Fig. 4.

RAS pathway mutation patterns and their association with JMML methylation subgroups. Genotype-specific DMPs were called for cases with somatic PTPN11 or KRAS mutations. a, b Unsupervised clustering of PTPN11-specific a and KRAS-specific b DMPs in all patients from the validation cohort (n = 147). Clinical annotation for “genotype” (somatic mutations in PTPN11, KRAS, and NRAS, germline or somatic CBL mutations; clinical diagnosis of neurofibromatosis: NF1; quintuple-negative: quint.-neg.; Noonan: clinical diagnosis of Noonan syndrome) and karyotype is depicted on top of the heatmap. DNA methylation levels are shown from light blue (0) to red (1). c, d Distribution of mutations in PTPN11 c, KRAS d and NRAS e and their association with methylation subgroups. Numbers in the mutation matrices and color shading indicate the number of mutated cases per position and methylation group