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2.
Hum Genet ; 138(4): 307-326, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30820706

RESUMO

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.


Assuntos
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
3.
Int J Epidemiol ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30476131

RESUMO

Background: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach. Methods: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk. Results: Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors. Conclusions: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development.

4.
Fam Cancer ; 17(1): 79-86, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28608265

RESUMO

We assessed the molecular characteristics and the frequency of mutations in mismatch-repair genes among Bedouin patients with colorectal cancer (CRC) in Israel. Bedouin patients with a diagnosis of CRC at a major hospital in the southern part of Israel were deemed eligible for this study. The primary screening method was immunohistochemical staining for mismatch-repair proteins (MLH1, MSH2, MSH6, and PMS2). For subjects with abnormal immunohistochemical staining, we performed microsatellite instability (MSI) analyses, and for tumors with a loss of MLH1 expression we also performed BRAF testing. In MSI high cases we searched further for germline mutations. Of the 24 patients enrolled, four subjects (16.7%) had MSI high tumors: one subject was found to harbor a biallelic PMS2 mutation, one subject had Lynch syndrome (LS) with MSH6 mutation and two subjects had a loss of MLH1/PMS2 proteins/BRAF wild type/normal MLH1 sequence. Ten patients (41.7%) were younger than 50 at the time of diagnosis and none had first degree relatives with CRC. In conclusion, in this cohort of 24 consecutive Arab Bedouins with CRC, one patient was found to harbor a constitutional mismatch repair deficiency, one patient had LS with MSH6 mutation, and two patients had unresolved loss of MLH1/PMS2 proteins/BRAF wild type phenotype.

5.
Cancer Discov ; 6(11): 1267-1275, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27655433

RESUMO

Known gene mutations account for approximately 50% of the hereditary risk for breast cancer. Moderate and low penetrance variants, discovered by genomic approaches, account for an as-yet-unknown proportion of the remaining heritability. A truncating mutation c.325C>T:p.Arg109* (R109X) in the ATP-dependent helicase ERCC3 was observed recurrently among exomes sequenced in BRCA wild-type, breast cancer-affected individuals of Ashkenazi Jewish ancestry. Modeling of the mutation in ERCC3-deficient or CRISPR/Cas9-edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair-deficient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed significant association with breast cancer risk (ORBC = 1.53, ORER+ = 1.73), particularly for the estrogen receptor-positive subset (P < 0.007). SIGNIFICANCE: A functionally significant recurrent ERCC3 mutation increased the risk for breast cancer in a genetic isolate. Mutated cell lines showed lower survival after in vitro exposure to DNA-damaging agents. Thus, similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC3 could constitute potential therapeutic targets in a subset of hereditary breast cancers. Cancer Discov; 6(11); 1267-75. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1197.


Assuntos
Neoplasias da Mama/genética , DNA Helicases/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Sistemas CRISPR-Cas , Feminino , Humanos , Judeus/genética , Pessoa de Meia-Idade , Mutação , Fatores de Risco
7.
Nat Commun ; 6: 7138, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26151821

RESUMO

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único
8.
Carcinogenesis ; 36(9): 982-91, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26045303

RESUMO

The key role of DNA repair in removing DNA damage and minimizing mutations makes it an attractive target for cancer risk assessment and prevention. Here we describe the development of a robust assay for apurinic/apyrimidinic (AP) endonuclease 1 (APE1; APEX1), an essential enzyme involved in the repair of oxidative DNA damage. APE1 DNA repair enzymatic activity was measured in peripheral blood mononuclear cell protein extracts using a radioactivity-based assay, and its association with lung cancer was determined using conditional logistic regression with specimens from a population-based case-control study with 96 lung cancer cases and 96 matched control subjects. The mean APE1 enzyme activity in case patients was 691 [95% confidence interval (CI) = 655-727] units/ng protein, significantly lower than in control subjects (mean = 793, 95% CI = 751-834 units/ng protein, P = 0.0006). The adjusted odds ratio for lung cancer associated with 1 SD (211 units) decrease in APE1 activity was 2.0 (95% CI = 1.3-3.1; P = 0.002). Comparison of radioactivity- and fluorescence-based assays showed that the two are equivalent, indicating no interference by the fluorescent tag. The APE1Asp148Glu SNP was associated neither with APE1 enzyme activity nor with lung cancer risk. Taken together, our results indicate that low APE1 activity is associated with lung cancer risk, consistent with the hypothesis that 'bad DNA repair', rather than 'bad luck', is involved in cancer etiology. Such assays may be useful, along with additional DNA repair biomarkers, for risk assessment of lung cancer and perhaps other cancers, and for selecting individuals to undergo early detection techniques such as low-dose CT.


Assuntos
Reparo do DNA/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/epidemiologia , Estudos de Casos e Controles , Dano ao DNA/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/análise , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Feminino , Fluorescência , Predisposição Genética para Doença , Humanos , Leucócitos Mononucleares/citologia , Pulmão/enzimologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Masculino , Polimorfismo de Nucleotídeo Único , Risco
9.
PLoS One ; 10(5): e0127643, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26010085

RESUMO

Though the role of brain derived neurotrophic factor (BDNF) as a marker for major depressive disorder (MDD) and antidepressant efficacy has been widely studied, the role of BDNF in distinct groups of patients remains unclear. We evaluated the diagnostic value of BDNF as a marker of disease severity measured by HAM-D scores and antidepressants efficacy among MDD patients. Fifty-one patients who met DSM-IV criteria for MDD and were prescribed antidepressants and 38 controls participated in this study. BDNF in serum was measured at baseline, 1st, 2nd and 8th treatment weeks. Depression severity was evaluated using the Hamilton Rating Scale for Depression (HAM-D). BDNF polymorphism rs6265 (val66met) was genotyped. We found a positive correlation between blood BDNF levels and severity of depression only among untreated women with severe MDD (HAM-D>24). Serum BDNF levels were lower in untreated MDD patients compared to control group. Antidepressants increased serum BDNF levels and reduced between-group differences after two weeks of treatment. No correlations were observed between BDNF polymorphism, depression severity, duration of illness, age and BDNF serum levels. Further supporting the role of BDNF in the pathology and treatment of MDD, we suggest that it should not be used as a universal biomarker for diagnosis of MDD in the general population. However, it has diagnostic value for the assessment of disease progression and treatment efficacy in individual patients.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Transtorno Depressivo Maior/sangue , Caracteres Sexuais , Adulto , Fator Neurotrófico Derivado do Encéfalo/genética , Estudos de Casos e Controles , Demografia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
10.
Int J Cancer ; 137(9): 2155-62, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25924736

RESUMO

Lung cancer rates in Israeli Jews have remained stable over the last five decades and are much lower than in most developed countries despite high historical smoking rates. We compared lung cancer risk in Jews and non-Jews in Israel and in the United States. Data were derived from a population-based, case-control study in Israel (638 cases, 496 controls) to estimate lung cancer risk associated with smoking. Data were also acquired from a case-control study in the United States with information on religious affiliation (5,093 cases, 4,735 controls). Smoking was associated with lung cancer risk in all religion/gender groups in both studies. However, major differences in risk magnitude were noted between Jews and non-Jews; ever smoking was associated with a moderately elevated risk of lung cancer in Jewish men and women in Israel (OR = 4.61, 2.90-7.31 and OR = 2.10, 1.36-3.24, respectively), and in Jewish men and women in the United States (OR = 7.63, 5.34-10.90 and OR = 8.50, 5.94-12.17) but were significantly higher in Israeli non-Jewish men (OR = 12.96, 4.83-34.76) and US non-Jewish men and women (OR = 11.33, 9.09-14.12 and OR = 12.78, 10.45-15.63). A significant interaction between smoking and religion was evident in light, moderate and heavy male and female smokers. The differences in risk level between Israeli Jews and non-Jews could not be explained by lung cancer genetic risk variants which were identified in GWAS (genes in the CHRNA5, TERT and CLPTM1L regions). Data from the two studies support the notion of a reduced risk of lung cancer in Jewish compared to non-Jewish smokers in different areas of the world.


Assuntos
Neoplasias Pulmonares/epidemiologia , Fumar/efeitos adversos , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Israel/epidemiologia , Judeus/genética , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Estados Unidos/epidemiologia
11.
Springerplus ; 3: 507, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25279299

RESUMO

BACKGROUND: Most patients with non-small cell lung cancer (NSCLC) present with advanced disease and have poor long-term prognosis. Advanced NSCLC that contains characteristic mutations in epidermal growth factor receptor (EGFR) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 19 insertions mutations are rare, and response to TKIs is still unclear. CASE DESCRIPTION: A young Arab patient was diagnosed with metastatic disease of NSCLC harboring an exon 19 insertion of 18 nucleotides. The patient showed a very impressive clinical and radiological response within few weeks treatment with TKI agent. DISCUSSION AND EVALUATION: To our best knowledge, This case is the first case in Arab woman and one of few cases described in the literature with this rare mutation responding to TKIs. CONCLUSIONS: Treatment with TKIs should be the standard choice in patients with metastatic disease NSCLC.

12.
Carcinogenesis ; 35(11): 2512-9, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25023989

RESUMO

Only a fraction of colorectal cancer heritability is explained by known risk-conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genome-wide association study (GWAS) meta-analysis of colorectal cancer in participants from a population-based case-control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery-replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome-wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 × 10(-9); nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study.


Assuntos
Carcinogênese , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Cromossomos Humanos Par 4/genética , Neoplasias Colorretais/patologia , Grupos Étnicos , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
13.
PLoS One ; 8(11): e80158, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24282520

RESUMO

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included alcohol intake, which is mainly metabolized to acetaldehyde by alcohol dehydrogenase and further oxidized to acetate by aldehyde dehydrogenase; consequently, the role of genes in the alcohol metabolism pathways is of particular interest. The aim of this study is to analyze the association between SNPs in ADH1B and ALDH2 genes and CRC risk, and also the main effect of alcohol consumption on CRC risk in the study population. METHODOLOGY/PRINCIPAL FINDINGS: SNPs from ADH1B and ALDH2 genes, included in alcohol metabolism pathway, were genotyped in 1694 CRC cases and 1851 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. A positive association between alcohol consumption and CRC risk was observed in male participants from the Molecular Epidemiology of Colorectal Cancer study (MECC) study (OR = 1.47; 95%CI = 1.18-1.81). Moreover, the SNPs rs1229984 in ADH1B gene was found to be associated with CRC risk: under the recessive model, the OR was 1.75 for A/A genotype (95%CI = 1.21-2.52; p-value = 0.0025). A path analysis based on structural equation modeling showed a direct effect of ADH1B gene polymorphisms on colorectal carcinogenesis and also an indirect effect mediated through alcohol consumption. CONCLUSIONS/SIGNIFICANCE: Genetic polymorphisms in the alcohol metabolism pathways have a potential role in colorectal carcinogenesis, probably due to the differences in the ethanol metabolism and acetaldehyde oxidation of these enzyme variants.


Assuntos
Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/efeitos adversos , Aldeído Desidrogenase/genética , Neoplasias Colorretais/genética , Etanol/metabolismo , Polimorfismo de Nucleotídeo Único , Acetaldeído/metabolismo , Aldeído-Desidrogenase Mitocondrial , Genótipo , Humanos , Modelos Logísticos , Masculino , Redes e Vias Metabólicas/genética , Oxirredução , Fatores de Risco
14.
Eur J Cancer ; 49(4): 923-30, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23099005

RESUMO

BACKGROUND: Faecal occult blood (FOB) testing is the most commonly chosen approach in organised population-based colorectal cancer screening programmes throughout the world. Several FOB tests are available which differ in their test qualities. While immunological tests are gaining popularity due to their lower labour intensive analysis and higher standardisation, they are heat labile and more expensive. We studied the real-life experience of a large population-based, organised, screening programme in Israel which employs FOB testing with Hemoccult Sensa, a guaiac test with increased sensitivity that is similar to that of the immunological tests for cancer. METHODS: Clalit Health Services is the largest health care provider in Israel. All eligible insurees are actively invited to perform a free-of-charge, home-based, faecal occult blood test, using Hemoccult Sensa. All tests with positive results are followed up and information on colonoscopy, surgical procedures and pathology findings is collected. RESULTS: During an 18 month period (July 2007-December 2008) 382,792 FOBT tests (in 325,851 people) were performed by the target population, of them 85% Jews and 15% Arabs. Seven hundred and eighteen colorectal cancers and 2652 adenomas were detected. The overall test positivity rate in repeatedly-tested people was 4.2%. The overall detection rate of colorectal cancer in the subsequent tests was 1.7/1000 reflecting 91% of the expected period-incidence of CRC. 70% of the cancers were detected at stages Duke's B2 and lower. Left-sided cancers were detected at a significantly better stage than right-sided cancers (P<0.001). Detection rates among Arabs were somewhat lower than among Jews but the screening programme led to a meaningful increase in national incidence rate in this subgroup by detecting tumours that were otherwise asymptomatic. CONCLUSION: The Clalit organised colorectal cancer screening programme, using low cost Hemoccult Sensa, has reached the targets of very high detection rate of cancers, most of them at low stage while keeping a low positivity rate. This approach demonstrates an efficient field-tested alternative to other, more costly, screening options.


Assuntos
Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer , Testes Hematológicos , Sangue Oculto , Idoso , Neoplasias Colorretais/sangue , Neoplasias Colorretais/epidemiologia , Feminino , Guaiaco , Humanos , Incidência , Indicadores e Reagentes , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico
15.
Fam Cancer ; 11(3): 329-35, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22371070

RESUMO

MUTYH is associated with colorectal cancer (CRC) risk. We studied the frequency of MUTYH and risk of CRC in Arabs, North African and European Jews. Participants were all 593 Sephardi Moroccan Jews (232 cases, 361 controls) and all 631 Arabs (327 cases, 304 controls) recruited into a population-based study of colorectal cancer in Israel, as well as a random sample of 189 Ashkenazi Jewish cases. Two MUTYH mutations, G396D and Y179C, were studied in 1,413 individuals, with MUTYH sequence analysis in 46 cases with CRC in a sibling or adenoma. No carriers of mutations in MUTYH were identified in Ashkenazi Jews and only one in Arabs. In Sephardi Jews, 28 carriers of G396D, 25 (4.2%) heterozygotes and 3 (0.5%) homozygotes were identified. Four (0.7%) were heterozygote carriers of the Y179C mutation. Two compound heterozygous carriers of Y179C and G396D were identified. Homozygote carriers of G396D had nonsignificantly elevated risk of CRC (OR = 11.0, 95% CI: 0.91-213.9, p = 0.06), and combined bi-allelic carriers of G396D and Y179C had increased risk, OR = 17.4, 95% CI = (1.9-316.7, p = 0.009). Four of five bi-allelic carriers reported a family history of CRC. Sequencing of 46 colorectal cancer cases with family history and additional adenomas, did not identify any other non-founder mutations. MUTYH carriers of the two common founder mutations are profoundly under-represented among both Ashkenazi Jews and Arabs. The prevalence of MUTYH carriers of the common mutations is much higher in Sephardi Jews. Bi-allelic carriers of mutations in MUTYH, are associated with highly risk of colorectal cancer.


Assuntos
Neoplasias Colorretais/genética , DNA Glicosilases/genética , Predisposição Genética para Doença , Mutação , Adenoma/etnologia , Adenoma/genética , Idoso , Idoso de 80 Anos ou mais , Árabes/genética , Sequência de Bases , Estudos de Casos e Controles , Neoplasias Colorretais/etnologia , Feminino , Efeito Fundador , Heterozigoto , Humanos , Israel , Judeus/genética , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular
16.
Cancer ; 118(8): 1989-93, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21952991

RESUMO

BACKGROUND: Variants of the mutY homolog gene MutYH, a DNA repair gene, are associated with increased risk of colorectal cancer; however, it remains unclear whether these variants also are associated with the risk of other cancers. The authors studied the risk of breast cancer associated with MutYH variants in a unique ethnic group of Sephardi Jews in Israel with a high prevalence of MutYH mutations. METHODS: The study participants were 930 Sephardi Jewish women of North African origin who were recruited into the population-based case-control Breast Cancer in Northern Israel Study (BCINIS) either as breast cancer cases or as healthy controls. All participants contributed a blood sample and completed an interview. Two MutYH variants, a glycine-to-aspartic acid substitution at codon 396 (G396D) and a tyrosine-to-cysteine substitution at codon 179 (Y179C), were studied. RESULTS: In the Sephardi Jews, among the healthy controls, 20 women (3.7%) were homozygote or heterozygote carriers of the G396D variant, and 4 women (0.7%) were heterozygote carriers of the Y179C variant. Breast cancer cases had a 6.7% prevalence of G396D, yielding a significantly elevated risk estimate for breast cancer (odds ratio, 1.86; 95% confidence interval, 1.02-3.39; P = .039). The tumors detected in carriers with MutYH variants were similar in characteristics to those without MutYH variants, as was the age at diagnosis. CONCLUSIONS: Carriers of variants in MutYH, although not very common, may have an increased risk of breast cancer in Jews of North African origin. Identification of such carriers and special surveillance protocols may be warranted.


Assuntos
DNA Glicosilases/genética , Judeus/genética , África do Norte/etnologia , Idoso , Neoplasias da Mama/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Israel , Pessoa de Meia-Idade , Mutação
17.
PLoS Biol ; 9(11): e1001199, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22110403

RESUMO

Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.


Assuntos
Proteína BRCA1/metabolismo , Neoplasias da Mama/metabolismo , Polaridade Celular , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Aurora Quinase A , Aurora Quinases , Proteína BRCA1/genética , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Mama/citologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Polaridade Celular/genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Variação Genética , Genótipo , Células HeLa , Heterozigoto , Humanos , Microtúbulos/fisiologia , Microtúbulos/ultraestrutura , Proteínas Serina-Treonina Quinases/metabolismo , Receptores Estrogênicos/análise
18.
Clin Cancer Res ; 17(23): 7303-12, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21976543

RESUMO

PURPOSE: Colorectal cancer studies typically include both colon and rectum tumors as a common entity, though this assumption is controversial and only minor differences have been reported at the molecular and epidemiologic level. We conducted a molecular study based on gene expression data of tumors from colon and rectum to assess the degree of similarity between these cancer sites at transcriptomic level. EXPERIMENTAL DESIGN: A pooled analysis of 460 colon tumors and 100 rectum tumors from four data sets belonging to three independent studies was conducted. Microsatellite instable tumors were excluded as these are known to have a different expression profile and have a preferential proximal colon location. Expression differences were assessed with linear models, and significant genes were identified using adjustment for multiple comparisons. RESULTS: Minor differences at a gene expression level were found between tumors arising in the proximal colon, distal colon, or rectum. Only several HOX genes were found to be associated with tumor location. More differences were found between proximal and distal colon than between distal colon and rectum. CONCLUSIONS: Microsatellite stable colorectal cancers do not show major transcriptomic differences for tumors arising in the colon or rectum. The small but consistent differences observed are largely driven by the HOX genes. These results may have important implications in the design and interpretation of studies in colorectal cancer.


Assuntos
Neoplasias do Colo/genética , Perfilação da Expressão Gênica , Neoplasias Retais/genética , Idoso , Idoso de 80 Anos ou mais , Colo/patologia , Neoplasias do Colo/classificação , Neoplasias do Colo/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Neoplasias Retais/classificação , Neoplasias Retais/patologia , Reto/patologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Hum Genet ; 130(5): 685-99, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21597964

RESUMO

Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.


Assuntos
Artrite/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Surdez/genética , Haplótipos/genética , Policondrite Recidivante/genética , Sequência de Bases , Simulação por Computador , Feminino , Efeito Fundador , Genótipo , Heterozigoto , Humanos , Judeus/genética , Deleção de Sequência
20.
Gastroenterology ; 140(7): 1919-26, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21419771

RESUMO

BACKGROUND & AIMS: The MSH2 A636P mutation is a founder mutation in Ashkenazi Jews that causes Lynch syndrome, with a prevalence of 0.4%-0.7%. Estimates of age-specific cumulative risk and lifetime risk for colorectal cancer (CRC) and endometrial cancer (EC) specific to carriers of this mutation are not available. METHODS: We studied 27 families with MSH2 A636P gene mutations identified in Israel; 13 were identified via a population-based, case-control study and 14 were identified from a clinical genetics service. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared with the general Ashkenazi population using modified segregation analysis. An ascertainment-corrected likelihood that combined population-based and clinic-based sampling provided a powerful analysis for estimating penetrance. We analyzed 74 cases of CRC (40 in the clinic series and 34 in the population-based series), diagnosed at median ages of 50 years (men) and 49 years (women) in the combined sample. RESULTS: The cumulative risk of CRC at age 70 was 61.62% for men (95% confidence interval [CI], 37.49%-76.45%) and 61.08% for women (95% CI, 39.39%-75.14%), with overall HRs of 31.8 (19.9-51.0) and 41.8 (27.4-64.0), respectively. There were 28 cases of EC, diagnosed at a median age of 53.0 years. The cumulative risk of EC was 55.64% (95% CI, 33.07%-70.58%) with an overall HR of 66.7 (41.7-106.7). CONCLUSIONS: Lifetime risks of CRC and EC in MSH2 A636P carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer screening is necessary for carriers of this mutation.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias do Endométrio/genética , Efeito Fundador , Judeus/genética , Proteína 2 Homóloga a MutS/genética , Mutação , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/enzimologia , Neoplasias Colorretais Hereditárias sem Polipose/etnologia , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/etnologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Testes Genéticos , Hereditariedade , Humanos , Israel/epidemiologia , Funções Verossimilhança , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Linhagem , Penetrância , Fenótipo , Modelos de Riscos Proporcionais , Sistema de Registros , Medição de Risco , Fatores de Risco , Fatores Sexuais , Adulto Jovem
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