Recurrent PTPRT/JAK2 mutations in lung adenocarcinoma among African Americans

Khadijah A Mitchell,Jennifer Walling,Wei Tang,Roxana Stefanescu ,Holly Stevenson ,Andrew T Girvin ,Justin Lack ,Joshua J Waterfall,Adriana Zingone,Emily L Rossi,Sharon R Pine,John K Simmons ,Elise D Bowman ,Rony F Arauz,Noah Nichols,Elizabeth Weingartner,Yuelin J Zhu ,Sanju Sinha,Marbin Pineda,Paul S Meltzer ,Daniel C Edelman,Bríd M Ryan

doi:10.1038/s41467-019-13732-y

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.

Highlights

Our current understanding of lung cancer biology is primarily derived from populations of European descent
We identified 4,136 somatic single-nucleotide variants (SNVs) and indel events (Supplementary Data 4; median/patient = 24, range = 0–426; Fig. 1a; Supplementary Data 4), reflecting the genetic heterogeneity of the population
The patient with the highest mutation burden was a current smoker with 64 pack-years of tobacco smoke consumption, who presented with adenocarcinoma

Summary

Introduction

Our current understanding of lung cancer biology is primarily derived from populations of European descent. Given the persistent disparities that exist in lung cancer incidence and survival between AAs and EAs, it is important to characterize tumor biology across racial and ethnic groups. Large-scale genomic studies have highlighted genetic heterogeneity in lung cancer[8,9,10]. Few studies have investigated the somatic mutation landscape of lung cancer in AAs, and of those that have, the studies often included a small panel of genes or focused on hotspot mutations; others have focused on tumor tissue only[12,13,14,15]. We report two genes, PTPRT and JAK2, that are recurrently mutated in lung adenocarcinoma (LUAD) among AAs

Methods

Results

Conclusion