Amplification of the chromosome 20q region is associated with expression of HPV-16 E7 in human airway and anogenital epithelial cells

Abstract

To study the role of human papillomavirus (HPV) infection in the development of genetic instability, we transduced normal human airway and anogenital epithelial cells with various combinations of HPV-16 E6, E7, and the reverse transcriptase component of telomerase (hTERT). Cell lines generated by co-expression of E7 with E6 and/or hTERT (i.e., E6/E7, E7/hTERT, and E6/E7/hTERT) exhibited extra copies of chromosome 20 and specific amplification of the 20q12-ter region, whereas those generated without E7 (i.e., hTERT alone or E6/hTERT) did not. Co-expression of hTERT and a dominant-negative version of cdk4 that has been shown to inactivate the retinoblastoma (pRb) pathway also resulted in 20q amplification. Interestingly, extra copies of chromosome 20 were observed in early passage keratinocytes that expressed E7 alone, and microarray expression analysis revealed that genes in the 20q region and on chromosome 5 were specifically upregulated in these cells. Our results indicate that chromosome 20q amplification is an early event that may be specifically caused by expression of E7 through inactivation of the pRb pathway in human epithelial cells.

Chromosomal Signatures of a Subset of High-Grade Premalignant Cervical Lesions Closely Resemble Invasive Carcinomas

“…The mean age of women included in this study was 33.3, ranging from 22 till 54 y. Only samples that contained hrHPV DNA, as determined by a general primer GP5+/GP6+-mediated PCRenzyme immunoassay method using a probe cocktail of 14 hrHPV types (types 16,18,31,33,35,39,45,51,52,56,58,59, 66, and 68), were included (23). Presence of CIN1 or CIN2/3 in the frozen specimens used for array CGH experiments was independently validated by two experienced pathologists (FJvK and CJLMM).…”

High-resolution genomic profiling of human papillomavirus-associated vulval neoplasia

“…Gain at 8q, resulting in amplification of the oncogene c-Myc (Issing et al, 1993), was also consistently identified, as was gain at chromosome 20, a specific marker of HPV-associated cancer that has been reported to result in elevated mRNA levels of the de novo DNA methyltransferase DNMT3B at 20q (Wilting et al, 2006). In vitro studies (Savelieva et al, 1997;Klingelhutz et al, 2005) have shown that gain at 20q is an early event in hrHPV-mediated immortalisation of epithelial cells, suggesting that increased DNMT3B expression may contribute to the sequential tumour suppressor gene promoter hypermethylation that has been identified during HPV-induced transformation (Henken et al, 2007). Overall, the most frequent event across our series was gain at 1p, shown elsewhere to correlate with increased expression of the JUN protooncogene (Taniguchi et al, 2007).…”

Model of Chromosomal Instability in Oral Carcinogenesis and Progression

“…In other models of cancer genesis and progression, like the colorectal adenoma-carcinoma sequence, the Barrett's esophagus and the ulcerative colitis transition to carcinoma, the role of APC and TP53 has been highlighted (Fodde et al, 2001;Giaretti et al, 2004;Rabinovitch et al, 2004). A role of TP53 in oral cancer chromosomal instability (Negrini et al, 2010) is also likely to occur due to different sources of TP53 inactivation including HPV infection in different sites of the oral cavity Klingelhutz et al, 2005;Tsantoulis et al, 2007). Studies that linked the genome-wide integrity analysis with gene expression profiles have provided powerful indications that chromosomal instability and aneuploidy massively deregulate the cellular transcriptome (Albertson et al, 2003).…”