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Genomic alterations of plasma cell-free DNAs in small cell lung cancer and their clinical relevance. Lung Cancer 2018 06;120:113-121

Date

05/12/2018

Pubmed ID

29748005

DOI

10.1016/j.lungcan.2018.04.008

Scopus ID

2-s2.0-85045459821   12 Citations

Abstract

OBJECTIVES: To identify genomic variations in cell-free DNA (cfDNA) and evaluate their clinical utility in small cell lung cancer (SCLC).

MATERIALS AND METHODS: We performed whole genome sequencing using plasma cfDNAs derived from 24 SCLC patients for copy number variation (CNV) analysis, and targeted sequencing using 17 pairs of plasma cfDNA and their matched gDNA for mutation analysis. We defined somatic mutations by comparing cfDNA to its matched gDNA with 5% variant alleles as the cutoff for mutation calls. We applied Kaplan-Meier to correlate the genomic alterations with overall survival (OS) and progression-free survival (PFS).

RESULTS: We observed widespread somatic copy-number alterations and mutations, including amplification of MYC at 8q24, FGF10 at 5p13, SOX2 at 3q26 and FGFR1 at 8p12, as well as deletion of TP53 at 17p13, RASSF1 at 3p21.3, RB1 at 13q14.2, FHIT at 3p14, and PTEN at 10q23. The most frequent mutations were genes involved in chromatin regulation (KMT2D, ARID1A, SETBP1 and PBRM1), PI3K/MTOR pathway(MTOR,PIK13G), Notch1 signalling pathway (NOTCH1), and DNA repair related gene ATRX. Kaplan-Meier analysis revealed poor OS and PFS in patients with somatic mutations in gene SETBP1 (P = 0.0061/0.0264, HR = 4.785/3.841, 95% CI = 2.014-28.25/1.286-16.58) and PBRM1 (P = 0.0276/0.0286, HR = 3.532/3.506, 95% CI = 1.275 to 25.34/1.26-24.87). Poor OS was also associated with somatic mutations in ATRX (P = 0.0099, HR = 4.024, 95% CI = 1.926-42.95), EP300 (P = 0.025/0.0622, HR = 3.382/2.891, 95% CI = 1.448-27.76/1.013-17.29), while poor PFS was associated with ATM mutation (P = 0.0038, HR = 4.604, 95% CI = 2.211-40.93). The mutation index produced by summing up the number of mutations in the five genes was significantly associated with the poor OS/PFS (P = 0.0185/0.0294) after adjusting the effect of the stage.

CONCLUSIONS: Our result supports blood plasma as a promising sample source for the genomic analysis in SCLC patients whose tumor tissues are scarcely available and demonstrates potential clinical utilities of cfDNA-based liquid biopsy for clinical management of this deadly disease.

Author List

Du M, Thompson J, Fisher H, Zhang P, Huang CC, Wang L

Author

Jonathan R. Thompson MD Assistant Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Aged
Aged, 80 and over
Biomarkers, Tumor
Cell-Free Nucleic Acids
DNA Mutational Analysis
DNA, Neoplasm
Female
Gene Dosage
Genomics
Humans
Lung Neoplasms
Male
Middle Aged
Mutation
Small Cell Lung Carcinoma
jenkins-FCD Prod-486 e3098984f26de787f5ecab75090d0a28e7f4f7c0