the 8 individuals heterozygous for pathogenic PKU variants and 22 healthy controls. In phenylalanine metabolism, L-phenylpyruvate can be generated from L-phenylalanine through two enzymatic reactions. The heatmap presents three representative metabolites (red: higher metabolite peaks in PAH carriers, blue: lower metabolite peaks in PAH carriers). PCA using the 220 metabolites clearly distinguished the PAH carriers from the PAH non-carriers. b Hallmark GSEA signatures from PCAWG lung cancer RNA-sequencing data ranked by normalized enrichment score (NES), representing the enrichment of each cancer hallmark in PAH carriers compared to non-carriers. Hallmark signatures are ranked by P-values (at nominal P < 0.05). c Box plot showing the transcriptional score (TS) using an immune checkpoint-related gene set (N = 38) across three groups: PAH carrier in Lung-SCC PCAWG, PAH non-carrier in Lung-SCC PCAWG/TCGA, and normal lung samples from GTEx. A high TS indicates increased immune microenvironment correlation within a group