Application of SNP microarrays to the genome-wide analysis of chromosomal instability in premalignant airway lesions.

Ichiro Nakachi, Jessica L. Rice, Christopher D. Coldren, Michael G. Edwards, Robert Stearman, Steven C. Glidewell, Marileila Varella-Garcia, Wilbur A. Franklin, Robert L. Keith, Marina T. Lewis, Bifeng Gao, Daniel T. Merrick, York E. Miller, Mark W. Geraci

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Chromosomal instability is central to the process of carcinogenesis. The genome-wide detection of somatic chromosomal alterations (SCA) in small premalignant lesions remains challenging because sample heterogeneity dilutes the aberrant cell information. To overcome this hurdle, we focused on the B allele frequency data from single-nucleotide polymorphism microarrays (SNP arrays). The difference of allelic fractions between paired tumor and normal samples from the same patient (delta-θ) provides a simple but sensitive detection of SCA in the affected tissue. We applied the delta-θ approach to small, heterogeneous clinical specimens, including endobronchial biopsies and brushings. Regions identified by delta-θ were validated by FISH and quantitative PCR in heterogeneous samples. Distinctive genomic variations were successfully detected across the whole genome in all invasive cancer cases (6 of 6), carcinoma in situ (3 of 3), and high-grade dysplasia (severe or moderate; 3 of 11). Not only well-described SCAs in lung squamous cell carcinoma, but also several novel chromosomal alterations were frequently found across the preinvasive dysplastic cases. Within these novel regions, losses of putative tumor suppressors (RNF20 and SSBP2) and an amplification of RASGRP3 gene with oncogenic activity were observed. Widespread sampling of the airway during bronchoscopy demonstrated that field cancerization reflected by SCAs at multiple sites was detectable. SNP arrays combined with delta-θ analysis can detect SCAs in heterogeneous clinical sample and expand our ability to assess genomic instability in the airway epithelium as a biomarker of lung cancer risk.

Original languageEnglish (US)
Pages (from-to)255-265
Number of pages11
JournalCancer Prevention Research
Volume7
Issue number2
DOIs
StatePublished - 2014
Externally publishedYes

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Chromosomal Instability
Single Nucleotide Polymorphism
Genome
Neoplasms
Gene Amplification
Genomic Instability
Carcinoma in Situ
Bronchoscopy
Gene Frequency
Squamous Cell Carcinoma
Lung Neoplasms
Carcinogenesis
Epithelium
Biomarkers
Biopsy
Polymerase Chain Reaction
Lung

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Application of SNP microarrays to the genome-wide analysis of chromosomal instability in premalignant airway lesions. / Nakachi, Ichiro; Rice, Jessica L.; Coldren, Christopher D.; Edwards, Michael G.; Stearman, Robert; Glidewell, Steven C.; Varella-Garcia, Marileila; Franklin, Wilbur A.; Keith, Robert L.; Lewis, Marina T.; Gao, Bifeng; Merrick, Daniel T.; Miller, York E.; Geraci, Mark W.

In: Cancer Prevention Research, Vol. 7, No. 2, 2014, p. 255-265.

Research output: Contribution to journalArticle

Nakachi, I, Rice, JL, Coldren, CD, Edwards, MG, Stearman, R, Glidewell, SC, Varella-Garcia, M, Franklin, WA, Keith, RL, Lewis, MT, Gao, B, Merrick, DT, Miller, YE & Geraci, MW 2014, 'Application of SNP microarrays to the genome-wide analysis of chromosomal instability in premalignant airway lesions.', Cancer Prevention Research, vol. 7, no. 2, pp. 255-265. https://doi.org/10.1158/1940-6207.CAPR-12-0485
Nakachi, Ichiro ; Rice, Jessica L. ; Coldren, Christopher D. ; Edwards, Michael G. ; Stearman, Robert ; Glidewell, Steven C. ; Varella-Garcia, Marileila ; Franklin, Wilbur A. ; Keith, Robert L. ; Lewis, Marina T. ; Gao, Bifeng ; Merrick, Daniel T. ; Miller, York E. ; Geraci, Mark W. / Application of SNP microarrays to the genome-wide analysis of chromosomal instability in premalignant airway lesions. In: Cancer Prevention Research. 2014 ; Vol. 7, No. 2. pp. 255-265.
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