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  • 1
    Keywords: CANCER ; CELL ; POPULATION ; GENOME ; HYBRIDIZATION ; SAMPLE ; SAMPLES ; DNA ; QUALITY ; BIOMARKERS ; ASSOCIATION ; chromosome ; polymorphism ; single nucleotide polymorphism ; BREAST-CANCER ; AMPLIFICATION ; HEALTH ; NUMBER ; REPRODUCIBILITY ; SNP ; RATES ; REGION ; GENOTYPES ; genotyping ; REGIONS ; GENETIC-ANALYSIS ; FEASIBILITY ; CGH ; REPRESENTATION ; ONCOLOGY ; PRODUCTS ; SNPs ; ARRAY ; biomarker ; analysis ; GENOTYPE ; USA ; LOSSES ; MULTIPLE DISPLACEMENT AMPLIFICATION ; cancer research ; COPY-NUMBER VARIATION ; GENOME-WIDE ASSOCIATION ; PLATFORM ; association study ; DISPLACEMENT ; NUCLEOTIDE ; WHOLE-GENOME AMPLIFICATION ; GENOME-WIDE ; CONCORDANCE
    Abstract: In large-scale genome-wide association studies based on high-density single nucleotide polymorphism (SNP) genotyping array, the quantity and quality of available genomic DNA (gDNA) is a practical problem. We examined the feasibility of using the Multiple Displacement Amplification (MDA) method of whole-genome amplification (WGA) for such a platform. The Affymetrix Early Access Mendel Nsp 250K GeneChip was used for genotyping 224,940 SNPs per sample for 28 DNA samples. We compared the call concordance using 14 gDNA samples and their corresponding 14 WGA samples. The overall mean genotype call rates in gDNA and the corresponding WGA samples were comparable at 97.07% [95% confidence interval (CI), 96.17-97.97] versus 97.77% (95% CI, 97.26-98.28; P = 0.154), respectively. Reproducibility of the platform, calculated as concordance in duplicate samples, was 99.45%. Overall genotypes for 97.74% (95% CI, 97.03-98.44) of SNPs were concordant between gDNA and WGA samples. When the analysis was restricted to well-performing SNPs (successful genotyping in gDNA and WGA in 〉 90% of samples), 99.11% (95% CI, 98.80-99.42) of the SNPs, on average, were concordant, and overall a SNP showed a discordant call in 0.92% (95% CI, 0.90-0.94) of paired samples. In a pair of gDNA and WGA DNA, similar concordance was reproducible on Illumina's Infinium 610 Quad platform as well. Although copy number analysis revealed a total of seven small telomeric regions in six chromosomes with loss of copy number, the estimated genome representation was 99.29%. In conclusion, our study confirms that high-density oligonucleotide array-based genotyping can yield reproducible data and MDA-WGA DNA products can be effectively used for genome-wide SNP genotyping analysis. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3499-508)
    Type of Publication: Journal article published
    PubMed ID: 19064567
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  • 2
    Keywords: POPULATION ; RISK-FACTORS ; OVARIAN-CANCER ; susceptibility loci ; CHINESE WOMEN ; AFRICAN-AMERICAN ; FGFR2 ; CONFER SUSCEPTIBILITY ; FAMILY REGISTRY ; WHOLE-GENOME
    Abstract: Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages 〈= 51 years. The SNPs with smallest P values were examined in a replication set of 3,470EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC(P 〈 4 x 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P 〈 6 x 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P 〈 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 x 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 24493630
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  • 3
    Keywords: CANCER ; GROWTH ; GROWTH-FACTOR ; MODEL ; MODELS ; POPULATION ; RISK ; GENE ; GENES ; microarray ; PHOSPHORYLATION ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; BREAST ; breast cancer ; BREAST-CANCER ; microarrays ; BRCA1 ; WOMEN ; MUTATION ; SNP ; LINKAGE DISEQUILIBRIUM ; MUTATIONS ; REPLICATION ; SUSCEPTIBILITY GENE ; EPIDERMAL-GROWTH-FACTOR ; SINGLE ; REGRESSION ; SINGLE NUCLEOTIDE POLYMORPHISMS ; CANDIDATE GENES ; GENOTYPE ; TESTS ; FAMILY-HISTORY ; GENOME-WIDE ASSOCIATION ; genome scan ; Affymetrix GeneChip ; POPULATION STRATIFICATION
    Abstract: High-density oligonucleotide microarrays containing a large number of single nucleotide polymorphisms (SNPs) have enabled genome-wide association (GWA) analysis to become a reality. We used the early access Affymetrix Mendel Nsp 250K chips in a GWA case-control pilot study to identify genomic regions associated with breast cancer. We included 30 randomly sampled incident invasive breast cancer cases aged 〈 45 years without deleterious mutations in the BRCA1 or BRCA2 genes, and 30 population controls individually matched on age, ethnicity and geographical area. The overall genotype call rate was 97.13 +/- A 1.33% for controls and 97.48 +/- A 1.42% for cases. Comparison was made between cases and controls for 203,477 genotyped SNPs using (a) unconditional logistic regression (ULR), (b) conditional logistic regression (CLR) models with adjustment for the matched pairs, (c) allelic tests for single marker tests and (d) haplotype trend regression (HTR). Genomic control and EIGENSTRAT methods were used for correction of population stratification in appropriate models. We demonstrate the similarity and dissimilarity of results from different statistical analyses. We found several possible significant regions harboring biologically meaningful known candidate genes, such as genes encoding fibroblast growth factor, transforming growth factor, epidermal growth factor, and estrogen synthesis enzymes to be associated with early-onset breast cancer. In single marker analysis, none of the SNPs were statistically significant after correction for multiple testing. However, haplotype association tests, using 90730 tag-SNPs, suggested two regions in GLG1 and UGT1 genes retaining significance even after Bonferroni correction. Nevertheless, without systematic replication, findings from this pilot study, especially the associations of breast cancer in relation to specific SNPs, should be interpreted with great caution
    Type of Publication: Journal article published
    PubMed ID: 18463975
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