Genomic alterations on 8p21-p23 are the most frequent genetic events in stage I squamous cell carcinoma of the lung

Abstract

Genetic alterations in the early stages of cancer have a close correlation with tumor initiation and potentially activate downstream pathways implicated in tumor progression; however, the method of initiation in sporadic neoplasias is largely unknown. In this study, whole-genome microarray-comparative genomic hybridization was performed to identify the early genetic alterations that define the prognosis of patients with stage I squamous cell carcinoma (SCC) of the lung. The most striking finding was the high frequency of copy number losses and hemizygous deletions on chromosome 8p, which occurred in 94.7% (18/19) and 63.2% (12/19) of the cases, respectively, with a delineated minimal common region of 8p21.1-p23.3. More specifically, three loci of homozygous deletions at 8p23.1 were noted in 21.1% (4/19) of the cases. This region contains the following possible target genes, which have previously not been implicated to play a pathogenic role in stage I SCCs: MSRA, MFHAS1, CLDN23, DEFB106A, DEFB105A, LOC441316, FAM90A7P and LOC441318. These findings indicate that genetic alterations on chromosome 8p may be the first step in the initiation of genomic instability in early SCCs, and the newly identified genes in the 8p23.1 chromosomal region might be of interest for the study of the pathophysiology of stage I SCC, as potential targets for therapeutic measures.

Keywords: copy number loss; homozygous deletion; microarray-comparative genomic hybridization; squamous cell carcinoma of the lung; tumor suppressor genes.

Figure 1

Examples of microarray-comparative genomic hybridization results from a patient sample (Tumor 2). (A) A log₂ ratio >0.25 represents a genomic copy number gain, and a log₂ ratio <−0.25 represents a genomic copy number loss. Clones are ordered from chromosome 1p to 22q. For the profiles, the x-axis represents the mapped position of the corresponding clone, and the intensity ratios are assigned to the y-axis. The homozygous deletions (HDs) at 8p23.1 are highlighted in yellow. (B) Genomic profiles of chromosome 8 from a patient sample (Tumor 2). The vertical lines indicate a ratio of <−1 in this bacterial artificial chromosome (BAC) clone, suggesting HD regions at 8p23.1. The HDs at 8p23.1 are highlighted in yellow.

Figure 2

A diagram showing weighted frequencies (%) of squamous cell carcinoma cases on the short arm of chromosome 8. In the profiles, the y-axis represents the mapped position of the corresponding clone, and the intensity ratios are assigned to the x-axis. Cytobands are shown at the bottom of the ideogram. Vertical lines indicate the lowest locus of chromosome 8 in the bacterial artificial chromosome (BAC) clone containing the MSRA, MFHAS1, CLDN23, DEFB106A, DEFB105A, LOC441316, LOC441317 (FAM90A7P) and LOC441318 genes. The homozygous deletions (HDs) at 8p23.1 are highlighted in yellow. Log₂ ratio <−1 in this BAC clone, suggesting that homozygous deletions occurred at the MSRA, MFHAS1, CLDN23, DEFB106A, DEFB105A, LOC441316, FAM90A7P and LOC441318 gene loci. Genes contained in clones are shown at the right.