Recurrent PTPRT/JAK2 mutations in lung adenocarcinoma among African Americans

Abstract

Reducing or eliminating persistent disparities in lung cancer incidence and survival has been challenging because our current understanding of lung cancer biology is derived primarily from populations of European descent. Here we show results from a targeted sequencing panel using NCI-MD Case Control Study patient samples and reveal a significantly higher prevalence of PTPRT and JAK2 mutations in lung adenocarcinomas among African Americans compared with European Americans. This increase in mutation frequency was validated with independent WES data from the NCI-MD Case Control Study and TCGA. We find that patients carrying these mutations have a concomitant increase in IL-6/STAT3 signaling and miR-21 expression. Together, these findings suggest the identification of these potentially actionable mutations could have clinical significance for targeted therapy and the enrollment of minority populations in clinical trials.

Fig. 1. Somatic mutation profile of lung cancer in AAs.

a Distribution of somatic mutation number across patient samples. b Summary of mutational signatures in LUAD and LUSC samples from the NCI-MD Case Control Study. c Oncoprint outlining the co-occurrence of somatic mutations in all samples in the NCI-MD Case Control Study (histo, histology; AD, adenocarcinoma; BAC, bronchioalveolar carcinoma; SCC, squamous cell carcinoma; adenosq, adenosquamous cell carcinoma; pack, pack-years of smoking; smk, smoking status). Dashed line indicates the median.

Fig. 2. PTPRT and JAK2 mutations in LUAD.

a PTPRT and JAK2 mutations in the NCI-MD Case Control Study using targeted sequencing and WES, and in TCGA using WES and b combined. c Graphical distribution of individual mutations in PTPRT in EAs and AAs. d GSEA of gene expression changes in PTPRT and JAK2 mutant samples compared with wild type. e Levels of miR-21 in PTPRT and JAK2 mutant samples compared with wild type. Error bars indicate the s.d. *P < 0.05, **P < 0.01, ***P < 0.001, two-sided Student’s t-test. Source data are provided as a Source Data file. WES, whole-exome sequencing; AA, African American, EA, European American; TCGA, The Cancer Genome Atlas; GSEA, Gene set enrichment analysis.