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1.
Neuroendocrinology ; 2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35472852

RESUMO

Introduction Telomere length (TL) is a potential indicator of cancer predisposition, however, the multitude of techniques used to measure it causes the results to be heterogeneous and, in some cases, controversial. In the last years, several studies adopted a strategy based on TL associated genetic variants to generate a polygenic score, often referred as teloscore, used in lieu of direct TL measurement. For pancreatic neuroendocrine neoplasms (PanNEN), this strategy has not been attempted yet. Methods A teloscore was generated using 11 SNPs (NAF1-rs7675998, ZNF676-rs409627, TERC-rs10936599, CTC1-rs3027234, PXK-rs6772228, DHX35-rs6028466, OBFC1-rs9420907, ZNF208-rs8105767, ACYP2-rs11125529, TERT-rs2736100 and ZBTB46-rs755017) and 291 PanNEN cases and 1686 controls collected by the PANcreatic Disease ReseArch (PANDoRA) consortium were genotyped to analyse the association of the teloscore and its individual SNPs with the risk of developing PanNEN. Results An association between genetically determined long telomeres and the risk of developing PanNEN (OR=1.99; CI 1.33-2.98; P=0.0008), for highest vs median (third) quintile was observed. In addition, two novel SNPs associated with PanNEN risk were identified: ZNF676-rs409627 (ORC/C_vs_G/G=2.27, CI 1.58-3.27, P=8.80×10-6) and TERT-rs2736100 (ORC/A_vs_C/C=2.03, CI 1.42-2.91, P=1.06×10-4). Conclusion In conclusion, this study provides for the first time a clear indication of the association between long genetically determined telomeres and increased risk of developing PanNEN.

2.
Sci Rep ; 12(1): 2875, 2022 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-35190600

RESUMO

Recent studies indicate the existence of a complex microbiome in the meconium of newborns that plays a key role in regulating many host health-related conditions. However, a high variability between studies has been observed so far. In the present study, the meconium microbiome composition and the predicted microbial metabolic pathways were analysed in a consecutive cohort of 96 full-term newborns. The effect of maternal epidemiological variables on meconium diversity was analysed using regression analysis and PERMANOVA. Meconium microbiome composition mainly included Proteobacteria (30.95%), Bacteroidetes (23.17%) and Firmicutes (17.13%), while for predicted metabolic pathways, the most abundant genes belonged to the class "metabolism". We observed a significant effect of maternal Rh factor on Shannon and Inverse Simpson indexes (p = 0.045 and p = 0.049 respectively) and a significant effect of delivery mode and maternal antibiotic exposure on Jaccard and Bray-Curtis dissimilarities (p = 0.001 and 0.002 respectively), while gestational age was associated with observed richness and Shannon indexes (p = 0.018 and 0.037 respectively), and Jaccard and Bray-Curtis dissimilarities (p = 0.014 and 0.013 respectively). The association involving maternal Rh phenotype suggests a role for host genetics in shaping meconium microbiome prior to the exposition to the most well-known environmental variables, which will influence microbiome maturation in the newborn.


Assuntos
Microbioma Gastrointestinal , Mecônio/microbiologia , Antibacterianos , Bacteroidetes , Estudos de Coortes , Feminino , Firmicutes , Microbioma Gastrointestinal/fisiologia , Idade Gestacional , Humanos , Recém-Nascido , Exposição Materna , Mecônio/metabolismo , Gravidez , Proteobactérias , Sistema do Grupo Sanguíneo Rh-Hr
3.
Eur J Hum Genet ; 30(4): 474-479, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34845334

RESUMO

There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 × 10-15 for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 × 10-13 for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population.


Assuntos
Estudo de Associação Genômica Ampla , Mieloma Múltiplo , Predisposição Genética para Doença , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco
4.
Semin Cancer Biol ; 79: 105-131, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-32818625

RESUMO

Pancreatic cancer (PC), particularly its most common form, pancreatic ductal adenocarcinoma (PDAC), is relatively rare but highly lethal. Knowledge about PC risk factors could in the long term contribute to early diagnosis and mortality reduction. We review the current status of research on germline genetic factors for PC risk. Genome-wide association studies (GWAS) successfully identified common loci convincingly associated with PC risk, an endeavor that is still ongoing. The function of only a handful of risk loci has being thoroughly characterized so far. Secondary analyses of existing GWAS data are being used to discover novel loci. GWAS data have also been used to study additional risk factors with a Mendelian randomization approach. Polygenic/multifactorial risk scores show much larger risks than individual variants, but their use for risk stratification in the population is not warranted yet. At the other end of the spectrum of inherited PC risk factors, rare high-penetrance variants co-segregating with the disease have been observed in familial cancer syndromes that include PC, or in families with multiple recurrence of PC alone. Rare variants predicted to have a deleterious effect on function are studied also with a case-control approach, by resequencing candidate genes or whole-exomes/whole-genomes. Telomere length and mitochondrial DNA copy number are useful additional DNA-based markers of PC susceptibility. The role of common variants in prognosis of PC patients has also been explored, albeit with more limited success than risk. Finally, genetics of pancreatic neuroendocrine tumors (PNET), a rarer and heterogeneous form of PC, is still understudied.


Assuntos
Carcinoma Ductal Pancreático/genética , Carcinoma/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Variações do Número de Cópias de DNA/genética , Reparo do DNA/genética , DNA Mitocondrial/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Fatores de Risco , Análise de Sequência de DNA , Homeostase do Telômero/genética
5.
Hum Mol Genet ; 31(8): 1346-1355, 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-34964454

RESUMO

Mitochondrial DNA copy number (mtDNAcn) variation has been associated with increased risk of several human diseases in epidemiological studies. The quantification of mtDNAcn performed with real-time PCR is currently considered the de facto standard among several techniques. However, the heterogeneity of the laboratory methods (DNA extraction, storage, processing) used could give rise to results that are difficult to compare and reproduce across different studies. Several lines of evidence suggest that mtDNAcn is influenced by nuclear and mitochondrial genetic variability, however this relation is largely unexplored. The aim of this work was to elucidate the genetic basis of mtDNAcn variation. We performed a genome-wide association study (GWAS) of mtDNAcn in 6836 subjects from the ESTHER prospective cohort, and included, as replication set, the summary statistics of a GWAS that used 295 150 participants from the UK Biobank. We observed two novel associations with mtDNAcn variation on chromosome 19 (rs117176661), and 12 (rs7136238) that reached statistical significance at the genome-wide level. A polygenic score that we called mitoscore including all known single nucleotide polymorphisms explained 1.11% of the variation of mtDNAcn (p = 5.93 × 10-7). In conclusion, we performed a GWAS on mtDNAcn, adding to the evidence of the genetic background of this trait.


Assuntos
Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Variações do Número de Cópias de DNA/genética , DNA Mitocondrial/genética , Humanos , Mitocôndrias/genética , Estudos Prospectivos
6.
Crit Rev Oncol Hematol ; 167: 103510, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34695574

RESUMO

In the last decades the association of leukocyte telomere length (LTL) and mitochondrial copy number (mtDNAcn) with cancer risk has been the focus of many reports, however the relation is not yet completely understood. A meta-analysis of 112 studies including 64,184 cancer cases and 278,641 controls that analysed LTL and mtDNAcn in relation to cancer risk has been conducted to further our understanding of the topic. Stratified analyses for tumor type were also performed. Overall, no association was observed for all cancer combined neither for LTL nor mtDNAcn. Significant associations were detected for these biomarkers and specific cancer type; however, a large degree of heterogeneity was present, even within the same tumor type. Alternatives approaches based on polymorphic variants, such as polygenic risk scores and mendelian randomization, could be adopted to unravel the causal correlation of telomere length and mitochondrial copy number with cancer risk.


Assuntos
Neoplasias , Telômero , Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Humanos , Leucócitos/metabolismo , Mitocôndrias/genética , Neoplasias/epidemiologia , Neoplasias/genética , Neoplasias/metabolismo , Telômero/genética
7.
Eur J Cancer Prev ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34653070

RESUMO

BACKGROUND: Gastric cancer is worldwide the fourth more common cancer type by incidence, and the third by mortality. We analyzed three missense variants of TAS2R38 gene: rs713598 (A49P), rs1726866 (V262A), and rs10246939 (I296V). These variants and their combination in haplotypes (proline, alanine and valine/tasters or alanine, valine and isoleucine/nontasters) and diplotypes are responsible for individual differences in bitter perception. The single-nucleotide polymorphisms and the related phenotypes are known to be associated with susceptibility to Gram-negative bacterial infections, such as Helicobacter pylori, and with risk of various cancer types. An association between intermediate tasters (as defined by TAS2R38 diplotypes) and increased risk of gastric cancer was reported in a Korean population. METHODS: We analyzed 2616 individuals of Latin American origin, representing the whole spectrum of lesions from gastritis to gastric cancer. RESULTS: Comparing cancer cases vs. noncancers we observed a decrease in risk associated with heterozygous carriers of rs10246939 (P = 0.006) and rs1726866 (P = 0.003) when compared with homozygotes of the more common allele. Also, the analysis of diplotypes/phenotypes reflected the same association, with super-tasters showing a borderline increased risk of developing gastric cancer compared to medium-tasters [odds ratio (OR) = 1.63; 95% confidence interval (CI), 1.04-2.56; P = 0.033]. Also, nontasters showed an increased risk when compared to medium-tasters although not reaching statistical significance (OR = 1.58; 95% CI, 0.80-2.87; P = 0.203). We also tested the interactions between the TAS2R38 genotypes and H. pylori cagA status in a subset of samples and found no interaction. CONCLUSION: In conclusion, our results suggest only a modest contribution of TAS2R38 gene genetic variability in gastric cancer etiology.

8.
Breast Cancer Res ; 23(1): 86, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34407845

RESUMO

BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Mutação em Linhagem Germinativa , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Prognóstico , Análise de Sobrevida
9.
Br J Cancer ; 125(8): 1135-1145, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34341517

RESUMO

BACKGROUND: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. METHODS: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. RESULTS: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. CONCLUSION: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.


Assuntos
Neoplasias da Mama/epidemiologia , Fumar Cigarros/epidemiologia , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/etiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , Fumar Cigarros/efeitos adversos , Fumar Cigarros/genética , Feminino , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Análise da Randomização Mendeliana
10.
Am J Hum Genet ; 108(7): 1190-1203, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34146516

RESUMO

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).


Assuntos
Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Anotação de Sequência Molecular , Regiões Promotoras Genéticas , Neoplasias da Mama/genética , Sistemas CRISPR-Cas , Linhagem Celular , Mapeamento Cromossômico , Cromossomos Humanos Par 2 , Feminino , Estudos de Associação Genética , Variação Genética , Humanos , Fatores de Risco , Deleção de Sequência
12.
Blood Cancer J ; 11(4): 74, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33854038

RESUMO

Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 × 10-6 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.


Assuntos
Mieloma Múltiplo/genética , Homeostase do Telômero , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Polimorfismo de Nucleotídeo Único , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Telômero/genética
13.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921254

RESUMO

Over the past decade, telomeres have attracted increasing attention due to the role they play in human fertility. However, conflicting results have been reported on the possible association between sperm telomere length (STL) and leukocyte telomere length (LTL) and the quality of the sperm parameters. The aim of this study was to run a comprehensive study to investigate the role of STL and LTL in male spermatogenesis and infertility. Moreover, the association between the sperm parameters and 11 candidate single nucleotide polymorphisms (SNPs), identified in the literature for their association with telomere length (TL), was investigated. We observed no associations between sperm parameters and STL nor LTL. For the individual SNPs, we observed five statistically significant associations with sperm parameters: considering a p < 0.05. Namely, ACYP2-rs11125529 and decreased sperm motility (p = 0.03); PXK-rs6772228 with a lower sperm count (p = 0.02); NAF1-rs7675998 with increased probability of having abnormal acrosomes (p = 0.03) and abnormal flagellum (p = 0.04); ZNF208-rs8105767 and reduction of sperms with normal heads (p = 0.009). This study suggests a moderate involvement of telomere length in male fertility; however, in our analyses four SNPs were weakly associated with sperm variables, suggesting the SNPs to be pleiotropic and involved in other regulatory mechanisms independent of telomere homeostasis, but involved in the spermatogenic process.


Assuntos
Hidrolases Anidrido Ácido/genética , Infertilidade Masculina/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas do Tecido Nervoso/genética , Ribonucleoproteínas/genética , Telômero/genética , Acrossomo/metabolismo , Acrossomo/patologia , Adulto , Feminino , Estudos de Associação Genética , Humanos , Infertilidade Masculina/patologia , Leucócitos/metabolismo , Leucócitos/patologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Espermatogênese/genética , Espermatozoides/metabolismo , Espermatozoides/patologia , Homeostase do Telômero/genética
14.
Sci Rep ; 11(1): 7570, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33828170

RESUMO

Although pancreatic ductal adenocarcinoma (PDAC) survival is poor, there are differences in patients' response to the treatments. Detection of predictive biomarkers explaining these differences is of the utmost importance. In a recent study two genetic markers (CD44-rs353630 and CHI3L2-rs684559) were reported to be associated with survival after PDAC resection. We attempted to replicate the associations in 1856 PDAC patients (685 resected with stage I/II) from the PANcreatic Disease ReseArch (PANDoRA) consortium. We also analysed the combined effect of the two genotypes in order to compare our results with what was previously reported. Additional stratified analyses considering TNM stage of the disease and whether the patients received surgery were also performed. We observed no statistically significant associations, except for the heterozygous carriers of CD44-rs353630, who were associated with worse OS (HR = 5.01; 95% CI 1.58-15.88; p = 0.006) among patients with stage I disease. This association is in the opposite direction of those reported previously, suggesting that data obtained in such small subgroups are hardly replicable and should be considered cautiously. The two polymorphisms combined did not show any statistically significant association. Our results suggest that the effect of CD44-rs353630 and CHI3L2-rs684559 cannot be generalized to all PDAC patients.


Assuntos
Carcinoma Ductal Pancreático/genética , Quitinases/genética , Receptores de Hialuronatos/genética , Neoplasias Pancreáticas/genética , Idoso , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Polimorfismo de Nucleotídeo Único
15.
Sci Rep ; 11(1): 4971, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33654187

RESUMO

The first thousand days of life from conception have a significant impact on the health status with short, and long-term effects. Among several anthropometric and maternal lifestyle parameters birth weight plays a crucial role on the growth and neurological development of infants. Recent genome wide association studies (GWAS) have demonstrated a robust foetal and maternal genetic background of birth weight, however only a small proportion of the genetic hereditability has been already identified. Considering the extensive number of phenotypes on which they are involved, we focused on identifying the possible effect of genetic variants belonging to taste receptor genes and birthweight. In the human genome there are two taste receptors family the bitter receptors (TAS2Rs) and the sweet and umami receptors (TAS1Rs). In particular sweet perception is due to a heterodimeric receptor encoded by the TAS1R2 and the TAS1R3 gene, while the umami taste receptor is encoded by the TAS1R1 and the TAS1R3 genes. We observed that carriers of the T allele of the TAS1R1-rs4908932 SNPs showed an increase in birthweight compared to GG homozygotes Coeff: 87.40 (35.13-139.68) p-value = 0.001. The association remained significant after correction for multiple testing. TAS1R1-rs4908932 is a potentially functional SNP and is in linkage disequilibrium with another polymorphism that has been associated with BMI in adults showing the importance of this variant from the early stages of conception through all the adult life.


Assuntos
Peso ao Nascer/genética , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas G/genética , Paladar/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino
16.
Nat Commun ; 12(1): 1078, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597508

RESUMO

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação , Pessoa de Meia-Idade , Mutação , Locos de Características Quantitativas/genética , Fatores de Risco
17.
Cancer Res ; 81(11): 3134-3143, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33574088

RESUMO

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10-8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, P interaction = 3.08 × 10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r 2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.


Assuntos
Carcinoma Ductal Pancreático/patologia , Cromossomos Humanos Par 2/genética , Predisposição Genética para Doença , Neoplasias Pancreáticas/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fumar/efeitos adversos , Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/metabolismo , Ciclina T/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Proteínas de Membrana/genética , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/metabolismo , Fatores de Risco , Fumar/genética
18.
Cancer Epidemiol Biomarkers Prev ; 30(4): 623-642, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33500318

RESUMO

BACKGROUND: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. METHODS: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. RESULTS: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (P adj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking. CONCLUSIONS: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. IMPACT: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.


Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estilo de Vida , Adulto , Idoso , Causas de Morte , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Estudos Prospectivos , Fatores de Risco , Análise de Sobrevida
19.
Br J Cancer ; 124(4): 842-854, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33495599

RESUMO

BACKGROUND: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. METHODS: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. RESULTS: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8). CONCLUSIONS: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.


Assuntos
Neoplasias da Mama/genética , Citocromo P-450 CYP3A/genética , Estrona/análogos & derivados , Pregnanodiol/análogos & derivados , Progesterona/urina , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Alelos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/urina , Estudos de Casos e Controles , Citocromo P-450 CYP3A/metabolismo , Estrona/genética , Estrona/urina , Feminino , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Pregnanodiol/genética , Pregnanodiol/urina , Pré-Menopausa
20.
J Natl Cancer Inst ; 113(3): 329-337, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32359158

RESUMO

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.


Assuntos
Neoplasias da Mama/genética , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Anamnese , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de Estrogênio/metabolismo , Fatores de Risco
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