Dataset Information

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.

SUBMITTER: Lusk CM

PROVIDER: S-EPMC6635071 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Lusk Christine M CM Watza Donovan D Dyson Greg G Craig Douglas D Ratliff Valerie V Wenzlaff Angela S AS Lonardo Fulvio F Bollig-Fischer Aliccia A Bepler Gerold G Purrington Kristen K Gadgeel Shirish S Schwartz Ann G AG

Clinical cancer research : an official journal of the American Association for Cancer Research 20190412 14

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 p ...[more]

PMID: 30979741

Similar Datasets

Project description:BackgroundHomologous recombination deficiency (HRD) is a well-known biomarker which could predict poly-ADP ribose polymerase 1 (PARP) inhibitor and platinum drug response. As an aggressive cancer, small-cell lung cancer (SCLC) is sensitive to platinum drugs, but relapse occurs rapidly. Herein, we aim to illustrate the genomic alteration patterns of homologous recombination repair (HRR)-related genes in a Chinese SCLC cohort and further analyze the relationship among HRR gene mutations and known biomarkers of immune checkpoint inhibitor (ICI) response, including tumor mutation burden (TMB) and programmed cell death-ligand 1 (PD-L1) expression.MethodsNext-generation sequencing (NGS)-based target capture sequencing of 543 cancer-related genes was performed to analyze the genomic profiles of 133 Chinese SCLC patients, and TMB was calculated. PD-L1 expression was evaluated in 90 out of 133 patients using the SP142 PD-L1 immunohistochemistry assay.ResultsAmong the 133 patients with SCLC, 47 (35.3%) had HRR gene mutations. ATM (8.3%) was the most frequently mutated HRR gene in the cohort, followed by NBN (4.5%). Pathogenic somatic and germline mutations of HRR genes were identified in 11 (23.4%) and 4 (8.5%) patients, respectively. HRR gene mutations cooccurred with KMT2D gene mutations. There were several differences in genomic alterations between patients with HRR gene mutations (HRR-Mut) and without HRR mutations (HRR-WT). The results revealed that TP53 and RB1 were commonly mutated genes in both groups. Mutations in the KMT2D gene and genes in the RTK-RAS pathway occurred more frequently in the HRR-Mut group. Furthermore, we found that mutations in HRR genes were associated with high TMB (Wilcoxon, p = 0.048), but there was no correlation of HRR gene mutation status with PD-L1 expression.ConclusionsWe exhaustively describe the genomic alteration profile of Chinese SCLC patients and provide further evidence that HRR gene mutations are prevalent in SCLC patients.

Project description:BackgroundIdentifying actionable driver mutations via tissue-based comprehensive genomic profiling (CGP) is paramount in treatment decisions for metastatic non-squamous, non-small-cell lung cancer (NSCLC). However, the role of CGP remains elusive in resectable NSCLC. Here, we elucidate the feasibility of CGP in early-stage NSCLC Korean patients and compare the tumor mutational burden (TMB) and mutation landscape using three different platforms.MethodsAll surgically resected NSCLC samples (N = 96) were analyzed to assess the concordance in TMB calculation and targetable mutations using whole-exome sequencing (WES) and TruSight Oncology 500 (TSO500). In all, 26 samples were analyzed with Foundation One CDx Assay (F1CDx). Programmed death-ligand 1 (PD-L1) expression was evaluated using Vectra Polaris.ResultsStage distribution post-surgery was 80% I (N = 77) and 20% II (N = 19). Ninety-nine percent (N = 95) were adenocarcinoma. The median TMB with WES and TSO500 was 1.6 and 4.7 mut/Mb, respectively (p < 0.05). Using all three platforms, the median TMB was 1.9, 5.5, and 4 mut/Mb for WES, TSO500, and F1CDx, respectively (p = 0.0048). Linear regression analysis of TMB values calculated between WES and TSO500 resulted in a concordance correlation coefficient of 0.83. For the PD-L1 tumor proportion score of <1% (negative, N = 18), 1-49% (low, N = 68), and ⩾50% (high, N = 10), the R2 values were 0.075, 0.79, and 0.95, respectively. The R2 values for TMB concordance were variable between the three platforms. Mutation landscape revealed EGFR mutation (51%, N = 49) as the most common actionable driver mutation, comprising L858R (N = 22), E19del (N = 20), and other non-common EGFR mutations (N = 7).ConclusionTSO500 and F1CDx showed robust analytical performance for TMB assessment with TSO500 showing stronger concordance of TMB with high PD-L1 expression. As the paradigm for the management of early-resected NSCLC continues to evolve, understanding TMB and the mutation landscape may help advance clinical outcomes for this subset of patients.

Project description:The identification of genes that are differentially methylated in colorectal cancer (CRC) has potential value for both diagnostic and therapeutic interventions specifically in high-risk populations such as African Americans (AAs). However, DNA methylation patterns in CRC, especially in AAs, have not been systematically explored and remain poorly understood. Here, we performed DNA methylome profiling to identify the methylation status of CpG islands within candidate genes involved in critical pathways important in the initiation and development of CRC. We used reduced representation bisulfite sequencing (RRBS) in colorectal cancer and adenoma tissues that were compared with DNA methylome from a healthy AA subject's colon tissue and peripheral blood DNA. The identified methylation markers were validated in fresh frozen CRC tissues and corresponding normal tissues from AA patients diagnosed with CRC at Howard University Hospital. We identified and validated the methylation status of 355 CpG sites located within 16 gene promoter regions associated with CpG islands. Fifty CpG sites located within CpG islands-in genes ATXN7L1 (2), BMP3 (7), EID3 (15), GAS7 (1), GPR75 (24), and TNFAIP2 (1)-were significantly hypermethylated in tumor vs. normal tissues (P<0.05). The methylation status of BMP3, EID3, GAS7, and GPR75 was confirmed in an independent, validation cohort. Ingenuity pathway analysis mapped three of these markers (GAS7, BMP3 and GPR) in the insulin and TGF-β1 network-the two key pathways in CRC. In addition to hypermethylated genes, our analysis also revealed that LINE-1 repeat elements were progressively hypomethylated in the normal-adenoma-cancer sequence. We conclude that DNA methylome profiling based on RRBS is an effective method for screening aberrantly methylated genes in CRC. While previous studies focused on the limited identification of hypermethylated genes, ours is the first study to systematically and comprehensively identify novel hypermethylated genes, as well as hypomethylated LINE-1 sequences, which may serve as potential biomarkers for CRC in African Americans. Our discovered biomarkers were intimately linked to the insulin/TGF-B1 pathway, further strengthening the association of diabetic disorders with colon oncogenic transformation.

Dataset Information

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

Purpose

Experimental design

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets