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1.
BMC Med Genomics ; 12(1): 131, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533728

RESUMO

BACKGROUND: Although APOBEC-mutational signature is found in tumor tissues of multiple cancers, how a common germline APOBEC3A/B deletion affects the mutational signature remains unclear. METHODS: Using data from 10 cancer types generated as part of TCGA, we performed integrative genomic and association analyses to assess inter-relationship of expressions for isoforms APOBEC3A and APOBEC3B, APOBEC-mutational signature, germline APOBEC3A/B deletions, neoantigen loads, and tumor infiltration lymphocytes (TILs). RESULTS: We found that expression level of the isoform uc011aoc transcribed from the APOBEC3A/B chimera was associated with a greater burden of APOBEC-mutational signature only in breast cancer, while germline APOBEC3A/B deletion led to an increased expression level of uc011aoc in multiple cancer types. Furthermore, we found that the deletion was associated with elevated APOBEC-mutational signature, neoantigen loads and relative composition of T cells (CD8+) in TILs only in breast cancer. Additionally, we also found that APOBEC-mutational signature significantly contributed to neoantigen loads and certain immune cell abundances in TILs across cancer types. CONCLUSIONS: These findings reveal new insights into understanding the genetic, biological and immunological mechanisms through which APOBEC genes may be involved in carcinogenesis, and provide potential genetic biomarker for the development of disease prevention and cancer immunotherapy.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31563898

RESUMO

BACKGROUND: Cigarette smoking is a common risk factor for diseases and cancers. Oral microbiota is also associated with diseases and cancers. However, little is known about the impact of cigarette smoking on the oral microbiota, especially among ethnic minority populations. METHODS: We investigated cigarette smoking in relationship with the oral microbiota in a large population of predominately low-income and African-American participants. Mouth rinse samples were collected from 1616 participants within the Southern Community Cohort Study, including 592 current-smokers, 477 former-smokers and 547 never-smokers. Oral microbiota was profiled by 16S ribosomal RNA gene deep sequencing. RESULTS: Current-smokers showed a different overall microbial composition from former-smokers (p=6.62×10-7) and never-smokers (p=6.00×10-8). The two probiotic genera, Bifidobacterium and Lactobacillus, were enriched among current-smokers when compared with never-smokers, with Bonferroni-corrected p values (PBonferroni ) of 1.28×10-4 and 5.89×10-7, respectively. The phylum Actinobacteria was also enriched in current-smokers when compared with never-smokers, with a median relative abundance of 12.35% versus 9.36%, respectively, and with a PBonferroni =9.11×10-11. In contrast, the phylum Proteobacteria was depleted in current smokers (PBonferroni =5.57×10-13), with the relative abundance being almost three times that of never-smokers (7.22%) when compared with that of current-smokers (2.47%). Multiple taxa within these two phyla showed differences in abundance/prevalence between current-smokers and never-smokers at PBonferroni <0.05. The differences in the overall microbial composition and abundance/prevalence of most taxa were observed among both African-Americans and European-Americans. Meanwhile, such differences were not observed between former-smokers and never-smokers. CONCLUSION: Smoking has strong impacts on oral microbial community, which was recovered after smoking cessation.

3.
Am J Hum Genet ; 105(3): 477-492, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31402092

RESUMO

Genome-wide association studies (GWASs) have identified hundreds of genetic risk variants for human cancers. However, target genes for the majority of risk loci remain largely unexplored. It is also unclear whether GWAS risk-loci-associated genes contribute to mutational signatures and tumor mutational burden (TMB) in cancer tissues. We systematically conducted cis-expression quantitative trait loci (cis-eQTL) analyses for 294 GWAS-identified variants for six major types of cancer-colorectal, lung, ovary, prostate, pancreas, and melanoma-by using transcriptome data from the Genotype-Tissue Expression (GTEx) Project, the Cancer Genome Atlas (TCGA), and other public data sources. By using integrative analysis strategies, we identified 270 candidate target genes, including 99 with previously unreported associations, for six cancer types. By analyzing functional genomic data, our results indicate that 180 genes (66.7% of 270) had evidence of cis-regulation by putative functional variants via proximal promoter or distal enhancer-promoter interactions. Together with our previously reported associations for breast cancer risk, our results show that 24 genes are shared by at least two cancer types, including four genes for both breast and ovarian cancer. By integrating mutation data from TCGA, we found that expression levels of 33 and 66 putative susceptibility genes were associated with specific mutational signatures and TMB of cancer-driver genes, respectively, at a Bonferroni-corrected p < 0.05. Together, these findings provide further insight into our understanding of how genetic risk variants might contribute to carcinogenesis through the regulation of susceptibility genes that are related to the biogenesis of somatic mutations.

4.
Int J Cancer ; 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31265136

RESUMO

A small number of circulating proteins have been reported to be associated with breast cancer risk, with inconsistent results. Herein, we attempted to identify novel protein biomarkers for breast cancer via the integration of genomics and proteomics data. In the Breast Cancer Association Consortium (BCAC), with 122,977 cases and 105,974 controls of European descendants, we evaluated the associations of the genetically predicted concentrations of >1,400 circulating proteins with breast cancer risk. We used data from a large-scale protein quantitative trait loci (pQTL) analysis as our study instrument. Summary statistics for these pQTL variants related to breast cancer risk were obtained from the BCAC and used to estimate odds ratios (OR) for each protein using the inverse-variance weighted method. We identified 56 proteins significantly associated with breast cancer risk by instrumental analysis (false discovery rate <0.05). Of these, the concentrations of 32 were influenced by variants close to a breast cancer susceptibility locus (ABO, 9q34.2). Many of these proteins, such as insulin receptor, insulin-like growth factor receptor 1 and other membrane receptors (OR: 0.82-1.18, p values: 6.96 × 10-4 -3.28 × 10-8 ), are linked to insulin resistance and estrogen receptor signaling pathways. Proteins identified at other loci include those involved in biological processes such as alcohol and lipid metabolism, proteolysis, apoptosis, immune regulation and cell motility and proliferation. Consistent associations were observed for 22 proteins in the UK Biobank data (p < 0.05). The study identifies potential novel biomarkers for breast cancer, but further investigation is needed to replicate our findings.

5.
Cancer Epidemiol Biomarkers Prev ; 28(8): 1308-1315, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31160347

RESUMO

BACKGROUND: Pathogenic variants in susceptibility genes lead to increased breast cancer risk. METHODS: To identify coding variants associated with breast cancer risk, we conducted whole-exome sequencing in genomic DNA samples from 831 breast cancer cases and 839 controls of Chinese women. We also genotyped samples, including 4,580 breast cancer cases and 6,695 controls, using whole exome-chip arrays. We further performed a replication study using a Multi-Ethnic Global Array in samples from 1,793 breast cases and 2,059 controls. A single marker analysis was performed using the Fisher exact test. RESULTS: We identified a missense variant (rs139379666, P2974L; AF = 0.09% for breast cancer cases, but none for controls) in the ATM gene for breast cancer risk using combing data from 7,204 breast cancer cases and 9,593 controls (P = 1.7 × 10-5). To investigate the functionality of the variant, we first silenced ATM and then transfected the overexpression vectors of ATM containing the risk alleles (TT) or reference alleles (CC) of the variant in U2OS and breast cancer SK-BR3 cells, respectively. Our results showed that compared with the reference allele, the risk allele significantly disrupts the activity of homologous recombination-mediated double-strand breaks repair efficiency. Our results further showed that the risk allele may play a defected regulation role in the activity of the ATM structure. CONCLUSIONS: Our findings identified a novel mutation that disrupts ATM function, conferring to breast cancer risk. IMPACT: Functional investigation of genetic association findings is necessary to discover a pathogenic variant for breast cancer risk.

6.
Cancer Res ; 79(13): 3192-3204, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31101764

RESUMO

Genome-wide association study-identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61 × 10-6, a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61 × 10-6 after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology. SIGNIFICANCE: This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer.

7.
J Natl Cancer Inst ; 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31143935

RESUMO

BACKGROUND: DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast cancer. However, these studies were limited by low statistical power and potential biases. Utilizing a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk. METHODS: Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (N=1,595). The prediction models were validated using data from the Women's Health Initiative (N=883). We applied these models to genome-wide association study (GWAS) data of 122,977 breast cancer cases and 105,974 controls to evaluate if the genetically predicted DNA methylation levels at CpGs are associated with breast cancer risk. All statistical tests were two-sided. RESULTS: Of the 62,938 CpG sites (CpGs) investigated, statistically significant associations with breast cancer risk were observed for 450 CpGs at a Bonferroni-corrected threshold of P<7.94 × 10-7, including 45 CpGs residing in 18 genomic regions which have not previously been associated with breast cancer risk. Of the remaining 405 CpGs located within 500 kilobase flaking regions of 70 GWAS-identified breast cancer risk variants, the associations for 11 CpGs were independent of GWAS-identified variants. Integrative analyses of genetic, DNA methylation and gene expression data found that 38 CpGs may affect breast cancer risk through regulating expression of 21 genes. CONCLUSION: Our new methodology can identify novel DNA methylation biomarkers for breast cancer risk and can be applied to other diseases.

8.
PLoS One ; 14(1): e0209010, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30601841

RESUMO

BACKGROUND: Inflammation contributes to breast cancer development through its effects on cell damage. This damage is usually dealt with by key genes involved in apoptosis and autophagy pathways. METHODS: We tested 206 single nucleotide polymorphisms (SNPs) in 54 genes related to inflammation, apoptosis and autophagy in a population-based breast cancer study of women of European (658 cases and 795 controls) and East Asian (262 cases and 127 controls) descent. Logistic regression was used to estimate odds ratios for breast cancer risk, and case-only analysis to compare breast cancer subtypes (defined by ER/PR/HER2 status), with adjustment for confounders. We assessed statistical interactions between the SNPs and lifestyle factors (smoking status, physical activity and body mass index). RESULTS AND CONCLUSION: Although no SNP was associated with breast cancer risk among women of European descent, we found evidence for an association among East Asians for rs1800925 (IL-13) and breast cancer risk (OR = 2.08; 95% CI: 1.32-3.28; p = 0.000779), which remained statistically significant after multiple testing correction (padj = 0.0350). This association was replicated in a meta-analysis of 4305 cases and 4194 controls in the Shanghai Breast Cancer Genetics Study (OR 1.12, 95% CI: 1.03-1.21, p = 0.011). Further, we found evidence of an interaction between rs7874234 (TSC1) and physical activity among women of East Asian descent.


Assuntos
Apoptose/fisiologia , Autofagia/fisiologia , Neoplasias da Mama/genética , Inflamação/genética , Adulto , Apoptose/genética , Autofagia/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética , Adulto Jovem
9.
Breast Cancer Res ; 21(1): 3, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642363

RESUMO

BACKGROUND: Breast cancer is a partially heritable trait and genome-wide association studies (GWAS) have identified over 180 common genetic variants associated with breast cancer. We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25, with the protective minor allele originating from indigenous American ancestry. Here we report on fine mapping of the 6q25 locus in an expanded sample of Latinas. METHODS: We performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPs in 2412 cases and 1620 controls of US Latina, Mexican, and Colombian women. In addition, we validated the top novel variants in studies of African, Asian and European ancestry. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model-based approach. RESULTS: We identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p = 3.3 × 10- 8 - 6.0 × 10- 9) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r2 > 0.9) with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.76 (0.70-0.84). In a replication in women of Latin American origin, we also observed a consistent effect (OR 0.88; 95% CI 0.78-0.99; p = 0.037). We also performed a meta-analysis of these SNPs in East Asians, African ancestry and European ancestry populations and also observed a consistent effect (rs3778609, OR 0.95; 95% CI 0.91-0.97; p = 0.0017). CONCLUSION: Our study adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 6/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Adulto , Idoso , Mama , Estudos de Casos e Controles , Mapeamento Cromossômico , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
10.
Lung Cancer ; 127: 90-95, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30642558

RESUMO

OBJECTIVES: Previous studies have suggested that poor oral health might increase the risk of lung cancer among European- and Asian- descendants. The association has not been investigated among African Americans or socially disadvantaged populations. In this nested case-control study, we investigated whether oral health was associated with lung cancer risk among a low-income population of African Americans and European Americans in the Southeastern United States. MATERIALS AND METHODS: A total of 403 incident lung cancer cases and 1612 matched controls from the Southern Community Cohort Study were included. Multivariate conditional logistic regression models were fitted to evaluate the risk of lung cancer linked to tooth loss, tooth decay, and history of periodontal disease. RESULTS: Tooth loss was significantly associated with an increased risk of lung cancer: the odds ratio (OR) of more than 10 teeth lost was 1.64 (95% CI: 1.00, 2.69). Tooth decay was also significantly associated with increased lung cancer risk; those with ≥ 6 decaying teeth had an OR of 1.65 (1.18, 2.31). An increased lung cancer risk was significantly associated with a history of periodontal disease among African Americans (OR = 1.56, 95% CI: 1.05, 2.31) and heavy smokers (OR = 2.05, 95% CI: 1.38, 3.05). CONCLUSION: Poor oral health is associated with increased lung cancer risk, and this association appears to vary by race and smoking behavior among a low-income population of African Americans and European Americans in the Southeastern United States.

11.
Gastroenterology ; 156(5): 1455-1466, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30529582

RESUMO

BACKGROUND & AIMS: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations. METHODS: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels. RESULTS: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci. CONCLUSIONS: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to ß-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Loci Gênicos , Polimorfismo de Nucleotídeo Único , Ásia/epidemiologia , Estudos de Casos e Controles , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/imunologia , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Medição de Risco , Fatores de Risco
12.
Int J Cancer ; 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30365870

RESUMO

Oral microbiome may play an important role in cancer pathogenesis. However, no study has prospectively investigated the association of the oral microbiome with subsequent risk of developing colorectal cancer (CRC). We conducted a nested case-control study including 231 incident CRC cases and 462 controls within the Southern Community Cohort Study with 75% of the subjects being African-Americans. The controls were individually matched to cases based on age, Ethnic group, smoking, season-of-study enrollment and recruitment method. Oral microbiota were assessed using 16S rRNA gene sequencing in pre-diagnostic mouth rinse samples. Multiple bacterial taxa showed an association with CRC risk at P < 0.05. Oral pathogens Treponema denticola and Prevotella intermedia were associated with an increased risk of CRC, with odds ratios (ORs) and 95% confidence intervals (CIs) of 1.76(1.19-2.60) and 1.55(1.08-2.22), respectively, for the individuals carrying these bacteria compared to non-carriers. In the phylum Actinobacteria, Bifidobacteriaceae was more abundant among CRC patients than among controls. In the phylum Bacteroidetes, Prevotella denticola and Prevotella sp. oral taxon 300 were associated with an increased CRC risk, while Prevotella melaninogenica was associated with a decreased risk of CRC. In the phylum Firmicutes, Carnobacteriaceae, Streptococcaceae, Erysipelotrichaceae, Streptococcus, Solobacterium, Streptococcus sp. oral taxon 058 and Solobacterium moorei showed associations with a decreased risk of CRC. Most of these associations were observed among both African- and European-Americans. Most of the associations were not significant after Bonferroni correction for multiple testing, which may be conservative. Our study suggests that the oral microbiome may play a significant role in CRC etiology. This article is protected by copyright. All rights reserved.

13.
Nat Genet ; 50(7): 968-978, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29915430

RESUMO

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

14.
Reprod Sci ; : 1933719118776788, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29848177

RESUMO

OBJECTIVE: To identify novel susceptibility genes for age at natural menopause (ANM). METHODS: Using transcription data generated in tissues from normal hypothalami (n = 73) and ovaries (n = 68) and high-density genotyping data provided by the Genotype-Tissue Expression (GTEx) database, we built 16 164 genetic models to predict gene expression across the transcriptome in these tissues. We used these models and summary statistics data from genome-wide association studies (GWAS) of ANM generated in 69 360 women of European ancestry to identify genes with their predicted expression related to ANM. RESULTS: We found the predicted expression of 34 genes to be significantly associated with ANM at a Bonferroni-corrected threshold of P < 3.09 ×10-6. These include 4 genes located more than 1 Mb away from any previously GWAS-identified ANM-associated variants, 24 genes that reside in known GWAS-identified loci but have not been previously implicated, and 6 genes previously implicated as ANM-associated genes. CONCLUSION: Results from this transcriptome-wide association study, which integrated Expression quantitative trait loci (eQTL) data with summary statistics of GWAS of ANM, improves our understanding of the genetics and biology of female reproductive aging.

15.
Am J Hum Genet ; 102(5): 890-903, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29727689

RESUMO

Genome-wide association studies (GWASs) have identified more than 150 common genetic loci for breast cancer risk. However, the target genes and underlying mechanisms remain largely unknown. We conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using normal or tumor breast transcriptome data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), and the Genotype-Tissue Expression (GTEx) project. We identified a total of 101 genes for 51 lead variants after combing the results of a meta-analysis of METABRIC and TCGA, and the results from GTEx at a Benjamini-Hochberg (BH)-adjusted p < 0.05. Using luciferase reporter assays in both estrogen-receptor positive (ER+) and negative (ER-) cell lines, we showed that alternative alleles of potential functional single-nucleotide polymorphisms (SNPs), rs11552449 (DCLRE1B), rs7257932 (SSBP4), rs3747479 (MRPS30), rs2236007 (PAX9), and rs73134739 (ATG10), could significantly change promoter activities of their target genes compared to reference alleles. Furthermore, we performed in vitro assays in breast cancer cell lines, and our results indicated that DCLRE1B, MRPS30, and ATG10 played a vital role in breast tumorigenesis via certain disruption of cell behaviors. Our findings revealed potential target genes for associations of genetic susceptibility risk loci and provided underlying mechanisms for a better understanding of the pathogenesis of breast cancer.

16.
Sci Rep ; 8(1): 5603, 2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29618726

RESUMO

Genome-wide association studies have identified numerous variants associated with lipid levels; yet, the majority are located in non-coding regions with unclear mechanisms. In the Insulin Resistance Atherosclerosis Family Study (IRASFS), heritability estimates suggest a strong genetic basis: low-density lipoprotein (LDL, h2 = 0.50), high-density lipoprotein (HDL, h2 = 0.57), total cholesterol (TC, h2 = 0.53), and triglyceride (TG, h2 = 0.42) levels. Exome sequencing of 1,205 Mexican Americans (90 pedigrees) from the IRASFS identified 548,889 variants and association and linkage analyses with lipid levels were performed. One genome-wide significant signal was detected in APOA5 with TG (rs651821, PTG = 3.67 × 10-10, LODTG = 2.36, MAF = 14.2%). In addition, two correlated SNPs (r2 = 1.0) rs189547099 (PTG = 6.31 × 10-08, LODTG = 3.13, MAF = 0.50%) and chr4:157997598 (PTG = 6.31 × 10-08, LODTG = 3.13, MAF = 0.50%) reached exome-wide significance (P < 9.11 × 10-08). rs189547099 is an intronic SNP in FNIP2 and SNP chr4:157997598 is intronic in GLRB. Linkage analysis revealed 46 SNPs with a LOD > 3 with the strongest signal at rs1141070 (LODLDL = 4.30, PLDL = 0.33, MAF = 21.6%) in DFFB. A total of 53 nominally associated variants (P < 5.00 × 10-05, MAF ≥ 1.0%) were selected for replication in six Mexican-American cohorts (N = 3,280). The strongest signal observed was a synonymous variant (rs1160983, PLDL = 4.44 × 10-17, MAF = 2.7%) in TOMM40. Beyond primary findings, previously reported lipid loci were fine-mapped using exome sequencing in IRASFS. These results support that exome sequencing complements and extends insights into the genetics of lipid levels.

18.
Hum Mol Genet ; 27(5): 853-859, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29325031

RESUMO

Functional disruptions of susceptibility genes by large genomic structure variant (SV) deletions in germlines are known to be associated with cancer risk. However, few studies have been conducted to systematically search for SV deletions in breast cancer susceptibility genes. We analysed deep (> 30x) whole-genome sequencing (WGS) data generated in blood samples from 128 breast cancer patients of Asian and European descent with either a strong family history of breast cancer or early cancer onset disease. To identify SV deletions in known or suspected breast cancer susceptibility genes, we used multiple SV calling tools including Genome STRiP, Delly, Manta, BreakDancer and Pindel. SV deletions were detected by at least three of these bioinformatics tools in five genes. Specifically, we identified heterozygous deletions covering a fraction of the coding regions of BRCA1 (with approximately 80kb in two patients), and TP53 genes (with ∼1.6 kb in two patients), and of intronic regions (∼1 kb) of the PALB2 (one patient), PTEN (three patients) and RAD51C genes (one patient). We confirmed the presence of these deletions using real-time quantitative PCR (qPCR). Our study identified novel SV deletions in breast cancer susceptibility genes and the identification of such SV deletions may improve clinical testing.

20.
Nat Genet ; 49(12): 1722-1730, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29083407

RESUMO

Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.


Assuntos
Doença da Artéria Coronariana/genética , Exoma/genética , Predisposição Genética para Doença/genética , Variação Genética , Metabolismo dos Lipídeos/genética , Grupo com Ancestrais do Continente Asiático/genética , Doença da Artéria Coronariana/etnologia , Europa (Continente) , Grupo com Ancestrais do Continente Europeu/genética , Extremo Oriente , Frequência do Gene , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lipídeos/análise
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