Fig. 6

PTPRH mutations are conserved in MMTV-PyMT and human lung cancer. Phosphotyrosine receptor, Ptprh was shown through Sanger sequencing to have C-T mutations in the MMTV-PyMT tumors while tail and lung samples were normal (a). Expanding targeted sequencing to additional samples revealed a conserved heterozygous mutation in 60% and homozygous mutation in 21% (b) of MMTV-PyMT tumors (n = 45). Sequencing revealed multiple mouse backgrounds (FVB, C57BL6, C57BL10, CAST, and MOLF) have varied mutations clustered in the functional domains of the Ptprh proteins (c). Increases in pEGFR signaling (d, e) and a decrease in tumor latency (F, * = P < 0.05, students two-tailed, unpaired t-test) was correlated with the mutant Ptprh allele (V483M) within the FVB background. Cell lines derived from Ptprh mutant (V483M) PyMT tumors showed an increased response to EGFR targeted therapy including erlotinib (g, n = 3, ** = P < 0.01, * = P < 0.05, students two-tailed, unpaired t-test). In human lung cancer (TCGA-pan-lung cancer) ~5% of patients have a mutation in PTPRH, which are mutually exclusive from EGFR (h). High EGFR activity, as determined by gene set enrichment analysis, is associated with mutations clustered within the four indicated structural and functional domains of PTPRH as seen by the colors in the lollipop plot for EGFR activity (i). All error bars presented are standard deviation