Genomic Characterization of Non-Small-Cell Lung Cancer in African Americans by Targeted Massively Parallel Sequencing.
OBJECTIVE
Technologic advances have enabled the comprehensive analysis of genetic perturbations in non-small-cell lung cancer (NSCLC); however, African Americans have often been underrepresented in these studies. This ethnic group has higher lung cancer incidence and mortality rates, and some studies have suggested a lower incidence of epidermal growth factor receptor mutations. Herein, we report the most in-depth molecular profile of NSCLC in African Americans to date.


METHODS
A custom panel was designed to cover the coding regions of 81 NSCLC-related genes and 40 ancestry-informative markers. Clinical samples were sequenced on a massively parallel sequencing instrument, and anaplastic lymphoma kinase translocation was evaluated by fluorescent in situ hybridization.


RESULTS
The study cohort included 99 patients (61% males, 94% smokers) comprising 31 squamous and 68 nonsquamous cell carcinomas. We detected 227 nonsilent variants in the coding sequence, including 24 samples with nonoverlapping, classic driver alterations. The frequency of driver mutations was not significantly different from that of whites, and no association was found between genetic ancestry and the presence of somatic mutations. Copy number alteration analysis disclosed distinguishable amplifications in the 3q chromosome arm in squamous cell carcinomas and pointed toward a handful of targetable alterations. We also found frequent SMARCA4 mutations and protein loss, mostly in driver-negative tumors.


CONCLUSIONS
Our data suggest that African American ancestry may not be significantly different from European/white background for the presence of somatic driver mutations in NSCLC. Furthermore, we demonstrated that using a comprehensive genotyping approach could identify numerous targetable alterations, with potential impact on therapeutic decisions.
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
Luiz H
LH
Araujo
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
Cynthia
C
Timmers
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
Erica Hlavin
EH
Bell
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
Konstantin
K
Shilo
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
Philip E
PE
Lammers
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
Weiqiang
W
Zhao
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
Thanemozhi G
TG
Natarajan
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
Clinton J
CJ
Miller
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
Jianying
J
Zhang
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
Ayse S
AS
Yilmaz
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
Tom
T
Liu
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
Kevin
K
Coombes
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.
Joseph
J
Amann
Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN. david.carbone@osumc.edu.
David P
DP
Carbone
D000328:Adult; D001741:Black or African American / Q000235:genetics* / Q000706:statistics & numerical data; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000453:epidemiology / Q000235:genetics*; D016000:Cluster Analysis; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D059645:Mutation Rate; D009687:Nuclear Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
C112476:ARID1A protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases