Allelic imbalances and microdeletions affecting the PTPRD gene in cutaneous squamous cell carcinomas detected using single nucleotide polymorphism microarray analysis - PubMed (original) (raw)

Allelic imbalances and microdeletions affecting the PTPRD gene in cutaneous squamous cell carcinomas detected using single nucleotide polymorphism microarray analysis

Karin J Purdie et al. Genes Chromosomes Cancer. 2007 Jul.

Abstract

Cutaneous squamous cell carcinomas (SCC) are the second most commonly diagnosed cancers in fair-skinned people; yet the genetic mechanisms involved in SCC tumorigenesis remain poorly understood. We have used single nucleotide polymorphism (SNP) microarray analysis to examine genome-wide allelic imbalance in 16 primary and 2 lymph node metastatic SCC using paired non-tumour samples to counteract normal copy number variation. The most common genetic change was loss of heterozygosity (LOH) on 9p, observed in 13 of 16 primary SCC. Other recurrent events included LOH on 3p (9 tumors), 2q, 8p, and 13 (each in 8 SCC) and allelic gain on 3q and 8q (each in 6 tumors). Copy number-neutral LOH was observed in a proportion of samples, implying that somatic recombination had led to acquired uniparental disomy, an event not previously demonstrated in SCC. As well as recurrent patterns of gross chromosomal changes, SNP microarray analysis revealed, in 2 primary SCC, a homozygous microdeletion on 9p23 within the protein tyrosine phosphatase receptor type D (PTPRD) locus, an emerging frequent target of homozygous deletion in lung cancer and neuroblastoma. A third sample was heterozygously deleted within this locus and PTPRD expression was aberrant. Two of the 3 primary SCC with PTPRD deletion had demonstrated metastatic potential. Our data identify PTPRD as a candidate tumor suppressor gene in cutaneous SCC with a possible association with metastasis.

PubMed Disclaimer

Figures

Figure 1

Allelic imbalances demonstrated by 10K SNP microarray analysis. (a) Comparison of SNP genotypes in 16 primary SCC and paired non-tumour samples. SNP loci shown in green indicate calls unchanged between tumor and non-tumour samples, loci shown in red immediately above indicate LOH in the tumor sample and loci shown in red on the top row indicate SNPs not called in the tumor samples. Localized areas of low call rate in the tumor sample may imply LOH in a tumor subpopulation or allelic gain. (b,c) DNA copy number alterations in 16 primary SCC (b) and in 2 primary-metastatic SCC pairs (c). A running average of 2 consecutive ratios of signal values is plotted on a log2 scale according to chromosomal position. Upper line represents log2(2) and lower line represents log2(0.5).

Figure 2

Chromosome band 9p23 microdeletion and aberrant PTPRD expression observed in SCC with metastatic potential. (a) Display of copy number values on chromosome 9 reveals 9p23 microdeletion within the PTPRD locus. A running average of 2 consecutive tumor:non-tumour signal value ratios is plotted on a log2 scale according to chromosomal position. Upper line represents log2(2) and lower line represents log2(0.5). For clarity each value is represented by a vertical line from log2(1). (b–d) Aberrant PTPRD expression in patient 12 SCC with heterozygous 9p23 microdeletion. One representative set of data summarizing the pattern of PTPRD expression observed in 7 normal skin samples is shown. RT indicates RNA was subjected to reverse transcription. Arrows indicate _PTPRD_-specific amplimers. (b) Schematic representation of location of RT-PCR primers as described previously (Sato et al., 2005). (c) RT-PCR amplification of PTPRD using forward primer in exon 3 within the region of heterozygous deletion and reverse primer in exon 5 (left panel) or primers in exons 35 and 36 outside the deleted region (right panel). (d) L isoform-specific RT-PCR with forward primer located in exon B8 outside (left panel) or in exon B9 within (right panel) the region of heterozygous deletion. The reverse primer was located in exon 5. Sequence trace shows splicing within the deleted L isoform amplimer. Arrow marks junction between B8 and exon 5. [Color figure can be viewed in the online issue, which is available at

www.interscience.wiley.com

]

References

1. Armstrong BK, Kricker A. The epidemiology of UV induced skin cancer. J Photochem Photobiol B. 2001;63:8–18. - PubMed
1. Ashton KJ, Weinstein SR, Maguire DJ, Griffiths LR. Chromosomal aberrations in squamous cell carcinoma and solar keratoses revealed by comparative genomic hybridization. Arch Dermatol. 2003;139:876–882. - PubMed
1. Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP, Halperin AJ, Ponten J. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci USA. 1991;88:10124–10128. - PMC - PubMed
1. Brown VL, Harwood CA, Crook T, Cronin JG, Kelsell DP, Proby CM. p16INK4a and p14ARF tumor suppressor genes are commonly inactivated in cutaneous squamous cell carcinoma. J Invest Dermatol. 2004;122:1284–1292. - PubMed
1. Clausen OP, Aass HC, Beigi M, Purdie KJ, Proby CM, Brown VL, Mattingsdal M, Micci F, Kolvraa S, Bolund L, DeAngelis PM. Are keratoacanthomas variants of squamous cell carcinomas? A comparison of chromosomal aberrations by comparative genomic hybridization. J Invest Dermatol. 2006;126:2308–2315. - PMC - PubMed

Allelic imbalances and microdeletions affecting the PTPRD gene in cutaneous squamous cell carcinomas detected using single nucleotide polymorphism microarray analysis - PubMed (original) (raw)