ABSTRACT
We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.
Subject(s)
Chromosomes, Human, Pair 17 , Diabetes Mellitus, Type 2/genetics , Hepatocyte Nuclear Factor 1-beta/genetics , Prostatic Neoplasms/genetics , Case-Control Studies , Genetic Predisposition to Disease , Haplotypes , Humans , Male , Polymorphism, Single NucleotideABSTRACT
Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.
Subject(s)
Breast Neoplasms/genetics , Chromosomes, Human, Pair 16/genetics , Chromosomes, Human, Pair 2/genetics , Genetic Predisposition to Disease , Genetic Variation , Receptors, Estrogen/biosynthesis , Breast Neoplasms/metabolism , Case-Control Studies , Female , HumansABSTRACT
Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.
Subject(s)
Chromosomes, Human, Pair 8/genetics , Genetic Linkage , Genetic Predisposition to Disease/genetics , Genetic Variation , Prostatic Neoplasms/genetics , Black or African American , Europe , Genomics/methods , Haplotypes/genetics , Humans , Male , Polymorphism, Single Nucleotide , United States , White PeopleABSTRACT
With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.
Subject(s)
Black People/genetics , Prostatic Neoplasms/genetics , White People/genetics , Alleles , Humans , Male , Microsatellite Repeats/genetics , Polymorphism, Single NucleotideABSTRACT
Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.
Subject(s)
Chromosomes, Human, Pair 15/genetics , Genetic Predisposition to Disease/genetics , Lung Neoplasms/genetics , Peripheral Vascular Diseases/genetics , Polymorphism, Single Nucleotide/genetics , Receptors, Nicotinic/genetics , Tobacco Use Disorder/genetics , Europe , Female , Genotype , Humans , Male , Multigene Family/genetics , New Zealand , Odds Ratio , Smoking/adverse effects , Smoking/geneticsABSTRACT
BACKGROUND: Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer. METHODS AND FINDINGS: The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11-3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents. CONCLUSIONS: Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.
Subject(s)
Amino Acid Substitution , Breast Neoplasms/genetics , Mutation, Missense , Neoplastic Syndromes, Hereditary/genetics , Point Mutation , Tumor Suppressor Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Adult , Age of Onset , Aged , Alleles , Breast Neoplasms/ethnology , Carcinoma in Situ/ethnology , Carcinoma in Situ/genetics , Carcinoma, Ductal, Breast/ethnology , Carcinoma, Ductal, Breast/genetics , Carcinoma, Intraductal, Noninfiltrating/ethnology , Carcinoma, Intraductal, Noninfiltrating/genetics , Carcinoma, Lobular/ethnology , Carcinoma, Lobular/genetics , Carcinoma, Medullary/ethnology , Carcinoma, Medullary/genetics , Case-Control Studies , Cluster Analysis , Cohort Studies , Female , Founder Effect , Gene Frequency , Genes, BRCA2 , Genetic Predisposition to Disease , Genotype , Haplotypes , Humans , Iceland/epidemiology , Middle Aged , Neoplastic Syndromes, Hereditary/ethnology , Odds Ratio , Polymorphism, Single Nucleotide , Risk , Sequence Deletion , Tumor Suppressor Proteins/physiology , Ubiquitin-Protein Ligases/physiologyABSTRACT
In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 x 10(-27)) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 x 10(-9)). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T(4)) and high concentration of triiodothyronine (T(3)).
Subject(s)
Chromosomes, Human, Pair 4 , Chromosomes, Human, Pair 9 , Genetic Predisposition to Disease/genetics , Genetic Variation , Thyroid Neoplasms/epidemiology , Thyroid Neoplasms/genetics , Chromosome Mapping , DNA-Binding Proteins/genetics , Europe/epidemiology , Forkhead Transcription Factors/genetics , Humans , Thyrotropin/blood , Thyroxine/blood , Transcription Factors , Triiodothyronine/bloodABSTRACT
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.
Subject(s)
Breast Neoplasms/genetics , Chromosomes, Human, Pair 5/genetics , Genetic Predisposition to Disease , Genetic Variation , Receptors, Estrogen/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Apoptosis , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/pathology , Carcinoma, Intraductal, Noninfiltrating/genetics , Carcinoma, Intraductal, Noninfiltrating/metabolism , Carcinoma, Intraductal, Noninfiltrating/pathology , Carcinoma, Lobular/genetics , Carcinoma, Lobular/metabolism , Carcinoma, Lobular/pathology , Carcinoma, Medullary/genetics , Carcinoma, Medullary/metabolism , Carcinoma, Medullary/pathology , Case-Control Studies , Cohort Studies , Female , Humans , International Agencies , Male , Middle Aged , Polymorphism, Single Nucleotide , Prognosis , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Ribosomal Proteins/genetics , Ribosomal Proteins/metabolismABSTRACT
We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 x 10(-13) and 7.7 x 10(-9), respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease.
Subject(s)
Chromosomes, Human, Pair 2 , Chromosomes, Human, X , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Prostatic Neoplasms/genetics , Case-Control Studies , Gene Frequency , Genetic Testing , Humans , Iceland , Linkage Disequilibrium , Male , Netherlands , Spain , Sweden , United StatesABSTRACT
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
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)).
Subject(s)
Chromosomes, Human, Pair 8/genetics , Genetic Predisposition to Disease , Mutation/genetics , Urinary Bladder Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Base Sequence , Case-Control Studies , Chromosomes, Human, Pair 3/genetics , Female , Genetic Markers , Humans , Linkage Disequilibrium/genetics , Male , Middle AgedABSTRACT
BACKGROUND: Mutations in the CHK2 gene at chromosome 22q12.1 have been reported in families with Li-Fraumeni syndrome. Chk2 is an effector kinase that is activated in response to DNA damage and is involved in cell-cycle pathways and p53 pathways. METHODS: We screened 139 breast tumors for loss of heterozygosity at chromosome 22q, using seven microsatellite markers, and screened 119 breast tumors with single-strand conformation polymorphism and DNA sequencing for mutations in the CHK2 gene. RESULTS: Seventy-four of 139 sporadic breast tumors (53%) show loss of heterozygosity with at least one marker. These samples and 45 tumors from individuals carrying the BRCA2 999del5 mutation were screened for mutations in the CHK2 gene. In addition to putative polymorphic regions in short mononucleotide repeats in a non-coding exon and intron 2, a germ line variant (T59K) in the first coding exon was detected. On screening 1172 cancer patients for the T59K sequence variant, it was detected in a total of four breast-cancer patients, two colon-cancer patients, one stomach-cancer patient and one ovary-cancer patient, but not in 452 healthy individuals. A tumor-specific 5' splice site mutation at site +3 in intron 8 (TTgt [a --> c]atg) was also detected. CONCLUSION: We conclude that somatic CHK2 mutations are rare in breast cancer, but our results suggest a tumor suppressor function for CHK2 in a small proportion of breast tumors. Furthermore, our results suggest that the T59K CHK2 sequence variant is a low-penetrance allele with respect to tumor growth.