Homozygous Deletions and Chromosome Amplifications in Human Lung Carcinomas Revealed by Single Nucleotide Polymorphism Array Analysis

Xiaojun Zhao,Javad Beheshti,William G Richards,Rameen Beroukhim,Barbara A Weir,Luc Girard,Katsuhiko Naoki,William R Sellers,Cheng Li,Fei Chen,Jeffrey C Lee,Mark A Rubin,Thomas Laframboise,Matthew Meyerson,John D Minna ,David C Christiani ,Ming Gang Lin ,Levi A Garraway ,Pasi A Jänne ,David J Sugarbaker

doi:10.1158/0008-5472.can-04-4603

Abstract

Genome-wide copy number changes were analyzed in 70 primary human lung carcinoma specimens and 31 cell lines derived from human lung carcinomas, with high-density arrays representing approximately 115,000 single nucleotide polymorphism loci. In addition to previously characterized loci, two regions of homozygous deletion were found, one near the PTPRD locus on chromosome segment 9p23 in four samples representing both small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) and the second on chromosome segment 3q25 in one sample each of NSCLC and SCLC. High-level amplifications were identified within chromosome segment 8q12-13 in two SCLC specimens, 12p11 in two NSCLC specimens and 22q11 in four NSCLC specimens. Systematic copy number analysis of tyrosine kinase genes identified high-level amplification of EGFR in three NSCLC specimens, FGFR1 in two specimens and ERBB2 and MET in one specimen each. EGFR amplification was shown to be independent of kinase domain mutational status.

Highlights

Mapping copy number alterations in the cancer genome has contributed to the subsequent identification of tumor suppressor genes and oncogenes
Analyses of all tumor samples, throughout the genome, identifies recurrent regions of copy number gain and loss in lung carcinomas (Fig. 1B and C; Supplementary Fig. S1 shows copy number estimates for each sample across the entire genome). In both non–small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC), the most frequent copy number gains were found in chromosome arm 5p, with z3 copies found in 25% and 43% of samples, respectively (Fig. 1B and C)
The present study represents the first application of genomewide copy number analysis in lung cancer by Single nucleotide polymorphism (SNP) array

Summary

Introduction

Mapping copy number alterations in the cancer genome has contributed to the subsequent identification of tumor suppressor genes and oncogenes. The delineation of cancer-specific homozygous deletions enabled the discovery of several different tumor suppressor genes, including RB1 [1], CDKN2A [2, 3], PTEN [4, 5], and SMAD4/DPC4 [6]. Array comparative genomic hybridization can provide high-resolution detection of copy number changes [20, 21]. SNP arrays that cover f10,000 SNP loci can be used to detect DNA copy number changes at the genome level, including high-level amplifications and homozygous deletions [27, 28]

Methods

Results

Conclusion