ABSTRACT
The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.
Subject(s)
Membrane Proteins/genetics , Neoplasm Proteins/genetics , Neoplasms/genetics , Polymorphism, Single Nucleotide , Telomerase/genetics , Aged , Carcinoma, Basal Cell/genetics , Case-Control Studies , Female , Gene Frequency , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Linkage Disequilibrium , Male , Middle Aged , Polymorphism, Single Nucleotide/physiology , Quantitative Trait Loci , Skin Neoplasms/geneticsABSTRACT
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.
Subject(s)
Carcinoma, Basal Cell/genetics , Chromosomes, Human, Pair 1/genetics , Genetic Predisposition to Disease , Melanoma/genetics , Mutation/genetics , Pigmentation/genetics , Skin Neoplasms/genetics , Adipose Tissue/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Aging , Alleles , Carcinoma, Basal Cell/diagnosis , Carcinoma, Squamous Cell/genetics , Chromosomal Proteins, Non-Histone/genetics , Chromosomal Proteins, Non-Histone/metabolism , Guanine Nucleotide Exchange Factors/genetics , Guanine Nucleotide Exchange Factors/metabolism , Humans , Middle Aged , Models, Genetic , Polymorphism, Single Nucleotide/genetics , Quantitative Trait, Heritable , RNA/metabolism , Skin Neoplasms/diagnosisABSTRACT
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.
Subject(s)
Agouti Signaling Protein/genetics , Carcinoma, Basal Cell/genetics , Melanoma/genetics , Monophenol Monooxygenase/genetics , Pigmentation/genetics , Skin Neoplasms/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Basal Cell/pathology , Case-Control Studies , Europe , Eye Color/genetics , Gene Frequency , Genetic Predisposition to Disease , Humans , Melanoma/pathology , Membrane Glycoproteins/genetics , Middle Aged , Neoplasm Metastasis , Odds Ratio , Oxidoreductases/genetics , Polymorphism, Single Nucleotide , Receptor, Melanocortin, Type 1/genetics , Registries , Skin Neoplasms/pathologyABSTRACT
We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 x 10(-12) for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.
