Cancer Letters

Cancer Letters

Volume 189, Issue 2, 28 January 2003, Pages 175-181
Cancer Letters

Combined effects of gender, skin type and polymorphic genes on clinical phenotype: use of rate of increase in numbers of basal cell carcinomas as a model system

https://doi.org/10.1016/S0304-3835(02)00516-5Get rights and content

Abstract

Patients with a basal cell carcinomas (BCC) have an increased risk of further tumors. We studied the individual and combined impact of gender, skin type and allelic genes cytochrome P450 (CYP2D6), vitamin D receptor (VDR), tumor necrosis factor-alpha, TNF-α) on the rate of increase in BCC numbers after first presentation. Individually, male gender, skin type 1, CYP2D6 EM, VDR TT and TNF-α GG were associated with more BCC/year (rate ratio (RR) 1.20–1.36) while RR for associations of combinations of two, three and four variables were greater than in their reference categories (RR 1.32–1.90, 2.20–2.84, 3.06–5.49, respectively). The data show that different factors mediate the numbers of BCC/year in males and females and, the individual contributions of variables to risk is modest.

Introduction

Various polymorphic genes have been linked with susceptibility and outcome in cancer [1], [2]. The identification of such genes prompts the question of how many loci, in combination, determine risk and, what is the relative importance of each gene in the presence of increasing numbers of other variables. Over recent years, we have used patients with cutaneous basal cell carcinomas (BCC) as a model system in which to study associations between genetic factors and disease risk and outcome [3], [4], [5], [6]. This particular cancer has the advantage that patients demonstrate marked, inter-individual diversity in several phenotypes including the rate at which further BCC develop during follow-up [3], [6], [7], [8]. We have described several phenotypes that are associated with how many BCC develop per year. For example, many patients develop no further BCC after first presentation with one tumor (mean 0.2 BCC/year). We termed this presentation pattern, single presentation phenotype 1 (SPP1). Other patients developed further tumors during follow-up (mean 0.6 BCC/year) but only presented with a single lesion at each presentation (SPP2). A further group comprising about 15% of patients demonstrated a presentational phenotype characterised by the appearance of multiple BCC (between 2 and 10 new tumours) at a presentation (multiple presentation phenotype, MPP). MPP patients developed relatively large numbers of BCC/year (mean 2.0) [4], [5].

The mechanisms that determine this marked inter-patient variability in numbers of BCC/year are unclear though we previously suggested that the rate of appearance of tumours is mediated by the efficiency of immune surveillance in recognising existing micro-tumours. This efficiency is in turn determined by environmental and host factors. We have attempted to identify host characteristics including allelic genes that are associated with numbers of BCC/year in patients with different phenotypes. For example, male gender (compared with females), skin type 1 (always burn on exposure to ultraviolet, UV, unable to tan) (compared with skin types 2–4) [4], and the polymorphic cytochrome P450 CYP2D6 EM, vitamin D receptor VDR TT and tumor necrosis factor-alpha (TNF-α) GG genes have been individually associated with the development of large numbers of BCC/year [4], [9].

The impact of a variable on the number of BCC/year is described by the rate ratio (RR). This approximates to the mean number of BCC per year in the test group/mean number of BCC per year in the reference category. A typical value for the RR for variables dichotomised as risk (e.g. male) and protective (e.g. female) is 1.3 [4]. While such values are associated with significant, between-group differences in BCC numbers/year, they are derived from the study of heterogenous groups. Thus, the RR for males is an average for a group comprising males with other risk (e.g. skin type 1, CYP2D6 EM, VDR TT, TNF GG) or, corresponding protective (e.g. skin types 2–4, other CYP2D6, VDR, TNF genotypes) variables. The reference category, female sex, is similarly heterogeneous. Thus, selection of males with progressively more risk variables will result in a smaller, increasingly homogeneous, high-risk group while selection of corresponding females with additional protective variables will define a smaller, more homogeneous low-risk, reference category. It is assumed that comparison of numbers of BCC/year in groups that comprise individuals with progressively more risk variables with that in the lower risk reference category will demonstrate increasingly larger values of RR.

Most studies of associations between allelic variants and disease phenotype have considered the impact of variables on phenotype in unstratified patient groups. The issue of heterogeneity within groups and, the extent to which addition of each further variable to combinations of factors affects risk has not generally been considered. We now describe studies to determine the effect of variables individually and in combinations on BCC numbers/year. Our aim was to define a combination of variables that describe a high risk group and corresponding lower risk reference category and, determine the extent of difference in RR between them. We used gender as the first variable [6], [7], [8] and then progressively stratified patients by skin type and CYP2D6, VDR, and TNF-α genotypes.

Section snippets

Patients

We studied 846 unrelated, Northern European Caucasians (29–90 years at first presentation) with one or more histologically proven BCC. They were recruited at first presentation or at annual follow-up in the North Staffordshire Hospital with Ethics Committee approval and informed consent between 1991 and 1998 [3], [4], [5], [6]. They represent about 20% eligible patients. We excluded subjects with basal cell naevus syndrome, xeroderma pigmentosum or BCC and any other malignancy but otherwise

Number of BCC/year and single variables

Table 1 shows BCC cases stratified by gender, skin type, CYP2D6, VDR, and TNF genotypes. We used negative binomial regression analysis to compare number of BCC/year in individual risk (males, skin type 1, CYP2D6 EM, VDR TT, TNF-α GG) and reference categories. The low-risk variables in the reference categories were grouped as skin types 2–4, CYP2D6 HET and PM, VDR Tt and tt and TNF GA and AA as numbers of BCC/year in subjects with these characteristics were similar [9]. When variables were

Discussion

We determined the impact of variables individually and in combination on the numbers of BCC developed per year. The variables were chosen as they have been previously associated with this model phenotype [11] and, their relatively favourable frequencies of risk/protective characteristics allowed combinations of gender, skin type and up to two genes. Clearly, the number of patients with some combinations of three or four variables was small and these findings should be interpreted cautiously.

References (16)

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