Profiling the Mutational Landscape in Known Driver Genes and Novel Genes in African American Non–Small Cell Lung Cancer Patients

Abstract

Purpose: Identifying novel driver genes and mutations in African American non-small cell lung cancer (NSCLC) cases can inform targeted therapy and improve outcomes for this traditionally underrepresented population.Experimental Design: Tumor DNA, RNA, and germline DNA were collected from African American NSCLC patients who participated in research conducted at the Karmanos Cancer Institute (KCI) in Detroit, Michigan. Known mutations were ascertained through the Sequenom LungCarta panel of 214 mutations in 26 genes, RET/ROS1 fusions, amplification of FGFR1, and expression of ALK. Paired tumor and normal DNA was whole-exome sequenced for a subset of cases without known driver mutations.Results: Of the 193 tumors tested, 77 known driver mutations were identified in 66 patients (34.2%). Sixty-seven of the 127 patients without a known driver mutation were sequenced. In 54 of these patients, 50 nonsynonymous mutations were predicted to have damaging effects among the 26 panel genes, 47 of which are not found in The Cancer Genome Atlas NSCLC white or African American samples. Analyzing the whole-exome sequence data using MutSig2CV identified a total of 88 genes significantly mutated at FDR q < 0.1. Only 5 of these genes were previously reported as oncogenic.Conclusions: These findings suggest that broader mutation profiling including both known and novel driver genes in African Americans with NSCLC will identify additional mutations that may be useful in treatment decision-making.

Whole-Exome Profiling of NSCLC Among African Americans

“…8,[46][47][48] However, supplementary data from many of these studies exhibit consistent results with those presented here for STK11, 49 RB1, 49 and JAK2. 9 In other cases, our data were not consistent, 8 which could be owing to different exposures related to geography, rates of admixture, or methodologies.…”

“…10 In recent years, studies using targeted exome sequencing approaches to analyze AA populations have been published. These studies reveal that much of the somatic mutation landscape of NSCLC is shared between EAs and AAs, 5,8,9 but also that some notable differences can be found, especially in lung adenocarcinoma (LUAD), including JAK2 and PTPRT. 5 Despite these observations, such ancestry differences in NSCLC genomics have yet to be systematically evaluated with whole-exome sequencing (WES) in an AA cohort.…”

“…2 In recent years, several large-scale genomic studies have begun to map differences in tumor biology between EAs and AAs. [4][5][6][7][8][9] These studies reveal that although most tumor biology is shared between EAs and AAs, specific and potentially actionable differences exist.…”

“…5 Despite these observations, such ancestry differences in NSCLC genomics have yet to be systematically evaluated with whole-exome sequencing (WES) in an AA cohort. A recent study by Lusk et al, 9 conducted WES on a subset of lung tumors without known driver mutations, the results of which suggested that an unbiased WES assessment in an unselected sample set was warranted. To fill this knowledge gap, we used WES on matched tumor and noninvolved tissue pairs.…”

Ultra-Deep Massive Parallel Sequencing of Plasma Cell-Free DNA Enables Large-Scale Profiling of Driver Mutations in Vietnamese Patients With Advanced Non-Small Cell Lung Cancer

“…Currently, clinical practice guidelines on NSCLC are largely based on results from studies of Caucasian cohorts (4). However, there is a growing body of clinical evidence that NSCLC patients present heterogeneous genetic constitution across different populations, suggesting that large-scale population-specific mutation profiles are of utmost importance to the development of clinical practice guidelines for a particular population (5)(6)(7).…”