Janice Gilford

Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers: studies in upper aerodigestive tract cancers.

Glutathione S-transferase GSTM1, GSTM3 and GSTT1 and cytochrome P450 CYP2D6, CYP1A1 and CYP2E1 loci are susceptibility candidates for cancers of the upper aerodigestive tract because putatively protective and risk genotypes have been identified from studies in other diseases associated with alcohol and tobacco consumption. We describe genotype frequencies in 398 oral, pharyngeal and laryngeal squamous cell carcinoma patients and 219 control individuals. Of the genotypes presumed to be protective, only GSTM1 A/B influenced susceptibility; the GSTM1 A/B frequency was lower in the patients than the control individuals both before [odds ratio = 0.3, 95% confidence interval (CI) 0.1-0.7] and after correction for imbalances in age, sex, smoking and alcohol consumption (odds ratio = 0.2, 95% CI 0.1-0.5). Of the putatively risk genotypes, GSTM3 AA, previously associated with susceptibility to skin cancer, was higher in the cases (odds ratio = 1.6, 95% CI 1.1-2.4). Dividing cases into oral/pharyngeal and laryngeal squamous cell carcinoma showed the GSTM3 AA frequency was higher in laryngeal squamous cell carcinoma than control individuals (odds ratio = 1.6, 95% CI 1.1-2.5) and the difference between control individuals and oral/pharyngeal squamous cell carcinoma approached significance (odds ratio = 1.7, 95% CI 1.0-2.8). The putatively protective GSTM3 BB genotype was lower in patients with glottic (1.0%) than supraglottic (3.0%) squamous cell carcinoma. We identified no differences between patients and control individuals in the frequencies of presumed risk genotypes (e.g. CYP2D6 EM, CYP1A1 m1/m1, CYP1A1 Ile/Ile, CYP2E1 DD, CYP2E1 c1c1, GSTT1 null) or, interactions between genotypes and smoking or alcohol consumption. We conclude, first, that mu class glutathione S-transferase influence risk of upper aerodigestive tract cancers thereby complementing studies in skin cancer patients showing GSTM1 A/B is protective, while GSTM3 AA moderately increases risk. The influence of GSTM1 A/B, but not GSTM1 A or GSTM1 B (mostly heterozygotes with GSTM1*0) suggests that two expressed alleles may attenuate risk. While we found immunohistochemical evidence of GSTM3 expression in the cilia lining the larynx, the biochemical consequences of the polymorphism are unclear. Indeed, the influence of the gene may reflect linkage disequilibrium with another gene. However, we did not find an association with GSTM1 genotypes. Second, we conclude that the CYP2D6, CYP2E1, CYP1A1 and GSTT1 alleles studied, although putatively good candidates, either do not determine the effectiveness of detoxification of tobacco-derived carcinogens in the upper aerodigestive tract or, that chronic consumption of tobacco and alcohol overwhelms enzyme defences, irrespective of genotype.

Susceptibility and outcome in oral cancer : preliminary data showing an association with polymorphism in cytochrome P450 CYP2D6

Members of the cytochrome P450 and glutathione S-transferase supergene families are candidates for susceptibility and outcome in oral squamous cell cancer. We determined GSTM1, GSTM3, GSTT1, CYP1A1 and CYP2D6 genotypes in 100 Caucasian cases and 467 control individuals. The frequency of homozygosity for mutant CYP2D6 alleles was higher in the cases (P = 0.001, OR = 3.2, 95% CI = 1.6-6.5) than control individuals. In the cases, the frequency of homozygosity for mutant alleles was greater and that of homozygosity for wild-type CYP2D6 alleles was lower in those diagnosed at > or = 65 years (P = 0.009) than in those diagnosed at < or = 64 years. The older cases included relatively more women and patients who did not consume tobacco or alcohol. The association of CYP2D6 with outcome was assessed using the Coxs proportional hazards model. The time to first cervical node metastasis was shorter in heterozygotes and homozygotes for mutant CYP2D6 alleles compared with homozygotes for wild-type alleles after correction for age at diagnosis, gender, alcohol and tobacco consumption and tumour differentiation (P = 0.04, hazard ratio 3.6, 95% CI 1.1-12.5). The mechanism for the association of CYP2D6 alleles with susceptibility and outcome is unclear though the data are compatible with the view that homozygosity for mutant alleles confers impaired detoxication of an unknown carcinogen. No associations between GSTM1, GSTM3, GSTT1 or CYP1A1 genotypes and susceptibility or, time to node metastases were identified. We previously showed that CYP2D6 genotypes were not associated with susceptibility to squamous cell cancer in the pharynx or larynx. Therefore, the data presented suggest that susceptibility to squamous cell cancer in the various parts of the upper aerodigestive tract is associated with different genes and allelic variants.

Susceptibility to multiple cutaneous basal cell carcinomas: significant interactions between glutathione S-transferase GSTM1 genotypes, skin type and male gender

The factors that determine development of single and multiple primary cutaneous basal cell carcinomas (BCCs) are unclear. We describe a case-control study firstly, to examine the influence of allelism at the glutathione S-transferase GSTM1 and GSTT1 and cytochrome P450 CYP2D6 loci on susceptibility to these tumours and, secondly, to identify interactions between genotypes and relevant individual characteristics, such as skin type and gender. Frequency distributions for GSTM1 genotypes in cases and controls were not different, although the frequency of GSTM1 A/B was significantly lower (P = 0.048) in the multiple BCCs than in controls. We found no significant differences in the frequencies of GSTT1 and CYP2D6 genotypes in cases and controls. Interactions between genotypes were studied by comparing multinomial frequency distributions in mutually exclusive groups. These identified no differences between cases and controls for combinations of the putatively high risk GSTM1 null, GSTT1 null, CYP2D6 EM genotypes. Interactions between GSTM1 A/B and the CYP2D6 PM and GSTT1-positive genotypes were also not different. Frequency distributions of GSTM1 A/B with CYP2D6 EM in controls and multiple BCCs were significantly different (P = 0.033). The proportion of males in the multiple BCC group (61.3%) was greater than in controls (47.0%) and single BCC (52.2%), and the frequency of the combination GSTM1 null/male gender was significantly greater in patients with multiple tumours (P = 0.002). Frequency distributions of GSTM1 null/skin type 1 were also significantly different (P = 0.029) and the proportion of subjects who were GSTM1 null with skin type 1 was greater (P = 0.009) in the multiple BCC group. We examined the data for interactions between GSTM1 null/skin type 1/male gender by comparing frequency distributions of these factors in the single and multiple BCC groups. The distributions were almost significantly different (exact P = 0.051). No significant interactions between GSTT1 null or CYP2D6 EM and skin type 1 were identified. Comparisons of frequency distributions of smoking with the GSTM1 null, GSTT1 null and CYP2D6 EM genotypes identified no differences between patients with single and multiple tumours.

The Multiple Sclerosis Severity Score: associations with MC1R single nucleotide polymorphisms and host response to ultraviolet radiation.

Background: Multiple sclerosis outcome may be influenced by ultraviolet radiation and vitamin D synthesis, suggesting skin type and genes determining this phenotype are candidates for disability. However, though associations between melanocortin 1 receptor (MC1R) single nucleotide polymorphisms and disability are reported, some data are incompatible with their expected influence on skin type. Objective: Determine which MC1R single nucleotide polymorphisms affect disability and establish if ultraviolet radiation modifies such associations. Methods: We studied using linear regression in 525 cases, associations of the Multiple Sclerosis Severity Score (MSSS) with skin type, gender, ultraviolet radiation exposure and six MC1R single nucleotide polymorphisms (rs1805005, rs1805006, rs2228479, rs1805007, rs1805008, rs1805009). Results: CG294 with GG294 genotypes (rs1805009) (coefficient = —1.44, 95% CI —2.30, —0.59, mean MSSS ± SD = 4.33 ± 2.87) and AC84 (rs1805006) (coefficient = 1.62, 95% CI 0.17, 3.06, mean MSSS = 7.62 ± 2.43) were associated with MSSS. Associations with Asp294His were found in those with skin types 1/2 and 3/4, and cases stratified by ultraviolet radiation exposure. However, they were seen only in cases with a history of childhood sunburn and not in those without sunburn. We found no significant associations between exposure parameters and MSSS. Conclusions: Multiple Sclerosis outcome is influenced by interactions between host response to ultraviolet radiation and MC1R single nucleotide polymorphisms. The influence of the single nucleotide polymorphisms appears distinct from their association with skin type.

Polymorphism in Detoxifying Enzymes and Susceptibility to Skin Cancer

ates, isomerization of urocanic acid and activation of a surprising range of cytokine genes within keratinocytes. The DNA photoproducts (1 8) and UVB-generated oxygen intermediates (19) have been implicated as damaging to cutaneous immunity. The possibility exists that polyrnorphisms at loci that encode excision and repair genes or at loci regulating free radical quenching may exist and could have a profound effect on cutaneous immunity. Similarly, polymorphisms at cytokine gene loci may contribute to UVB-S. Finally, UVB radiation produces multiple, mechanistically distinct immune aberrations. Locally, at the irradiated site, UVB radiation (1) impairs induction of CH, (2) promotes hapten-specific tolerance and (3) creates a sustained immunosuppressive microenvironment (20). Systemically, UVB radiation (1) impairs both delayed and CH to a variety of antigens (21) and (2) induces active, nonspecific unresponsiveness. Our studies have revealed genetics factors operating in only one of these aberrations, but we suspect that, in time, other polymorphic genetic factors will be identified that contribute to the damaging immune effects of UVB radiation and thereby alter an individual’s risk of developing sunlight-induced skin cancer.

Progression of disability in multiple sclerosis: A study of factors influencing median time to reach an EDSS value

BACKGROUND The extended disability severity scale (EDSS) is clinically useful in assessing disability in multiple sclerosis (MS) patients. It is also being used in studies to determine how genes and environment influence disability. However, since it has a complex relationship with functional scores and mobility and is strongly determined by disease duration its use can be limiting. OBJECTIVE Study associations of variables with progression described by time from disease onset until EDSS. METHODS We used a variable based on below/above median time from MS onset to reach a single EDSS value to define slow or fast progression. We compared patient categorization using this variable and MSSS, and in 533 patients (EDSS 1-8) and 242 of these patients with EDSS1-4, studied associations with skin type, gender, ultraviolet radiation and MC1R Asp294His. RESULTS Classifying patients into quartiles of slow/fast progression showed mean MSSS increased with faster progression (p<0.001). For EDSS 1-8: MSSS, late onset age and childhood sunburning were associated with fast and MC1R CG/GG(294) with slow progression. Combinations of skin type (1/2 or 3/4) with childhood weekend exposure (< or ≥median) or sunburning (yes/no) were not associated with progression. However, in patients with EDSS1-4, relative to other combinations, those with no sunburning history and types 1/2 demonstrated slow progression (odds ratio=0.15, 95% CI=0.04, 0.57). CONCLUSION This method, though a pilot, allows study of associations of variables with EDSS. It is based on local patients and could substitute for MSSS. In patients with EDSS1-4 but not 1-8, skin type 1/2 with no history of childhood sunburning was associated with slow progression. This is compatible with the view that disability develops through a first stage dependent on inflammation.