basal cell carcinoma ( bcc ) is the most common skin neoplasm , accounting for over 75% of all skin cancers . though bcc occurs mainly sporadically , multiple tumours with an early onset are associated with rare genetic disorders like gorlin syndrome and xeroderma pigmentosum . bcc tumours grow slowly and seldom metastasize ; the recurrence and tissue destruction cause extensive morbidity . uv radiation is a major environmental factor associated with increased incidence of bcc due to increased leisure sun exposure . in specific instances arsenic exposure has also been associated with increased risk of non - melanoma skin cancers , including bcc . the aetiology of bcc ultimately involves an interplay between genetic and environmental factors like uv radiation . the consequent mutations in the critical genes result in growth advantage to the affected cells leading to clonal expansion . mechanistically apoptosis prevents carcinogenesis by eliminating cells with excessive damage that escape the dna repair machinery . we hypothesized that variants in the genes involved in apoptosis can potentially modulate disease susceptibility . genetic variants in critical genes can potentially modify susceptibility to bcc through subtle influences on critical cellular processes like dna repair , cell cycle and apoptosis . adp - ribosylation factor - like tumour suppressor gene 1 ( arlts1 ) is a member of the ras superfamily , involved in apoptotic signalling . previously this gene has been suggested to be associated with susceptibility of multiple cancer types . therefore in this study we investigated the role of variants in the arlts1 gene on bcc susceptibility in cases and matching controls recruited from areas of hungary , romania and slovakia . cases and controls were recruited as part of a large study on risk of various cancers due to environmental exposures in hungary , romania and slovakia between 2002 and 2004 . the recruitment was carried out in the counties of bacs , bekes , csongrad and jasz - nagykun - szolnok in hungay ; bihor and arad in romania ; and banska bistrica and nitra in slovakia . 529 skin cancer cases , mean age 63.5 ( median 66 ; range 2 - 85 ) , were invited on the basis of histopa - thological examinations by pathologists . 533 hospital - based controls , mean age 60 ( median 61 ; range 28 - 82 ) , were included in the study , subject to fulfilment of a set of criteria . those controls included general surgery , orthopaedic and trauma patients with conditions such as appendicitis , abdominal hernias , duodenal ulcers , cholelithiasis and fractures ; patients with malignant tumours , diabetes and cardiovascular diseases were excluded . they were also broadly matched with cases for age , gender , country of residence and ethnicity . dna was isolated from blood samples from cases and controls using qiagen mini - preparation kits and genotyped for variants in the arlts1 gene by direct dna sequencing . a 237-bp product containing exon 2 of the arlts1 gene was amplified and sequenced bidirectionally using primers 5'-gat atc ctc gtg tac gtg ctg ( forward ) and 5'-gag caa aga tat gct gct ctg t ( reverse ) . the sequencing reaction products were analyzed on an abi prism 3100 genetic analyzer and primary sequence data checked using sequence analysis software ( applied biosystem , forster city , ca ) . genotype frequencies in cases and controls for all snps were tested for deviation from the hardy - weinberg equilibrium using chi^2 or fisher 's exact test . age , gender and nationality adjusted odds ratio ( or ) , 95% confidence intervals ( ci ) for risk of bcc associated with each genotype and variant allele of five snps were calculated with logistic regression using sas version 9.1 ( sas institute , cary , nc ) . cases and controls were recruited as part of a large study on risk of various cancers due to environmental exposures in hungary , romania and slovakia between 2002 and 2004 . the recruitment was carried out in the counties of bacs , bekes , csongrad and jasz - nagykun - szolnok in hungay ; bihor and arad in romania ; and banska bistrica and nitra in slovakia . 529 skin cancer cases , mean age 63.5 ( median 66 ; range 2 - 85 ) , were invited on the basis of histopa - thological examinations by pathologists . 533 hospital - based controls , mean age 60 ( median 61 ; range 28 - 82 ) , were included in the study , subject to fulfilment of a set of criteria . those controls included general surgery , orthopaedic and trauma patients with conditions such as appendicitis , abdominal hernias , duodenal ulcers , cholelithiasis and fractures ; patients with malignant tumours , diabetes and cardiovascular diseases were excluded . they were also broadly matched with cases for age , gender , country of residence and ethnicity . dna was isolated from blood samples from cases and controls using qiagen mini - preparation kits and genotyped for variants in the arlts1 gene by direct dna sequencing . a 237-bp product containing exon 2 of the arlts1 gene was amplified and sequenced bidirectionally using primers 5'-gat atc ctc gtg tac gtg ctg ( forward ) and 5'-gag caa aga tat gct gct ctg t ( reverse ) . the sequencing reaction products were analyzed on an abi prism 3100 genetic analyzer and primary sequence data checked using sequence analysis software ( applied biosystem , forster city , ca ) . genotype frequencies in cases and controls for all snps were tested for deviation from the hardy - weinberg equilibrium using chi^2 or fisher 's exact test . age , gender and nationality adjusted odds ratio ( or ) , 95% confidence intervals ( ci ) for risk of bcc associated with each genotype and variant allele of five snps were calculated with logistic regression using sas version 9.1 ( sas institute , cary , nc ) . the genotyping of a 237 bp - fragment of exon 2 of the arlts1 resulted in detection of 5 single nucleotide polymorphisms in 529 bcc cases and 533 controls . the sample size of this study was sufficient to detect under the dominant model the effect of polymorphisms with a minor allele frequency higher than 0.2 and an associated or equal to or higher than 1.5 with a power of 80% . two snps ( 297g > a and 396g > c ) were synonymous , 2 non - synonymous snps ( 392 c > t and 442 t > c ) resulted in p131l and c148r amino acid changes , and the g446a snp resulted in w149x truncating polymorphism . genotype distribution for all five polymorphisms based on allele frequencies were in accordance with hardy - weinberg equilibrium . the minor allele frequencies for five polymorphisms ranged from 0.01 ( 396g > c ) to 0.45 ( 442 t > c ) ( table 1 ) . genotype and allele distribution of variants in the arlts1 gene in bcc cases and controls * the number of cases and controls included in the study was 529 and 533 , respectively . the sequencing for genotyping failed for one sample among cases . * * global p - values calculated from chi^2 test for genotype as a single event and allele effects were adjusted for age , gender and nationality . or and corresponding 95% ci intervals associated with each genotype and variant allele are detailed in table 1 . for none of the five polymorphisms was any statistical significant difference observed for genotype and allele frequencies between bcc cases and controls . the analysis of resultant haplotypes due to 5 snps in the gene showed presence of 8 out of 32 possible haplotypes . in controls , however , only 4 haplotypes were detected . the major haplotype gcgtg consisted of common alleles of all 5 polymorphisms and together with gcgcg haplotype accounted for over 90 percent of all cases and controls . however , no differences in distribution of haplotypes between cases and controls were observed ( table 2 ) . linkage disequilibrium was observed between 392 c > t and 442t > c ( d ' = 1.0 ) , and between 442t > c and 446g > a ( d ' = 1.0 ) ( fig . the variant t - allele for the p131l ( 392c > t ) polymorphism occurred only in the presence of one or two t - alleles of the c148r ( 442t > c ) polymorphism . similarly , a - allele for the w149x ( 446g > a ) polymorphism was detected only in the presence of the t - allele of the c148 t ( 442t > c ) polymorphism . consequently , the variant allele for the w149x ( 446g > a ) polymorphism occurred together only with the common allele genotype of the p131l ( 392c > t ) polymorphism . distribution of major haplotypes in the arlts1 gene in bcc cases and controls * global p - value for haplotype effect calculated from chi^2 test . in this study we evaluated the association of polymorphisms in the arlts1 gene with modulation of bcc risk . our results showed that none of the coding sequence polymorphisms in the arlts1 gene was associated with risk modulation of bcc . while data showed linkage disequilibrium between three of the polymorphisms , the resultant haplotypes did not show differential distribution between cases and controls . in the initial study the truncating w149x ( 446g > a ) polymorphism in the arlts1 gene was reported to be associated with increased risk of familial breast cancer ; in latter studies c148r ( 442t > c ) polymorphism in the gene was also associated with marginal risk of familial breast cancer and melanoma [ 9 - 11 ] . at the same time no association was observed with risk of various sporadic cancers [ 12 - 14 ] . arlts1 is a member of the ras superfamily and resides on chromosome 13q14 , which is frequently deleted in a variety of haematopoietic and solid tumours . promoter hypermethylation of arlts1 and consequent down regulation of expression has been reported in b - cell chronic lymphocytic leukaemia and lung cancers . moreover the restoration of arlts1 in negative ovarian cells has been reported to reduce tumorigenic potential in nude mice . functionally , the w149x polymorphism has been shown to induce apoptosis in the infected cells at a significantly reduced level rather than complete ablation . this was hypothesized as the potential reason for retention of a rather drastic polymorphism in the population and could probably also explain the lack of associations with many cancer types including the bcc in the present study . in an earlier investigation on the same study population we observed an association of reduced risk of bcc with a variant allele of the xrcc3 gene and a gender - specific increased risk due to a variant in the nbs1 genes . both the xrcc3 and nbs1 genes are involved in the repair of dna double strand breaks . while dna repair capacity is potentially a critical determinant of risk of bcc , the results from this study suggest that influence of arlts1 variants on apoptosis , if any , does not impact the risk of bcc , which is one of the largest cancer types . however , despite a large sample size , the power of our study could be limited for detection of risk associated with polymorphisms with minor allele frequencies less than 10 percent . our data show lack of an association between polymorphisms and resultant haplotypes in the arlts1 gene and risk of bcc . the hypothesis of association of multiple cancer types with arlts1 variants is not supported by the data in this study .
polymorphisms in the arlts1 gene , a member of the ras super - family , have been associated with susceptibility in different cancer types . 
 the involvement of the gene in apoptotic signalling motivated us to study the role of arlts1 polymorphic variations in basal cell carcinoma of the skin ( bcc ) . in a case - control study 
 , 529 cases diagnosed with bcc and 533 controls from hungary , romania and slovakia were genotyped for the s99s ( 297g > a ) , p131l ( 392c > t ) , l132l ( 396g > c ) , c148r ( 442t > c ) and w149x ( 446g > a ) polymorphisms in the arlts1 gene . 
 no significant association between any of the single nucleotide polymorphisms ( snp ) and risk of bcc ( s99s , odds ratio ( or ) 0.96 , 95% confidence interval ( ci ) 0.60 - 1.53 ; p131l , or 1.31 95%ci 0.74 - 2.31 ; l132l , or 0.50 , 95%ci 0.02 - 7.07 ; c148r , or 0.50 , 95%ci 0.69 - 1.18 ; and w149x , or 1.01 , 95%ci 0.37 - 2.79 ) was detected . 
 furthermore , no significant difference in the distribution of haplotypes due to five polymorphisms in the arlts1 gene was found between the bcc cases and controls . 
 our data rule out an association between variants in arlts1 and risk of bcc in the investigated population .