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1.
J Pathol ; 259(4): 359-361, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36541926

RESUMO

A recent study published in The Journal of Pathology used an shRNA library targeting all known human genes involved in metabolism to identify genes important for gastric cancer. The screen identified aspartyl-tRNA synthetase (DARS) as a potential drug target, and patients whose tumors had high DARS levels had a worse prognosis, particularly among diffuse-type gastric cancer. These findings identify a potential therapeutic target for precision medicine of gastric cancer patients, and may be useful for further investigations to discover additional interacting targets. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Medicina de Precisão , Genoma , Genômica , Reino Unido
2.
Br J Cancer ; 128(6): 1077-1085, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36564567

RESUMO

BACKGROUND: Prostate cancer (PrCa) is one of the most hereditable human cancers, however, only a small fraction of patients has been shown to carry deleterious variants in known cancer predisposition genes. METHODS: Whole-exome sequencing was performed in multiple affected members of 45 PrCa families to select the best candidate genes behind part of the PrCa missing hereditability. Recurrently mutated genes were prioritised, and further investigated by targeted next-generation sequencing in the whole early-onset and/or familial PrCa series of 462 patients. RESULTS: PRUNE2 stood out from our analysis when also considering the available data on its association with PrCa development. Ten germline pathogenic/likely pathogenic variants in the PRUNE2 gene were identified in 13 patients. The most frequent variant was found in three unrelated patients and identical-by-descent analysis revealed that the haplotype associated with the variant is shared by all the variant carriers, supporting the existence of a common ancestor. DISCUSSION: This is the first report of pathogenic/likely pathogenic germline variants in PRUNE2 in PrCa patients, namely in those with early-onset/familial disease. Importantly, PRUNE2 was the most frequently mutated gene in the whole series, with a deleterious germline variant identified in 2.8% of the patients, representing a novel prostate cancer predisposition gene.


Assuntos
Predisposição Genética para Doença , Neoplasias da Próstata , Humanos , Masculino , Sequenciamento do Exoma , Mutação em Linhagem Germinativa , Neoplasias da Próstata/genética , Fatores de Transcrição/genética
3.
J Genet Couns ; 32(6): 1226-1231, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37747056

RESUMO

Breast cancer is the most common cancer in women in the United States (U.S.) and the leading cause of cancer related death among U.S. Hispanics/Latinas (H/Ls). H/Ls have lower rates of screening and longer time to follow up after an abnormal mammogram. We developed a comprehensive community health educator (promotores)-led education and risk identification program for Spanish-speaking H/Ls in California to increase mammography screening, genetic testing, and the understanding of the impact of family history on cancer risk. Due to COVID-19, we adapted the program to a virtual platform. The experience of transforming the program to a virtual platform provided unique opportunities for collaboration between researchers, community partners, and participants. Promotores are major partners in community based participatory research and in the provision of health care services, but their voices are often excluded from scientific reports. This commentary is an effort to provide a platform for promotores to share their experiences and for the readers to understand their approach in bridging the gap between health care services and communities.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Estados Unidos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Mamografia , Saúde Pública , Hispânico ou Latino
4.
Br J Cancer ; 124(2): 315-332, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32901135

RESUMO

There are well-established disparities in cancer incidence and outcomes by race/ethnicity that result from the interplay between structural, socioeconomic, socio-environmental, behavioural and biological factors. However, large research studies designed to investigate factors contributing to cancer aetiology and progression have mainly focused on populations of European origin. The limitations in clinicopathological and genetic data, as well as the reduced availability of biospecimens from diverse populations, contribute to the knowledge gap and have the potential to widen cancer health disparities. In this review, we summarise reported disparities and associated factors in the United States of America (USA) for the most common cancers (breast, prostate, lung and colon), and for a subset of other cancers that highlight the complexity of disparities (gastric, liver, pancreas and leukaemia). We focus on populations commonly identified and referred to as racial/ethnic minorities in the USA-African Americans/Blacks, American Indians and Alaska Natives, Asians, Native Hawaiians/other Pacific Islanders and Hispanics/Latinos. We conclude that even though substantial progress has been made in understanding the factors underlying cancer health disparities, marked inequities persist. Additional efforts are needed to include participants from diverse populations in the research of cancer aetiology, biology and treatment. Furthermore, to eliminate cancer health disparities, it will be necessary to facilitate access to, and utilisation of, health services to all individuals, and to address structural inequities, including racism, that disproportionally affect racial/ethnic minorities in the USA.


Assuntos
Disparidades nos Níveis de Saúde , Grupos Minoritários/estatística & dados numéricos , Neoplasias/etnologia , Etnicidade/estatística & dados numéricos , Feminino , Humanos , Masculino , Estados Unidos/etnologia
5.
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.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Haplótipos , Polimorfismo de Nucleotídeo Único , África/epidemiologia , Brasil/epidemiologia , Chile/epidemiologia , Cromossomos Humanos Par 17/genética , Colômbia/epidemiologia , Feminino , Efeito Fundador , Estudo de Associação Genômica Ampla/métodos , Humanos , Portugal/epidemiologia , Espanha/epidemiologia
6.
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 , Hispânico ou Latino/genética , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
7.
Cancer Causes Control ; 30(7): 687-696, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31102083

RESUMO

BACKGROUND: Gastric cancer is an important cause of death among racial/ethnic minorities in the U.S. The objective of this study was to investigate racial disparities in survival among gastric cancer patients within demographic and disease subgroups. METHODS: Patients diagnosed with invasive epithelial gastric cancer between 2006 and 2015 were identified from the California Cancer Registry. Cox proportional hazards regression was used to identify factors associated with survival among non-Hispanic whites (NHWs, n = 7,475), non-Hispanic blacks (NHBs, n = 1,246), Hispanics (n = 6,274), and Asians/Pacific Islanders (APIs, n = 4,204). Survival was compared across race/ethnicity within subgroups of demographic and disease factors. Five-year relative survival was also calculated within subgroups. RESULTS: There were notable differences in patient characteristics by race/ethnicity, but predictors of survival were similar for each group. Overall, APIs (HR = 0.83, 95% CI: 0.79, 0.88, p < 0.0001) and Hispanics (HR = 0.94, 95% CI: 0.90, 0.99, p = 0.0104) had better survival than NHWs, but NHBs and NHWs did not have different prognosis (HR = 1.06, 95% CI: 0.98, 1.15, p = 0.2237). The survival advantage of APIs persisted in nearly every demographic and disease subgroup, but Hispanics and NHBs had similar survival as NHWs in most groups. Race was not a significant predictor of survival among those with public or no insurance and patients with cardia tumors. CONCLUSIONS: There are some differences in survival by race/ethnicity, but race/ethnicity alone cannot explain disparate outcomes in gastric cancer. Future studies, particularly ones that investigate the role of population-specific etiological factors and molecular tumor profiles, are needed to further understand factors associated with survival.


Assuntos
Neoplasias Gástricas/etnologia , Neoplasias Gástricas/epidemiologia , Adulto , Idoso , California/epidemiologia , Etnicidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Grupos Raciais , Análise de Sobrevida
8.
Alzheimers Dement ; 15(7): 995-1003, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30240574

RESUMO

In 2016, the UC Davis Latino Aging Research Resource Center and UC Davis Alzheimer's Disease Center brought together experts from across the country to consolidate current knowledge and identify future directions in aging and diversity research. This report disseminates the research priorities that emerged from this conference, building on an earlier Gerontological Society of America preconference. We review key racial/ethnic differences in cognitive aging and dementia and identify current knowledge gaps in the field. We advocate for a systems-level framework for future research whereby environmental, sociocultural, behavioral, neuropathological, genetic, and psychometric levels of analysis are examined together to identify pathways and mechanisms that influence disparities. We then discuss steps to increase the recruitment and retention of racial/ethnic minorities in aging studies, as none of the recommendations will be possible without strong collaboration between racial/ethnic minority communities and researchers. This approach is consistent with the National Institute on Aging Health Disparities Research Framework.


Assuntos
Envelhecimento , Doença de Alzheimer , Pesquisa Biomédica , Grupos Minoritários , Grupos Raciais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/etnologia , Disparidades nos Níveis de Saúde , Hispânico ou Latino , Humanos , Seleção de Pacientes , Estados Unidos
9.
Gastroenterology ; 152(5): 983-986.e6, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28024868

RESUMO

Up to 10% of cases of gastric cancer are familial, but so far, only mutations in CDH1 have been associated with gastric cancer risk. To identify genetic variants that affect risk for gastric cancer, we collected blood samples from 28 patients with hereditary diffuse gastric cancer (HDGC) not associated with mutations in CDH1 and performed whole-exome sequence analysis. We then analyzed sequences of candidate genes in 333 independent HDGC and non-HDGC cases. We identified 11 cases with mutations in PALB2, BRCA1, or RAD51C genes, which regulate homologous DNA recombination. We found these mutations in 2 of 31 patients with HDGC (6.5%) and 9 of 331 patients with sporadic gastric cancer (2.8%). Most of these mutations had been previously associated with other types of tumors and partially co-segregated with gastric cancer in our study. Tumors that developed in patients with these mutations had a mutation signature associated with somatic homologous recombination deficiency. Our findings indicate that defects in homologous recombination increase risk for gastric cancer.


Assuntos
Proteína BRCA1/genética , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genética , Neoplasias Gástricas/genética , Proteínas Supressoras de Tumor/genética , Idoso , Idoso de 80 Anos ou mais , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Reparo de DNA por Recombinação/genética
10.
PLoS Genet ; 11(3): e1004925, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25781923

RESUMO

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10-4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model.


Assuntos
Apraxias/genética , Proteínas de Transporte/genética , Exoma/genética , Estudos de Associação Genética , Proteínas de Membrana/genética , Apraxias/patologia , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Genética Populacional , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino
11.
Hum Mol Genet ; 24(5): 1478-92, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25378557

RESUMO

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.


Assuntos
Mapeamento Cromossômico , Neoplasias do Endométrio/genética , Loci Gênicos , Fator 1-beta Nuclear de Hepatócito/genética , Alelos , Estudos de Casos e Controles , Linhagem Celular Tumoral , Biologia Computacional , Bases de Dados Genéticas , Epigênese Genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Fator 1-beta Nuclear de Hepatócito/metabolismo , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco , População Branca/genética
13.
J Pathol ; 236(2): 155-64, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25712196

RESUMO

Heritable genetic variants can significantly affect the lifetime risk of developing cancer, including polyposis and colorectal cancer (CRC). Variants in genes currently known to be associated with a high risk for polyposis or CRC, however, explain only a limited number of hereditary cases. The identification of additional genetic causes is, therefore, crucial to improve CRC prevention, detection and treatment. We have performed genome-wide and targeted DNA copy number profiling and resequencing in early-onset and familial polyposis/CRC patients, and show that deletions affecting the open reading frame of the tumour suppressor gene FOCAD are recurrent and significantly enriched in CRC patients compared with unaffected controls. All patients carrying FOCAD deletions exhibited a personal or family history of polyposis. RNA in situ hybridization revealed FOCAD expression in epithelial cells in the colonic crypt, the site of tumour initiation, as well as in colonic tumours and organoids. Our data suggest that monoallelic germline deletions in the tumour suppressor gene FOCAD underlie moderate genetic predisposition to the development of polyposis and CRC.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Deleção de Genes , Mutação em Linhagem Germinativa/genética , Proteínas Supressoras de Tumor/genética , Polipose Adenomatosa do Colo/metabolismo , Adulto , Estudos de Casos e Controles , Cromossomos Humanos Par 9/genética , Neoplasias Colorretais/metabolismo , Variações do Número de Cópias de DNA/genética , Células Epiteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Fases de Leitura Aberta/genética , Proteínas Supressoras de Tumor/metabolismo
14.
Nat Genet ; 39(8): 984-8, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17618284

RESUMO

Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome-wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Idoso , Cromossomos Humanos Par 8 , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
15.
Hum Genet ; 134(2): 231-45, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25487306

RESUMO

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.


Assuntos
Cromossomos Humanos Par 5/genética , Loci Gênicos , Proteínas de Membrana/genética , Modelos Genéticos , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Telomerase/genética , Cromossomos Humanos Par 5/metabolismo , Bases de Dados de Ácidos Nucleicos , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Haplótipos , Humanos , Proteínas de Membrana/biossíntese , Proteínas de Neoplasias/biossíntese , Regiões Promotoras Genéticas , Fatores de Risco , Telomerase/biossíntese
16.
Hum Mol Genet ; 21(4): 934-46, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22076443

RESUMO

In genome-wide association studies (GWASs) of colorectal cancer, we have identified two genomic regions in which pairs of tagging-single nucleotide polymorphisms (tagSNPs) are associated with disease; these comprise chromosomes 1q41 (rs6691170, rs6687758) and 12q13.13 (rs7163702, rs11169552). We investigated these regions further, aiming to determine whether they contain more than one independent association signal and/or to identify the SNPs most strongly associated with disease. Genotyping of additional sample sets at the original tagSNPs showed that, for both regions, the two tagSNPs were unlikely to identify a single haplotype on which the functional variation lay. Conversely, one of the pair of SNPs did not fully capture the association signal in each region. We therefore undertook more detailed analyses, using imputation, logistic regression, genealogical analysis using the GENECLUSTER program and haplotype analysis. In the 1q41 region, the SNP rs11118883 emerged as a strong candidate based on all these analyses, sufficient to account for the signals at both rs6691170 and rs6687758. rs11118883 lies within a region with strong evidence of transcriptional regulatory activity and has been associated with expression of PDGFRB mRNA. For 12q13.13, a complex situation was found: SNP rs7972465 showed stronger association than either rs11169552 or rs7136702, and GENECLUSTER found no good evidence for a two-SNP model. However, logistic regression and haplotype analyses supported a two-SNP model, in which a signal at the SNP rs706793 was added to that at rs11169552. Post-GWAS fine-mapping studies are challenging, but the use of multiple tools can assist in identifying candidate functional variants in at least some cases.


Assuntos
Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 1/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Mapeamento Cromossômico , Biologia Computacional , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Haplótipos , Humanos , Modelos Logísticos , Software
17.
Gastroenterology ; 144(1): 53-5, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22999960

RESUMO

Several single-nucleotide polymorphisms (SNPs) have been associated with colorectal cancer (CRC) susceptibility. Most CRCs arise from adenomas, and SNPs therefore might affect predisposition to CRC by increasing adenoma risk. We found that 8 of 18 known CRC-associated SNPs (rs10936599, rs6983267, rs10795668, rs3802842, rs4444235, rs1957636, rs4939827, and rs961253) were over-represented in CRC-free patients with adenomas, compared with controls. Ten other CRC-associated SNPs (rs6691170, rs6687758, rs16892766, rs7136702, rs11169552, rs4779584, rs9929218, rs10411210, rs4813802, and rs4925386) were not associated significantly with adenoma risk. Genetic susceptibility to CRC in the general population is likely to be mediated in part by predisposition to adenomas.


Assuntos
Adenoma/genética , Carcinoma/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Alelos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
18.
PLoS Genet ; 7(6): e1002105, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21655089

RESUMO

Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.


Assuntos
Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 4/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intercelular/genética , Idoso , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/metabolismo , Estudos de Casos e Controles , Neoplasias Colorretais/metabolismo , Frequência do Gene , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Transdução de Sinais
19.
Gut ; 62(6): 871-81, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22490517

RESUMO

OBJECTIVE: Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data. DESIGN: Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39,266) and in combination with gender, age and FH (n=11,324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks. RESULTS: The median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2 × 10(-16)), confirmed in external validation sets (Sweden p=1.2 × 10(-6), Finland p=2 × 10(-5)). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk. CONCLUSION: Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Alelos , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/etnologia , Estudos de Viabilidade , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Medição de Risco , Fatores de Risco , Escócia/epidemiologia
20.
Cancer Res Commun ; 4(8): 2147-2152, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39056190

RESUMO

Precision medicine holds great promise for improving cancer outcomes. Yet, there are large inequities in the demographics of patients from whom genomic data and models, including patient-derived xenografts (PDX), are developed and for whom treatments are optimized. In this study, we developed a genetic ancestry pipeline for the Cancer Genomics Cloud, which we used to assess the diversity of models currently available in the National Cancer Institute-supported PDX Development and Trial Centers Research Network (PDXNet). We showed that there is an under-representation of models derived from patients of non-European ancestry, consistent with other cancer model resources. We discussed these findings in the context of disparities in cancer incidence and outcomes among demographic groups in the US, as well as power analyses for biomarker discovery, to highlight the immediate need for developing models from minority populations to address cancer health equity in precision medicine. Our analyses identified key priority disparity-associated cancer types for which new models should be developed. SIGNIFICANCE: Understanding whether and how tumor genetic factors drive differences in outcomes among U.S. minority groups is critical to addressing cancer health disparities. Our findings suggest that many additional models will be necessary to understand the genome-driven sources of these disparities.


Assuntos
Neoplasias , Medicina de Precisão , Humanos , Estados Unidos/epidemiologia , Neoplasias/genética , Neoplasias/epidemiologia , Animais , National Cancer Institute (U.S.) , Genômica/métodos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
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