Biomedical subjects

R C Strange

Publications and source records attributed to R C Strange.

At least 37 records · Page 2Linked to original sources

PubMed2002

[Influence of glutathione s-transferase and cytochrome p450 polymorphisms on prognosis of head and neck cancer].

BACKGROUND: The polymorphic gene loci of the detoxifying enzymes GST and CYP are susceptibility factors for head and neck cancer. Recently, they have been associated with outcome in several cancers. METHODS: Accordingly, we have examined, in patients with squamous cell carcinoma (SCC) of the head and neck, associations between GSTM1, GSTT1, GSTM3, GSTP1, CYP2D6, CYP1A1 and CYP2E1 genotypes and outcome parameters, tumor extension, histological grade, presence of lymph nodes, and recurrence free survival over 5 years. Genotypes were determined by PCR; logistic regression and a step-wise model were used to investigate the influence of the individual genes. RESULTS: GSTT1 0 was associated with T3/T4 tumor lesions in the pharynx and oral cavity (p = 0.029), but not laryngeal SCC cases. GSTT1 0 was also associated with histological differentiation (G3) in the oral cavity /pharynx, but not laryngeal SCC cases, although this association only approached significance (p = 0.069). CYP2D6 PM and HET were associated with lymph node involvement in the laryngeal SCC cases. CONCLUSIONS: The data demonstrate site-dependent associations between GSTT1 null and CYP2D6 PM and tumor extension and lymph node involvement in SCC of the head and neck.

Carcinoma, Squamous Cell↗

PubMed2001

Prostate cancer risk: associations with ultraviolet radiation, tyrosinase and melanocortin-1 receptor genotypes.

Exposure to ultraviolet radiation may reduce prostate cancer risk, suggesting that polymorphism in genes that mediate host pigmentation will be associated with susceptibility to this cancer. We studied 210 prostate cancer cases and 155 controls to determine whether vitamin D receptor (VDR, Taql and Fokl variants), tyrosinase (TYR, codon 192 variant) and melanocortin-1 receptor (MC1R, Arg151Cys, Arg160Trp, Val92Met, Asp294His and Asp84Glu variants) genotypes are associated with risk. UV exposure was determined using a questionnaire. MC1R Arg(160)/Arg(160) homozygotes were at increased risk (P = 0.027, odds ratio = 1.94) while TYR A2/A2 homozygotes were at reduced risk of prostate cancer (P = 0.033, odds ratio = 0.48). These associations remained significant after correction for UV-exposure. Stratification of cases and controls by quartiles of exposure, showed that the protective effect of TYR A1A2 (P = 0.006, odds ratio 0.075) and A2A2 (P = 0.003, odds ratio 0.055) was particularly strong in subjects who had received the greatest exposure. Our data show for the first time, that allelism in genes linked with skin pigment synthesis is associated with prostate cancer risk possibly because it mediates the protective effects of UV. Importantly, susceptibility is associated with an interaction between host predisposition and exposure.

Adult↗

PubMed2001

Glutathione-S-transferase family of enzymes.

The loci encoding the glutathione-S-transferase (GST) enzymes comprise a large supergene family located on at least seven chromosomes. The function of the GST enzymes has traditionally been considered to be the detoxication of electrophiles by glutathione conjugation. A wide variety of endogenous (e.g. by-products of reactive oxygen species activity) and exogenous (e.g. polycyclic aromatic hydrocarbons) electrophilic substrates have been identified. Interestingly, recent data has suggested a role, at least for the pi class gene product, in jun kinase inhibition. Since many GST genes are polymorphic, there has been considerable interest in determining whether particular allelic variants are associated with altered risk (or outcome) of a variety of diseases. We describe recent studies in patients with asthma and cutaneous basal cell carcinoma that demonstrate associations between GSTP1 and GSTT1 genotypes and disease phenotypes. Thus, GSTP1val(105)/val(105) was protective against asthma symptoms and GSTT1 null was associated with a subgroup of basal cell carcinoma patients who develop large numbers of primary tumours in clusters. Importantly, these associations were characterised by relatively large odds ratios (0.11 and 7.4, respectively) implying that the allelic variants exert a substantial biological effect. These and other data indicate the importance of GST polymorphism in determining disease phenotype.

Asthma↗

PubMed2001

Exposure to ultraviolet radiation: association with susceptibility and age at presentation with prostate cancer.

A positive association between latitude and prostate cancer mortality has been interpreted to indicate that ultraviolet radiation (UVR) protects against development of this cancer. We aimed to examine this hypothesis. We compared exposure between 210 cases and 155 controls. Childhood sunburn (odds ratio 0.18, 95% CI 0.08-0.38), regular foreign holidays(0.41, 0.25-0.68), sunbathing score (0.83, 0.76-0.89), and low exposure to UVR (3.03, 1.59-5.78) were associated with development of prostate cancer. Furthermore, cases with low UVR exposure developed cancer at a younger median age (67.7 years, IQR 61.5-74.6) than cases with higher exposure (72.1 years, 67.5-76.4); p=0.006. These findings are compatible with UVR having a protective role against prostate cancer.

Case-Control Studies↗

PubMed2001

Cutaneous basal cell carcinomas: distinct host factors are associated with the development of tumors on the trunk and on the head and neck.

BACKGROUND: Patients with basal cell carcinoma (BCC) demonstrate marked variation in clinical phenotype, suggesting the presence of distinct subgroups. Patients with truncal lesions comprise an interesting subgroup, because, although the pathogenesis of these tumors is unclear, there is evidence to suggest that their development is mediated by different mechanisms than the mechanisms that mediate the development of BCC on other sites. The authors now speculate that some patients inherit a predisposition to truncal BCC and develop disproportionately more BCC on this site than other patients. METHODS: The authors studied 100 patients who, at the time of initial presentation, had a truncal BCC lesion and 493 patients who had a lesion on the head and neck. The 493 patients with head and neck lesions included 36 patients who subsequently developed a truncal BCC and 457 patients who do not. RESULTS: Initial presentation with a truncal tumor was associated with significantly more subsequent BCC lesions on this site compared with patients who presented initially with a head and neck lesion. The mean truncal tumor accrual after initial presentation in patients who presented with an initial truncal BCC lesion was 0.13 BCC lesions per year compared with 0.03 BCC lesions per year in patients who presented with an initial head and neck lesion (P < 0.001). Patients with truncal lesions were significantly younger at the time of initial presentation and developed more clusters of BCC lesions (2--10 new tumors at any presentation) compared with patients who did not develop tumors on the trunk. CONCLUSIONS: These data suggest that the development of a truncal BCC is not random but, rather, is associated with a predisposition. In contrast, the accrual of nontruncal BCC lesions was similar in patients with and without initial truncal lesions, suggesting that different mechanisms determine the development of truncal BCC and nontruncal BCC.

Adult↗

PubMed2001

Simultaneous identification of GSTP1 Ile105-->Val105 and Ala114-->Val114 substitutions using an amplification refractory mutation system polymerase chain reaction assay: studies in patients with asthma.

BACKGROUND: The glutathione S-transferase (GST) enzyme GSTP1 utilizes byproducts of oxidative stress. We previously showed that alleles of GSTP1 that encode the Ile105-->Val105 substitution are associated with the asthma phenotypes of atopy and bronchial hyperresponsiveness (BHR). However, a further polymorphic site (Ala114-->Val114) has been identified that results in the following alleles: GSTP1*A (wild-type Ile105-->Ala114), GSTP1*B (Val105-->Ala114), GSTP1*C (Val105-->Val114) and GSTP1*D (Ile105-->Val114). METHODS: Because full identification of GSTP1 alleles may identify stronger links with asthma phenotypes, we describe an amplification refractory mutation system (ARMS) assay that allows identification of all genotypes. We explored whether the GSTP1 substitutions influence susceptibility to asthma, atopy and BHR. RESULTS: Among 191 atopic nonasthmatic, atopic asthmatic and nonatopic nonasthmatic individuals, none had the BD, CD, or DD genotypes. GSTP1 BC was significantly associated with reduced risk for atopy (P = 0.031). Compared with AA, trend test analysis identified a significant decrease in the frequency of GSTP1 BC with increasing severity of BHR (P = 0.031). Similarly, the frequency of GSTP1 AA increased with increasing BHR. CONCLUSION: These data suggest that GSTP1*B and possibly GSTP1*C are protective against asthma and related phenotypes.

Adult↗

PubMed2001

Genetic factors determining cutaneous basal cell carcinoma phenotype.

BACKGROUND: Basal cell carcinoma (BCC) patients demonstrate considerable phenotypic diversity. The basis of this heterogeneity is poorly understood. We have shown that presentational phenotypes are associated with BCC numbers. Thus, patients with a cluster of new BCC at any presentation comprise a subgroup, termed MPP, that is at increased risk of developing numerous lesions. Patients with more than one cluster (multiple cluster MPP) are at particular risk. PROCEDURE: We determined in a cohort of BCC cases, whether: (i) tumor accrual was altered after clustering; and (ii) multiple cluster MPP is associated with characteristics linked with sensitivity to UV or, GSTT1, GSTM1, GSTM3, GSTP1, MC1R, CYP2D6, TNF-alpha, and VDR genotypes previously associated with BCC presentational phenotypes. RESULTS: (i) After clustering BCC accrual increased; and (ii) exposure to UV in single and multiple cluster MPP cases were similar. In multiple cluster cases, mean age at first presentation with a single tumor occurred earlier and, the frequencies of CYP2D6 EM (94.4%) and GSTT1 null (41.2%) were significantly greater (P = 0.028 and P = 0.004) than in single cluster cases (67.1 and 14.3%). The odds ratios for these associations with the multiple cluster MPP were large; 15.5 and 7.39, respectively. CONCLUSIONS: The finding of clusters of new, primary BCC is a critical event that is followed by markedly increased accrual of further tumors. Clustering occurs at a relatively late age and may be associated with a failure in immune surveillance. We propose the MPP is not the consequence of excessive UV exposure but reflects the presence of a distinct BCC subgroup defined by a combination of risk genes.

Basal Cell Carcinoma↗

PubMed2001

HLA-DRB1 and disease outcome in multiple sclerosis.

The association between susceptibility to multiple sclerosis (MS) and the class II MHC allele HLA-DRB1*15 is well established although a possible relationship between this allele and outcome in MS is less clear. HLA-DRB1 typing was performed on 375 unrelated white patients with clinically definite MS and on 367 healthy controls. Putative associations of the gene with outcome were examined by dividing patients into two groups: those with an EDSS of 0-5.5 (mild/moderate disease) and those with an EDSS of 6-10 (severe disease). In order to minimise the effects of disease variability patients with a disease duration of at least 10 years or 15 years were examined. As subsidiary HLA-DRB1*03 and HLA-DRB1*04 associations have been previously reported, the effect of these alleles was also examined. As expected, HLA-DRB1*15 was found more frequently in patients than in controls (P < 0.000001). HLA-DRB1*15 positive patients had a significantly earlier age at onset than HLA-DRB1*15 negative patients. No significant associations were noted between HLA-DRB1*15 and outcome in the total patient group or in patients with a disease duration of 10 years or longer. In patients with a disease duration of at least 15 years HLA-DRB1*15 negative status was associated with a worse prognosis, although this did not remain significant after correction for multiple testing. It is thus likely that the contribution of HLA in MS is primarily towards onset and initial triggering mechanisms rather than influencing disease progression, chronicity and severity.

Adult↗

PubMed2001

Cyclin D1 polymorphism and expression in patients with squamous cell carcinoma of the head and neck.

We have previously reported that the cyclin D1 (CCND1) GG870 genotype was associated with poorly differentiated tumors and reduced disease-free interval in patients with squamous cell carcinoma of the head and neck (SCCHN). We have now examined the association of this and a second CCND1 polymorphism with gene expression and outcome in SCCHN patients. Analysis of a CCND1 G/C1722 polymorphism revealed that CCND1 CC1722 genotype was associated with poorly differentiated tumors [P = 0.005; odds ratio (OR), 5.7; 95% CI, 1.7 to 19.2), and reduced disease-free interval (P = 0.003; Hazard Ratio (HR), 7.3; 95% CI, 1.1 to 27.2.) independently from the influence of CCND1 GG870 genotype. Patients whose tumors were negative for cyclin D1 were associated with reduced disease-free interval (P = 0.028; HR, 4.1; 95% CI, 1.4 to 14.2). Although G/C1722 genotypes were not associated with expression, we found a significant trend between reduced expression of cyclin D1 in patients with the CCND1 GG870 genotype (P = 0.04). Splicing of CCND1 mRNA in head and neck tissues was modulated by CCND1 A/G870 alleles, thus CCND1 transcript a was spliced equally from CCND1 A870 and G870 alleles, whereas CCND1 transcript b was spliced mainly from the CCND1 A870 allele. Our analysis has also identified differences in cyclin D1 genotype and protein expression and the pathogenesis of SCCHN in males and females. Thus, CCND1 CC1722 genotype was more common in female patients (P = 0.019; OR, 3.3; 95% CI, 1.3 to 10) and cyclin D1 expression was more frequent (chi-square1, 3.96; P = 0.046) and at higher levels (P = 0.004) in tumors from female patients. In summary, our data show that the two CCND1 polymorphic sites are independently associated with tumor biology and clinical outcome. CCND1 A/G870 alleles affect gene expression in head and neck tissues. We also provide preliminary evidence that the molecular genetics of SCCHN development may be influenced by patient gender.

Alleles↗

PubMed2001

Susceptibility and modifier genes in cutaneous basal cell carcinomas and their associations with clinical phenotype.

While ultraviolet radiation (UV) is critical in the pathogenesis of basal cell carcinomas (BCC), its role in determining the phenotypic variation shown by patients is unknown. Thus, patients manifest variation in BCC numbers, patterns of presentation and tumour site. We have used this diversity to classify patients into subgroups that are associated with different risks of developing tumours. Two phenotypes are particularly interesting. Firstly, presentation with clusters of BCC. These patients, termed multiple presentation phenotype (MPP), had two to five BCC at one presentation, suggesting rapid accrual over short periods of time. They comprised 15% of our 1200 BCC patients. A minority of patients demonstrated multiple clustering events, a phenomenon that is associated with a genetic pre-disposition. The second risk phenotype, characterised by tumours on the trunk, is also associated with a pre-disposition. Both phenotypes were characterised by a susceptibility to develop numerous BCC. Thus, all our patients with more than five BCC had one or both of these phenotypes. We are using a candidate gene approach to identify loci associated with risk of these phenotypes (susceptibility genes) and tumour numbers in them (modifier genes). Interestingly, we did not identify differences in UV exposure between patients with high- and low-risk phenotypes.

Basal Cell Carcinoma↗

PubMed2001

Polymorphisms in glutathione S-transferases are associated with altered risk of nonmelanoma skin cancer in renal transplant recipients: a preliminary analysis.

Non-melanoma skin cancer (NMSC) represents a significant cause of morbidity and mortality among renal transplant recipients, with tumors behaving more aggressively than those in nontransplant patients. Not all immunosuppressed patients develop NMSC, however, and in those that do, the rate of accrual and numbers of lesions vary considerably. Though ultraviolet light is critical, it is unlikely that this alone explains the observed phenotypic diversity, suggesting the possible involvement of genetic factors. Furthermore, although twin studies in nontransplant patients with NMSC suggest a low genetic component, several genes associated with susceptibility and outcome in these patients have been identified. Thus, having previously shown that polymorphism in members of the glutathione S-transferase (GST) supergene family is associated with altered NMSC risk in nontransplant patients, we examined allelism in GSTM1, GSTP1, GSTM3, and GSTT1 in 183 renal transplant recipients. GSTM1 null was associated with increased squamous cell carcinoma (SCC) risk (p = 0.042, OR = 3.1). This remained significant after correction for age, gender, and ultraviolet light exposure (p = 0.012, OR = 8.4) and was particularly strong in patients with higher ultraviolet light exposure (e.g., sunbathing score > 3, p = 0.003, OR = 11.5) and in smokers (p = 0.021, OR = 4.8). Analysis of the interaction between GSTM1 null and sunbathing score showed that the two factors were synergistic and individuals with both risk parameters demonstrated a shorter time from transplantation to development of the first SCC (p = 0.012, hazard ratio = 7.1). GSTP1*Ile homozygotes developed larger numbers of SCC (p = 0.002, rate ratio = 7.6), particularly those with lower ultraviolet light exposure and cigarette consumption. GSTM3 and GSTT1 also demonstrated significant associations, though some genotype frequencies were low. These preliminary data suggest that genetic factors mediating protection against oxidative stress are important in NMSC development in immunosuppressed patients and may be useful in identifying high-risk individuals.

Adult↗

PubMed2001

[Influence of genetic variation in the major histocompatibility complex on head and neck cancer susceptibility].

BACKGROUND: While cigarette smoking and alcohol consumption are risk factors for squamous cell carcinomas (SCC) of the head and neck, genetic factors are also significant. The gene of tumor necrosis factor (TNF) is located in the major histocompatibility complex class III and the cytokine has pleiotropic actions some of which are anticarcinogenic. As this gene complex is polymorphic with microsatellite markers identified it is a further candidate for head and neck cancer susceptibility. METHODS: We used a case-control approach to study the influence of polymorphism at the A-D markers on susceptibility in 113 controls, 265 laryngeal and 123 oral cavity/pharyngeal SCC cases. Genotypes were identified on polyacrylamide gels in an automated DNA sequencer after amplification with fluorescently-labeled primers. RESULTS: We found no differences in allele frequencies between controls and oral cavity/pharyngeal SCC cases but the frequency of B3 was greater in the laryngeal SCC cases than controls (p = 0.004, odds ratio 2.8). Homozygosity for B3 conferred an increased risk of laryngeal cancer compared with controls (p = 0.021, odds ratio 10.8). CONCLUSIONS: The data provide the first evidence that allelism at MHC class III microsatellite markers is associated with risk to laryngeal SCC.

Aged↗

PubMed2001

Outcome in prostate cancer associations with skin type and polymorphism in pigmentation-related genes.

Epidemiological studies have suggested that UV exerts a protective effect on prostate cancer. Accordingly, we determined, in 210 prostate cancer cases, whether parameters of exposure, skin type and polymorphism in MC1R, VDR and TYR were associated with the outcome parameters, histological grade, clinical stage and presence of bone metastases. We used logistic regression analysis, with correction for age and metastases, stage and grade in the models, to determine if the frequencies of individual factors were different in the patient groups. The development of metastases was not associated with UV exposure parameters. Paradoxically, patients with skin type 1 were at significantly reduced risk [P = 0.027, odds ratio (OR) 0.17, 95% CI 0.03-0.82] of developing metastases compared with cases with skin type 4. MC1R Val92/Val92 and VDR ff were associated with increased risk of metastases (ORs 4.30 and 4.98, respectively). Further, cumulative exposure (P = 0.005, OR 0.85/year) and increasing proportion of outdoor occupation (P = 0.001, OR 0.84/unit) were associated with reduced risk of advanced stage tumours. Skin types, MC1R or VDR genotypes were not significantly associated with advanced stage. None of the exposure parameters, skin types or genotypes were associated with tumour grade. While MC1R Val92/Val92 and VDR ff were only associated with bone metastases, TYR genotypes were associated with each of the outcome parameters. Thus, in logistic regression models that included age, but not advanced stage and high grade histology, TYR A1A2 was significantly associated with reduced risk of metastases (P = 0.033, OR 0.41). Similarly, in models that included age but not the other outcome parameters, associations between TYR A2A2 and high-grade and advanced stage were significant (P = 0.040, OR 0.41) or approached significance (P = 0.052, OR 0.44), respectively. These data indicate for the first time that pigmentation response to UV is associated with outcome in prostate cancer.

Adenocarcinoma↗

PubMed2001

Basal cell carcinomas: association of allelic variants with a high-risk subgroup of patients with the multiple presentation phenotype.

Previous studies have shown that patients who present at first or a later presentation with a cluster of new basal cell carcinoma (BCC) comprise a subgroup, termed multiple presentation phenotype (MPP), that is at increased risk of developing further lesions. In this study, we examined the hypothesis that patients who develop multiple clusters are a high-risk subgroup. We found, in a total group of 926 BCC patients, 32 patients with 2-5 BCC clusters (multiple cluster MPP) and 113 cases with only one cluster (single cluster MPP). Multiple cluster MPP cases had mean of 11.3 BCC compared with 3.7 in single cluster MPP cases during similar follow-up. Ultraviolet (UV) exposure in these groups was similar. We determined whether the multiple cluster MPP was associated with characteristics associated with sensitivity to UV or glutathione S-transferase (GST) GSTT1, GSTM1, cytochrome P450 (CYP) CYP2D6, tumour necrosis factor (TNF)-alpha and vitamin D receptor (VDR) genotypes previously associated with BCC presentational phenotypes. While the frequencies of blue eyes and male gender were greater in multiple cluster than single cluster cases, these differences were not significant. In multiple cluster cases, mean age at first presentation with single tumours occurred earlier and the frequencies of CYP2D6 extensive metabolizer (EM) (94.4%) and GSTT1 null (41.2%) were significantly greater (P = 0.028 and P = 0.004) than in single cluster cases (67.1% and 14.3%, respectively). The odds ratios for the individual associations of CYP2D6 EM and GSTT1 null with the multiple cluster MPP were relatively larger; 15.5 and 7.39, respectively. TNF-alpha and VDR genotypes were not associated with multiple cluster MPP. We propose that the MPP is not the consequence of excessive UV exposure but rather reflects the presence of a distinct BCC subgroup which is defined by combinations of risk genes.

Alleles↗

PubMed2001

Phenol sulphotransferase SULT1A1*1 genotype is associated with reduced risk of colorectal cancer.

Sulphation is an important detoxification pathway for numerous xenobiotics; however, it also plays an important role in the metabolism and bioactivation of many dietary and environmental mutagens, including heterocyclic amines implicated in the pathogenesis of colorectal and other cancers. A major sulphotransferase (SULT) enzyme in humans, SULT1A1, is polymorphic with the most common variant allele, SULT1A1*2, occurring at a frequency of about 32% in the Caucasian population. This allele codes for an allozyme with low enzyme activity and stability compared to the wild-type (SULT1A1*1) enzyme, and therefore SULT1A1 genotype may influence susceptibility to mutagenicity following exposure to heterocyclic amines and other environmental toxins. Previously, a significant association of SULT1A1*1 genotype with old age has been observed, suggesting a 'chemoprotective' role for the high-activity phenotype. Here we have compared the frequencies of the most common SULT1A1 alleles in 226 colorectal cancer patients and 293 previously described control patients. We also assessed whether SULT1A1 genotype was related to various clinical parameters in the patient group, including Duke's classification, differentiation, site, nodal involvement and survival. There was no significant difference in allele frequency between the control and cancer patient populations, nor was there a significant association with any of the clinical parameters studied. However, when the age-related difference in allele frequency was considered, a significantly reduced risk of colorectal cancer (odds ratio = 0.47; 95% confidence interval = 0.27-0.83; P = 0.009), was associated with homozygosity for SULT1A1*1 in subjects under the age of 80 years. These results suggest that the high activity SULT1A1*1 allozyme protects against dietary and/or environmental chemicals involved in the pathogenesis of colorectal cancer.

Adolescent↗

PubMed2001

Metabolic gene polymorphism frequencies in control populations.

Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were determined. Major and significant differences in these frequencies were observed between Caucasians (n = 12,525), Asians (n = 2,136), and Africans and African Americans (n = 996), and some, but much less, heterogeneity was observed within Caucasian populations from different countries. No differences in allele frequencies were seen by age, sex, or type of controls (hospital patients versus population controls). No examples of linkage disequilibrium between the different loci were detected based on comparison of observed and expected frequencies for combinations of specific alleles.

Black People↗

PubMed2000

Basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is characterized by marked interpatient variation in tumor accrual. The authors previously reported that presentation with a cluster of BCC is associated with an inherited predisposition to develop many additional lesions suggesting clustering is a critical event. A cluster is defined as the presence of two or more new, primary BCCs, at initial or later presentation. METHODS: The authors recruited 927 cases and determined whether 1) clustering was an early or late event and 2) tumor accrual was altered after clustering. RESULTS: In the cases, 669 patients developed only 1 lesion, 112 patients presented more than once but with single lesions (single presentation phenotype[SPP]-more), 94 cases had a cluster at first presentation (multiple presentation phenotype [MPP]-cluster initial), and 52 cases first presented with 1 lesion but later had a cluster (MPP-cluster later). The authors found that 1) clustering occurred relatively late. The mean ages at first presentation with 1 BCC of the SPP-more (61.5 years) and MPP-cluster later patients (60.4 years) were similar although presentations with clusters in the MPP-cluster initial (67.6 years, P = 0.0002) and -cluster later cases (68.1 years, P = 0.002) occurred significantly later. 2) Clustering was associated with increased accrual. Thus, 26 patients (MPP-cluster later/a) in the MPP-cluster later group had a additional BCC postcluster. Mean accrual post-cluster (1.99 BCC/year) in these cases was significantly increased (P = 0.0001) compared with precluster accrual (0.39 BCC/year). CONCLUSIONS: The authors found that the formation of BCC clusters represents a critical event such that after a cluster presentation, tumor accrual is significantly increased. Cluster presentation is a relatively late event suggesting reduced effectiveness in immune surveillance.

Age Factors↗

PubMed2000

A pilot study investigating the role of NAT1 and NAT2 polymorphisms in gastric adenocarcinoma.

In humans, aromatic and heterocyclic amine carcinogens may be acetylated by the expression products of either of the N-acetyltransferase genes, NAT1 or NAT2. This conjugation reaction can result in either activation or detoxication of these carcinogens depending on the tissue involved. Recent studies suggest that polymorphisms in NAT1 or NAT2 may modulate cancer risk. To determine if genetic differences in NAT1 and NAT2 could alter risk of gastric cancer, we tested for the presence of polymorphic N-acetyltransferase alleles (both NAT1 and NAT2) in a preliminary study of 94 gastric adenocarcinoma patients and 112 control subjects from North Staffordshire, England. We used established PCR protocols to genotype for NAT2 and NAT1 alleles (NAT2*4, NAT2*5, NAT2*6, NAT2*7, NAT2*14; NAT1*3, NAT1* 4, NAT1*10, and NAT1*11), and implemented an oligonucleotide ligation assay (OLA) to test for low-activity NAT1 alleles [NAT1*14 (G560A), NAT1*15 (C559T), and NAT1*17 (C190T)]. No significant increased risk was observed for NAT2 acetylation genotypes. However, among all cases, we found that individuals inheriting a variant NAT1 allele, NAT1*10, have a significantly elevated risk for gastric cancer (OR = 2.2, 95% CI 1. 2-3.9, P < 0.01). Interestingly, the risk observed for NAT1*10 appears to be solely associated with advanced-stage tumors (OR = 4.8, P < 0.001), suggesting a possible role in progression to advanced disease. This preliminary finding needs confirmation in a larger, detailed epidemiological study.

Acetylation↗