Low frequency of allelic loss in skin tumours from immunosuppressed individuals

Abstract

Summary Organ transplant recipients receiving immunosuppression show a dramatically increased risk of non-melanoma skin cancer. The cause of this increase is not known. We report that the rate of loss of heterozygosity (at all the loci we examined) was significantly lower in tumours from immunosuppressed individuals than in tumours from immunocompetent subjects [20 out of 148 (14%) vs 157 out of 428 (37%); P < 0.0001]. These results suggest that tumours in immunosuppressed individuals have a different molecular pathogenesis.Keywords: loss of heterozygosity; non-melanoma skin cancer; immunosuppression; tumour suppressor; human papilloma virus; squamous cell carcinoma Patients receiving immunosuppressive therapy after organ transplantation show up to a 250-fold increase in the incidence of nonmelanoma skin cancers (NMSCs) and their precursor lesions (Abel, 1989; Hartevelt et al, 1990; Espana et al, 1995; Glover et al, 1997). In such patients the high prevalence of infection by a spectrum of human papilloma virus (HPV) types together with a high incidence of other neoplasms associated with a viral pathogenesis has suggested a role for virus during NMSC development (Barr et al, 1989). However, in skin, unlike cervical carcinoma, compelling evidence that HPVs play a causative role, rather than being mere passengers, is lacking. It is also possible that other viruses such as the recently described Kaposi's sarcoma herpes-like virus (KSHV) (Boshoff et al, 1996) or as yet unidentified viruses may be important. We therefore sought indirect evidence for a different molecular pathogenesis in these tumours that would provide support for a causal role for one or more types of virus, including viruses that had not yet been identified.Tumour-suppressor gene inactivation commonly occurs by mutation of one allele accompanied by chromosome loss of the wild-type allele (Knudson, 1991). Other mechanisms of tumoursuppressor gene activation can occur, including binding of the products of virally encoded oncogenes or changes in methylation status of tumour-suppressor genes (Vousden, 1993;Kinzler and Vogelstein, 1996). If, in tumours from immunosuppressed individuals, tumour-suppressor genes are being inactivated by alternative means, then the rate or pattern of loss of heterozygosity might be expected to differ from those in immunocompetent individuals. We examined this hypothesis. Ten-micrometre tissue sections were carefully microdissected to separate tumour from adjacent normal epithelium, and the DNA was extracted using phenol-chloroform (Jackson et al, 1995). In all cases, control DNA from either adjacent normal skin or blood was used. Tumour and control DNA was subject to polymerase chain reaction (PCR) amplification using one [y-32P]ATP (Life Sciences, Amersham, UK) end-labelled primer as previously described (Rehman et al, 1996), using microsatellite markers 3p (D3S1293), 9p (D9S162, D9S171), 9q (D9S197), 13q (D13S170), 17p (D17S796) and 17q (D17S785) (Research Genetics, Huntsville, AL, USA). PCR products were resolved on a ...

p16INK4a and p14ARF Tumor Suppressor Genes Are Commonly Inactivated in Cutaneous Squamous Cell Carcinoma

“…These results, however, are in keeping with a previous study which reported less allelic loss at chromosome 9p in skin tumors from immunosuppressed compared with immunocompetent patients (Rehman et al, 1997). The explanation for these findings remain elusive, but one could speculate that the significantly higher prevalence of human papillomavirus found in immunosuppressed cutaneous SCC obviates the need for direct genetic/epigenetic TSG alterations, similar to the mechanism proven in anogenital carcinomas (Harwood and Proby, 2002).…”

Molecular profiling of cutaneous squamous cell carcinomas and actinic keratoses from organ transplant recipients

“…This observation and the results of our study suggest that perhaps the suppression of the immune system in OTRs may influence the development of SCCs in these patients. This phenomenon has been reported before by Rehman et al, who demonstrated that the LOH rate in SCCs from OTRs was less than half of that in SCCs from immunocompetent patients [43]. Moreover, there could also be a direct effect of the applied immunosuppressive drugs on the molecular pathogenesis of SCCs in OTRs, which has also been suggested before by others [44].…”

Patient-specific mutation databases for oral cancer

“…Tumours in patients receiving immunosuppressive therapy showed a low frequency of AI. Similar findings have been reported by Rehman et al (1997), who suggested that tumours that develop in immunosuppressed patients in which there may be decreased immunosurveillance, may be able to bypass the need to inactivate certain tumour suppressor proteins. Inclusion of a high proportion of stage 1 and 2 tumours in this analysis has identified several cases with small interstitial deletions at key chromosomal loci, and our data support the existence of several tumour suppressor gene areas at the short arms of chromosomes 3, 8 and 9.…”