RESUMEN
In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.
Asunto(s)
Carcinoma Basocelular/genética , Caspasa 8/genética , Factor de Transcripción GATA3/genética , Proteínas de Homeodominio/genética , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Proteínas/genética , Neoplasias Cutáneas/genética , Factores de Transcripción/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Islandia , Masculino , Proteínas de la Membrana , Persona de Mediana Edad , Proteína Proto-Oncogénica N-Myc , Población Blanca/genética , Adulto JovenRESUMEN
Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 × 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.
Asunto(s)
Proteínas de Unión al Calcio/genética , Cromosomas Humanos Par 20/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de la Membrana/genética , Neoplasias de la Vejiga Urinaria/genética , Población Blanca/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Proteína Jagged-1 , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proteínas Serrate-JaggedRESUMEN
To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782[G], P = 5.5 × 10(-17), OR = 1.29) and RGS22 (rs7006527[C], P = 8.7 × 10(-13), OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation.
Asunto(s)
Antígenos de Superficie/genética , Carcinoma Basocelular/genética , Reguladores de Proteínas de Unión al GTP/genética , Variación Genética , Mutación de Línea Germinal , Transglutaminasas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Células Germinativas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Neoplasias Cutáneas/genética , Adulto JovenRESUMEN
To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
Asunto(s)
Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias/genética , Proteína p53 Supresora de Tumor/metabolismo , Humanos , Polimorfismo de Nucleótido Simple , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.
Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Proteínas de Transporte de Membrana/genética , Neoplasias de la Vejiga Urinaria/genética , Población Blanca/genética , Adulto , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 18/genética , Progresión de la Enfermedad , Femenino , Sitios Genéticos/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Reproducibilidad de los Resultados , Factores de Riesgo , Adulto Joven , Transportadores de UreaRESUMEN
Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
Asunto(s)
Cromosomas Humanos Par 4 , Predisposición Genética a la Enfermedad , Variación Genética , Neoplasias de la Vejiga Urinaria/genética , Alelos , Supervivencia sin Enfermedad , Europa (Continente) , Femenino , Genotipo , Humanos , Masculino , Modelos Genéticos , Mutación , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Recurrencia , Riesgo , FumarRESUMEN
We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 x 10(-10) and the allelic odds ratio was 1.15 (95% confidence interval 1.10-1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.
Asunto(s)
Antígenos de Neoplasias/genética , Predisposición Genética a la Enfermedad , Variación Genética , Glicoproteínas de Membrana/genética , Proteínas de Neoplasias/genética , Neoplasias de la Vejiga Urinaria/genética , Alelos , Antígenos de Neoplasias/inmunología , Estudios de Casos y Controles , Mapeo Cromosómico , Cromosomas Humanos Par 8 , Proteínas Ligadas a GPI , Frecuencia de los Genes , Genes Reporteros , Estudio de Asociación del Genoma Completo , Haplotipos , Heterocigoto , Homocigoto , Humanos , Desequilibrio de Ligamiento , Modelos Logísticos , Masculino , Análisis Multivariante , Mutación Missense , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Reproducibilidad de los Resultados , Neoplasias de la Vejiga Urinaria/inmunologíaRESUMEN
In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 x 10(-9)). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 x 10(-9)), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 x 10(-10)). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.
Asunto(s)
Carcinoma Basocelular/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Neoplasias Cutáneas/genética , Carcinoma Basocelular/complicaciones , Carcinoma de Células Escamosas/genética , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 9/genética , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/genética , Estudio de Asociación del Genoma Completo , Humanos , Queratina-5/genética , Desequilibrio de Ligamiento/genética , Melanoma/patología , Proteínas de la Membrana/genética , Datos de Secuencia Molecular , Proteínas de Neoplasias/genética , Neoplasias Cutáneas/complicacionesRESUMEN
To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide SNP association study of 930 Icelanders with BCC and 33,117 controls. After analyzing 304,083 SNPs, we observed signals from loci at 1p36 and 1q42, and replicated these associations in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, P = 4.4 x 10(-12)) and rs801114 on 1q42 (OR = 1.28, P = 5.9 x 10(-12)). The 1p36 locus contains the candidate genes PADI4, PADI6, RCC2 and ARHGEF10L, and the gene nearest to the 1q42 locus is the ras-homolog RHOU. Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers.
Asunto(s)
Carcinoma Basocelular/genética , Cromosomas Humanos Par 1/genética , Predisposición Genética a la Enfermedad , Melanoma/genética , Mutación/genética , Pigmentación/genética , Neoplasias Cutáneas/genética , Tejido Adiposo/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento , Alelos , Carcinoma Basocelular/diagnóstico , Carcinoma de Células Escamosas/genética , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Persona de Mediana Edad , Modelos Genéticos , Polimorfismo de Nucleótido Simple/genética , Carácter Cuantitativo Heredable , ARN/metabolismo , Neoplasias Cutáneas/diagnósticoRESUMEN
We conducted a genome-wide SNP association study on 1,803 urinary bladder cancer (UBC) cases and 34,336 controls from Iceland and The Netherlands and follow up studies in seven additional case-control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 x 10(-12)). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1. 15 x 10(-7)).
Asunto(s)
Cromosomas Humanos Par 8/genética , Predisposición Genética a la Enfermedad , Mutación/genética , Neoplasias de la Vejiga Urinaria/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Estudios de Casos y Controles , Cromosomas Humanos Par 3/genética , Femenino , Marcadores Genéticos , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana EdadRESUMEN
Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.
Asunto(s)
Proteína de Señalización Agouti/genética , Carcinoma Basocelular/genética , Melanoma/genética , Monofenol Monooxigenasa/genética , Pigmentación/genética , Neoplasias Cutáneas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Basocelular/patología , Estudios de Casos y Controles , Europa (Continente) , Color del Ojo/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Melanoma/patología , Glicoproteínas de Membrana/genética , Persona de Mediana Edad , Metástasis de la Neoplasia , Oportunidad Relativa , Oxidorreductasas/genética , Polimorfismo de Nucleótido Simple , Receptor de Melanocortina Tipo 1/genética , Sistema de Registros , Neoplasias Cutáneas/patologíaRESUMEN
The variants within the human melanocortin 1 receptor (MC1R) gene are associated with an increased risk of different skin cancers. In this study, we genotyped by direct sequencing, 529 cases of basal cell carcinoma of the skin (BCC) and 533 healthy controls for polymorphisms in the entire MC1R gene. In addition to 10 common polymorphisms, we detected 23 rare variants in the gene. The presence of any nonsynonymous MC1R variant was associated with an increased risk in the carriers (odds ratio OR 1.66, 95% confidence interval CI 1.28-2.14) corresponding to a population attributable fraction of about 27%. The odds ratio for the risk in the carriers of 2 MC1R variants was 2.69 (95% CI 1.77-4.08). The risk of BCC in the carriers of MC1R variants with fair complexion was almost twice as much as in the corresponding noncarriers. The carriers of the R163Q variant with a medium skin complexion were at a 3-fold higher risk than the noncarrier counterparts. The interaction, of effect on the BCC risk, between the MC1R variants and types of skin response to sun exposure was greater than multiplicative. We also observed a multiplicative interaction of risk due to the MC1R variants and the common allele (high risk) of the T241M polymorphism in the XRCC3 gene. Our data confirmed the status of the nonsynonymous MC1R variants as independent genetic risk factors for BCC. However, the mechanism through which the variants influence the risk likely involves complex interactions with other genetic and host risk factors.
Asunto(s)
Carcinoma Basocelular/genética , Proteínas de Unión al ADN/genética , Polimorfismo Genético , Receptor de Melanocortina Tipo 1/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Arginina , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Glutamina , Humanos , Hungría , Masculino , Metionina , Persona de Mediana Edad , Factores de Riesgo , Rumanía , Análisis de Secuencia de ADN , Eslovaquia , TreoninaRESUMEN
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) 0.601.53; P131L, OR 1.31 95%CI 0.742.31; L132L, OR 0.50, 95%CI 0.027.07; C148R, OR 0.50, 95%CI 0.691.18; and W149X, OR 1.01, 95%CI 0.372.79) 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.
RESUMEN
In addition to environmental exposures like UV radiation and, in some cases, arsenic contamination of drinking water, genetic factors may also influence the individual susceptibility to basal cell carcinoma of skin (BCC). In the present study, 529 cases diagnosed with BCC and 533 controls from Hungary, Romania and Slovakia were genotyped for one polymorphism in each of seven DNA repair genes. The variant allele for T241M (C>T) polymorphism in the XRCC3 gene was associated with a decreased cancer risk [odds ratio (OR), 0.73; 95% confidence interval (CI), 0.61-0.88; P = 0.0007, multiple testing corrected P = 0.004]. The risk of multiple BCC was significantly lower among variant allele carriers than in non-carriers (P = 0.04). Men homozygous for the C-allele for E185Q (G>C) polymorphism in the NBS1 gene showed an increased BCC risk (OR, 2.19; 95% CI, 1.23-3.91), but not women (OR, 0.84; 95% CI, 0.49-1.47). In men, the age and nationality adjusted OR for the genotype CC (XRCC3)/CC (NBS1) was 8.79 (95% CI, 2.10-36.8), compared with the genotype TT (XRCC3)/GG (NBS1). The data from this study show overall risk modulation of BCC by variant allele for T241M polymorphism in XRCC3 and gender-specific effect by E185Q polymorphism in NBS1.
