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1.
Breast Cancer Res ; 22(1): 108, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087180

RESUMO

BACKGROUND: The BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry. METHODS: BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia. RESULTS: The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was ~ 100 generations in Iberia and that it was introduced to South America early during the European colonization period. CONCLUSIONS: Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening.

2.
Cancer Res ; 80(9): 1893-1901, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32245796

RESUMO

Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2+ tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07-1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2+ tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer. SIGNIFICANCE: The positive association between Indigenous American genetic ancestry and HER2+ breast cancer suggests that the high incidence of HER2+ subtypes in Latinas might be due to population and subtype-specific genetic risk variants.


Assuntos
Neoplasias da Mama/química , Neoplasias da Mama/etnologia , Hispano-Americanos/genética , Receptor ErbB-2/análise , Adulto , Grupo com Ancestrais do Continente Africano/etnologia , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Idoso , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Neoplasias da Mama/genética , Colômbia/etnologia , Grupo com Ancestrais do Continente Europeu/etnologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Índios Norte-Americanos , Índios Sul-Americanos , América Latina/etnologia , Modelos Lineares , Modelos Logísticos , México/etnologia , Pessoa de Meia-Idade , Peru/etnologia , Receptor ErbB-2/genética , Receptores Estrogênicos/sangue , Receptores de Progesterona/sangue , Estados Unidos , Adulto Jovem
3.
J Natl Cancer Inst ; 112(6): 590-598, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31553449

RESUMO

BACKGROUND: More than 180 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified; these SNPs can be combined into polygenic risk scores (PRS) to predict breast cancer risk. Because most SNPs were identified in predominantly European populations, little is known about the performance of PRS in non-Europeans. We tested the performance of a 180-SNP PRS in Latinas, a large ethnic group with variable levels of Indigenous American, European, and African ancestry. METHODS: We conducted a pooled case-control analysis of US Latinas and Latin American women (4658 cases and 7622 controls). We constructed a 180-SNP PRS consisting of SNPs associated with breast cancer risk (P < 5 × 10-8). We evaluated the association between the PRS and breast cancer risk using multivariable logistic regression, and assessed discrimination using an area under the receiver operating characteristic curve. We also assessed PRS performance across quartiles of Indigenous American genetic ancestry. All statistical tests were two-sided. RESULTS: Of 180 SNPs tested, 142 showed directionally consistent associations compared with European populations, and 39 were nominally statistically significant (P < .05). The PRS was associated with breast cancer risk, with an odds ratio per SD increment of 1.58 (95% confidence interval [CI = 1.52 to 1.64) and an area under the receiver operating characteristic curve of 0.63 (95% CI = 0.62 to 0.64). The discrimination of the PRS was similar between the top and bottom quartiles of Indigenous American ancestry. CONCLUSIONS: The 180-SNP PRS predicts breast cancer risk in Latinas, with similar performance as reported for Europeans. The performance of the PRS did not vary substantially according to Indigenous American ancestry.

4.
Endocr Connect ; 8(9): 1310-1317, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31454788

RESUMO

Papillary thyroid cancer (PTC) is the second most commonly diagnosed malignancy in U.S. Latinas and in Colombian women. Studies in non-Latinos indicate that BRAF and TERT mutations are PTC prognostic markers. This study aimed to determine the prevalence and clinical associations of BRAF and TERT mutations in PTC Latino patients from Colombia. We analyzed mutations of BRAF (V600E) and TERT promoter (C228T, C250T) in tumor DNA from 141 patients (75 with classical variant PTC, CVPTC; 66 with follicular variant PTC, FVPTC) recruited through a multi-center study. Associations between mutations and clinical variables were evaluated with Fisher exact tests. Survival was evaluated with Kaplan-Meier plots. Double-mutant tumors (BRAF+/TERT+, n = 14 patients) were more common in CVPTC (P = 0.02). Relative to patients without mutations (n = 48), double mutations were more common in patients with large tumors (P = 0.03), lymph node metastasis (P = 0.01), extra-thyroid extension (P = 0.03), and advanced stage (P = 6.0 × 10-5). In older patients, TERT mutations were more frequent (mean age 51 years vs 45 years for wild type TERT, P = 0.04) and survival was lower (HR = 1.20; P = 0.017); however, given the small sample size, the decrease in survival was not statically significant between genotypes. Comparisons with published data in US whites revealed that Colombian patients had a higher prevalence of severe pathological features and of double-mutant tumors (10 vs 6%, P = 0.001). Mutations in both oncogenes show prognostic associations in Latinos from Colombia. Our study is important to advance Latino PTC precision medicine and replicates previous prognostic associations between BRAF and TERT in this population.

5.
J Clin Endocrinol Metab ; 10(3): 1098-1103, 2016 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-26691890

RESUMO

CONTEXT: A recent study reported the non-synonymous G534E (rs7080536, allele A) variant in the HABP2 gene as causal in familial non-medullary thyroid cancer (NMTC). OBJECTIVE: The objective of this study was to evaluate the causality of HABP2 G534E in the TCUKIN study, a multi-center population based study of NMTC cases from the British Isles. DESIGN AND SETTING: A case-control analysis of rs7080536 genotypes was performed using 2,105 TCUKIN cases and 5,172 UK controls. PARTICIPANTS: Cases comprised 2,105 NMTC cases. Patients sub-groups with papillary (N=1,056), follicular (N=691) and Hurthle cell (N=86) TC cases were studied separately. Controls comprised 5,172 individuals from the 1958 Birth Cohort (58C) and the National Blood Donor Service (NBS) study. The controls had previously been genotyped using genome-wide SNP arrays by the Wellcome Trust Case Control Consortium study. OUTCOME: Measures: Association between HABP2 G534E (rs7080536A) and NMTC risk was evaluated using logistic regression. RESULTS: The frequency of HABP2 G534E was 4.2% in cases and 4.6% in controls. We did not detect an association between this variant and NMTC risk (OR=0.896, 95% CI: 0.746-1.071, P=0.233). We also failed to detect an association between HABP2 G534E and cases with papillary (1056 cases, G534E frequency= 3.5%, OR=0.74, P=0.017), follicular (691 cases, G534E frequency= 4.7%, OR=1.00, P=1.000) or Hurthle cell (86 cases, G534E frequency= 6.3%, OR=1.40, P=0.279) histology. CONCLUSIONS: We found that HABP2 G534E is a low-to-moderate frequency variant in the British Isles and failed to detect an association with NMTC risk, independent of histological type. Hence, our study does not implicate HABP2 G534E or a correlated polymorphism in familial NMTC and additional data are required before using this variant in NMTC risk assessment.

6.
Endocr Relat Cancer ; 22(5): 841-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26290501

RESUMO

The G allele of the rs6983267 single-nucleotide polymorphism, located on chromosome 8q24, has been associated with increased risk of several cancer types. The association between rs6983267G and thyroid cancer (TC) has been tested in different populations, mostly of European ancestry, and has led to inconclusive results. While significant associations have been reported in the British and Polish populations, no association has been detected in populations from Spain, Italy and the USA. To further investigate the role of rs6983267G in TC susceptibility, we evaluated rs6983267 genotypes in three populations of different continental ancestry (British Isles, Colombia and Japan), providing a total of 3067 cases and 8575 controls. We detected significant associations between rs6983267G and TC in the British Isles (odds ratio (OR)=1.19, 95% CI: 1.11-1.27, P=4.03×10(-7)), Japan (OR=1.20, 95% CI: 1.03-1.41, P=0.022) and a borderline significant association of similar effect direction and size in Colombia (OR=1.19, 95% CI: 0.99-1.44, P=0.069). A meta-analysis of our multi-ethnic study and previously published non-overlapping datasets, which included a total of 5484 cases and 12 594 controls, confirmed the association between rs6983267G and TC (P=1.23×10(-7), OR=1.13, 95% CI: 1.08-1.18). Our results therefore support the notion that rs6983267G is a bona fide TC risk variant that increases the risk of disease by ∼13%.


Assuntos
Cromossomos Humanos Par 8/genética , Loci Gênicos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genética , Estudos de Casos e Controles , Colômbia/epidemiologia , Humanos , Japão/epidemiologia , Metanálise como Assunto , Prognóstico , Fatores de Risco , Reino Unido/epidemiologia
7.
Mol Cancer ; 12: 1, 2013 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-23286373

RESUMO

BACKGROUND: Prevalence of colorectal cancer (CRC) in the British Bangladeshi population (BAN) is low compared to British Caucasians (CAU). Genetic background may influence mutations and disease features. METHODS: We characterized the clinicopathological features of BAN CRCs and interrogated their genomes using mutation profiling and high-density single nucleotide polymorphism (SNP) arrays and compared findings to CAU CRCs. RESULTS: Age of onset of BAN CRC was significantly lower than for CAU patients (p=3.0 x 10-5) and this difference was not due to Lynch syndrome or the polyposis syndromes. KRAS mutations in BAN microsatellite stable (MSS) CRCs were comparatively rare (5.4%) compared to CAU MSS CRCs (25%; p=0.04), which correlates with the high percentage of mucinous histotype observed (31%) in the BAN samples. No BRAF mutations was seen in our BAN MSS CRCs (CAU CRCs, 12%; p=0.08). Array data revealed similar patterns of gains (chromosome 7 and 8q), losses (8p, 17p and 18q) and LOH (4q, 17p and 18q) in BAN and CAU CRCs. A small deletion on chromosome 16p13.2 involving the alternative splicing factor RBFOX1 only was found in significantly more BAN (50%) than CAU CRCs (15%) cases (p=0.04). Focal deletions targeting the 5' end of the gene were also identified. Novel RBFOX1 mutations were found in CRC cell lines and tumours; mRNA and protein expression was reduced in tumours. CONCLUSIONS: KRAS mutations were rare in BAN MSS CRC and a mucinous histotype common. Loss of RBFOX1 may explain the anomalous splicing activity associated with CRC.


Assuntos
Adenocarcinoma Mucinoso/genética , Neoplasias Colorretais/genética , Deleção de Genes , Proteínas de Ligação a RNA/genética , Adenocarcinoma Mucinoso/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Bangladesh/etnologia , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Análise Mutacional de DNA , Grupo com Ancestrais do Continente Europeu , Feminino , Dosagem de Genes , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Fatores de Processamento de RNA , Proteínas de Ligação a RNA/metabolismo , Reino Unido , Adulto Jovem , Proteínas ras/genética
8.
Int J Cancer ; 121(12): 2668-73, 2007 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17721920

RESUMO

Human papilloma virus (HPV) infection is considered as an important aetiological factor for anal squamous cell carcinoma (ASCC) but is not sufficient for tumour progression. This carcinoma is poorly understood at the molecular level. Using the largest cohort of cases to date we investigated the molecular mechanisms underlying ASCC development, in particular the roles of TP53, MDM2 and AKT. Viral infection in our cohort occurred at high frequency (73%, 94/128) with HPV16 accounting for the majority (86%, 81/94) of infected cases. Only 4% (5/119) of ASCCs showed TP53 (exons 5-8) mutations, but a high frequency (91%, 100/110) of nuclear protein expression of TP53 was observed. There was a significant association (p < 0.001) between nuclear accumulation of TP53 and MDM2 protein although no MDM2 mutations were found, and copy number was normal. Cellular accumulation of phosphorylated-AKT was observed in 66% (82/125) of ASCCs and an association demonstrated between nuclear accumulation of MDM2 and activated AKT (p < 0.001). We observed a high frequency of copy number gain at PIK3CA (47%), and some coding sequence mutations (4%). Amplification of PIK3CA was associated with presence of phosphorylated-AKT (p= 0.008). There was no association between virus infection and TP53 nuclear accumulation (p = 0.5). However, a significant association was found between infection and MDM2 nuclear staining, and between infection and activated AKT (p = 0.04, p = 0.01, respectively). We propose that activation of AKT, possibly through the PI3K-AKT pathway, is an important component of ASCC tumorigenesis that contributes to MDM2 and TP53 accumulation in the nucleus.


Assuntos
Neoplasias do Ânus/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Mutação , Papillomaviridae/isolamento & purificação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Alphapapillomavirus/isolamento & purificação , Substituição de Aminoácidos , Neoplasias do Ânus/virologia , Carcinoma de Células Escamosas/virologia , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Proteínas Nucleares/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Fosfatidilinositol 3-Quinases/genética , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Estudos Retrospectivos , Deleção de Sequência , Proteína Supressora de Tumor p53/metabolismo , Infecções Tumorais por Vírus/complicações , Infecções Tumorais por Vírus/virologia
9.
Gastroenterology ; 132(2): 527-30, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17258725

RESUMO

BACKGROUND & AIMS: We report a patient of Indian descent with parental consanguinity, who developed 10 carcinomas and 35 adenomatous polyps at age 23 and duodenal adenocarcinoma at age 25. He also had dysmorphic features, mental retardation, and café-au-lait spots but no brain tumor. We aimed to establish his molecular diagnosis. METHODS: Germ-line screening for APC and MYH/MUTYH mutations was normal as was immunohistochemistry for MLH1 and MSH2 proteins. Investigation by array-comparative genomic hybridization revealed deletion of a small region on chromosome 7. Using polymerase chain reaction, this region was refined to a 400-kilobase deletion, which included exons 9-15 of the PMS2 gene, and all coding regions of oncomodulin, TRIAD3, and FSCN1. RESULTS: The deletion was confirmed as homozygous, and both parents were carriers. Immunohistochemistry showed absent PMS2 expression in all tumors and normal tissue. Most tumors showed microsatellite instability, more marked at dinucleotide than mononucleotide repeats. The tumors harbored no somatic mutations in APC, BRAF, AXIN2, or beta-catenin, but KRAS2 and TGFBR2 mutations were found. CONCLUSIONS: Our patient represents a novel phenotype for homozygous PMS2 mutation and perhaps the most severe colorectal cancer phenotype-in terms of numbers of malignancies at an early age-described to date. PMS2 mutations-and perhaps other homozygous mismatch repair mutations-should be considered in any patient presenting with multiple gastrointestinal tumors, since our patient could not be distinguished clinically from cases with attenuated familial adenomatous polyposis or MUTYH-associated polyposis.


Assuntos
Pólipos Adenomatosos/genética , Adenosina Trifosfatases/genética , Neoplasias Colorretais/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Deleção de Genes , Homozigoto , Polipose Intestinal/genética , Polipose Adenomatosa do Colo/diagnóstico , Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/patologia , Adulto , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , DNA Glicosilases/genética , Diagnóstico Diferencial , Neoplasias Duodenais/genética , Evolução Fatal , Regulação Neoplásica da Expressão Gênica , Humanos , Polipose Intestinal/diagnóstico , Polipose Intestinal/patologia , Masculino , Instabilidade de Microssatélites , Endonuclease PMS2 de Reparo de Erro de Pareamento , Mutação , Linhagem , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Índice de Gravidade de Doença , Proteínas ras
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