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Hum Genet ; 138(4): 307-326, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30820706


Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10- 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10- 4, replication P = 6.7 × 10- 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.

Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco
Nat Commun ; 10(1): 419, 2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664635


The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

Nat Commun ; 9(1): 1340, 2018 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-29632299


Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology.

Eur J Cancer ; 78: 37-44, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28412587


IMPORTANCE: Online prognostication tools such as PREDICT and Adjuvant! are increasingly used in clinical practice by oncologists to inform patients and guide treatment decisions about adjuvant systemic therapy. However, their validity for young breast cancer patients is debated. OBJECTIVE: To assess first, the prognostic accuracy of PREDICT's and Adjuvant! 10-year all-cause mortality, and second, its breast cancer-specific mortality estimates, in a large cohort of breast cancer patients diagnosed <50 years. DESIGN: Hospital-based cohort. SETTING: General and cancer hospitals. PARTICIPANTS: A consecutive series of 2710 patients without a prior history of cancer, diagnosed between 1990 and 2000 with unilateral stage I-III breast cancer aged <50 years. MAIN OUTCOME MEASURES: Calibration and discriminatory accuracy, measured with C-statistics, of estimated 10-year all-cause and breast cancer-specific mortality. RESULTS: Overall, PREDICT's calibration for all-cause mortality was good (predicted versus observed) meandifference: -1.1% (95%CI: -3.2%-0.9%; P = 0.28). PREDICT tended to underestimate all-cause mortality in good prognosis subgroups (range meandifference: -2.9% to -4.8%), overestimated all-cause mortality in poor prognosis subgroups (range meandifference: 2.6%-9.4%) and underestimated survival in patients < 35 by -6.6%. Overall, PREDICT overestimated breast cancer-specific mortality by 3.2% (95%CI: 0.8%-5.6%; P = 0.007); and also overestimated it seemingly indiscriminately in numerous subgroups (range meandifference: 3.2%-14.1%). Calibration was poor in the cohort of patients with the lowest and those with the highest mortality probabilities. Discriminatory accuracy was moderate-to-good for all-cause mortality in PREDICT (0.71 [95%CI: 0.68 to 0.73]), and the results were similar for breast cancer-specific mortality. Adjuvant!'s calibration and discriminatory accuracy for both all-cause and breast cancer-specific mortality were in line with PREDICT's findings. CONCLUSIONS: Although imprecise at the extremes, PREDICT's estimates of 10-year all-cause mortality seem reasonably sound for breast cancer patients <50 years; Adjuvant! findings were similar. Prognostication tools should be used with caution due to the intrinsic variability of their estimates, and because the threshold to discuss adjuvant systemic treatment is low. Thus, seemingly insignificant mortality overestimations or underestimations of a few percentages can significantly impact treatment decision-making.

Neoplasias da Mama/tratamento farmacológico , Adulto , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prognóstico , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Adulto Jovem
Hum Mol Genet ; 19(14): 2886-97, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20418484


Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 x 10(-3)) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (P(trend) < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69-0.90, P(trend) = 3.6 x 10(-4) and HR = 1.25, 95% CI: 1.10-1.41, P(trend) = 4.2 x 10(-4)), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25-1.92, P(trend) = 6 x 10(-5) and HR = 1.37, 95% CI: 1.16-1.62, P(trend) = 1.7 x 10(-4)). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.

Neoplasias da Mama/genética , Carcinoma/genética , Genes BRCA1 , Genes BRCA2 , Polimorfismo de Nucleotídeo Único , Adulto , Epistasia Genética/fisiologia , Feminino , Frequência do Gene , Loci Gênicos/fisiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação/fisiologia , Polimorfismo de Nucleotídeo Único/fisiologia , Fatores de Risco