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1.
BMC Cancer ; 22(1): 209, 2022 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-35216576

RESUMO

BACKGROUND: The Kaiser Permanente Research Bank (KPRB) is collecting biospecimens and surveys linked to electronic health records (EHR) from approximately 400,000 adult KP members. Within the KPRB, we developed a Cancer Cohort to address issues related to cancer survival, and to understand how genetic, lifestyle and environmental factors impact cancer treatment, treatment sequelae, and prognosis. We describe the Cancer Cohort design and implementation, describe cohort characteristics after 5 years of enrollment, and discuss future directions. METHODS: Cancer cases are identified using rapid case ascertainment algorithms, linkage to regional or central tumor registries, and direct outreach to KP members with a history of cancer. Enrollment is primarily through email invitation. Participants complete a consent form, survey, and donate a blood or saliva sample. All cancer types are included. RESULTS: As of December 31, 2020, the cohort included 65,225 cases (56% female, 44% male) verified in tumor registries. The largest group was diagnosed between 60 and 69 years of age (31%) and are non-Hispanic White (83%); however, 10,076 (16%) were diagnosed at ages 18-49 years, 4208 (7%) are Hispanic, 3393 (5%) are Asian, and 2389 (4%) are Black. The median survival time is 14 years. Biospecimens are available on 98% of the cohort. CONCLUSIONS: The KPRB Cancer Cohort is designed to improve our understanding of treatment efficacy and factors that contribute to long-term cancer survival. The cohort's diversity - with respect to age, race/ethnicity and geographic location - will facilitate research on factors that contribute to cancer survival disparities.


Assuntos
Bancos de Espécimes Biológicos , Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias , Melhoria de Qualidade , Adolescente , Adulto , Idoso , Estudos de Coortes , Registros Eletrônicos de Saúde , Feminino , Humanos , Seguro Saúde , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estados Unidos , Adulto Jovem
2.
JCO Oncol Pract ; 17(4): e575-e581, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33428469

RESUMO

PURPOSE: Current US guidelines recommend more intensive breast cancer screening and preventive strategies for patients at more than 20% lifetime risk for breast and ovarian cancer (high risk for breast and ovarian cancer [HRBOC]). Guidelines recommend that yearly mammograms alternating with magnetic resonance imaging (MRI) screening should be considered as early as 30 years old. Furthermore, BRCA mutation carriers should consider bilateral mastectomy and bilateral oophorectomy after age 35. It was unclear what the uptake of screening and risk-reducing strategies were for patients who were cancer-free and cancer survivors seen by Kaiser Permanente Mid-Atlantic States (KPMAS) Genetics. METHODS: We retrospectively studied female patients (members of KPMAS between 2005 and 2016) diagnosed as HRBOC and/or tested for breast cancer-related mutations by KPMAS Genetics during 2013-2016. We identified cancer diagnoses, mammogram and breast MRI screening, mastectomies, and oophorectomies that occurred before and after the Genetics visit during the study period. RESULTS: Our cohort included 813 women with a HRBOC diagnosis, with a median 51 years of age at diagnosis, 45% White, 38% Black, and 15% other ethnicity. Most cancers occurred prior to the Genetics visit: 513/527 breast cancer diagnoses and 55/57 ovarian cancer diagnoses. Fewer than five prophylactic mastectomies and 89 prophylactic oophorectomies were identified. Among 228 patients who were 30-75 years old, breast cancer-free at the time of HRBOC diagnosis, and members for over 6 months, 190 (83%) had at least one screening test (mammogram or MRI) after the consultation with Genetic, but 79% never had an MRI before or after the consultation. CONCLUSION: Our findings suggest that earlier detection of patients with HRBOC and closer monitoring is needed.


Assuntos
Neoplasias da Mama , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Detecção Precoce de Câncer , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Mastectomia , Pessoa de Meia-Idade , Estudos Retrospectivos
3.
JCO Clin Cancer Inform ; 3: 1-10, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31487201

RESUMO

PURPOSE: To evaluate health care systems for the availability of population-level data on the frequency of use and results of clinical molecular marker tests to inform precision cancer care. METHODS: We assessed cancer-related molecular marker test data availability across 12 US health care systems in the Cancer Research Network. Overall, these systems provide care to a diverse population of more than 12 million people in the United States. We performed qualitative analyses of test data availability for five blood-based protein, nine germline, and 14 tissue-based tumor marker tests in each health care system's electronic health record and tumor registry using key informants, test code lists, and manual review of data types and output. We then performed quantitative analyses to estimate the proportion of patients with cancer with test utilization data and results for specific molecular marker tests. RESULTS: Health systems were able to systematically capture population-level data on all five blood protein markers, six of 14 tissue-based tumor markers, and none of the nine germline markers. Successful, systematic data capture was achievable for tests with electronic data feeds for test results (blood protein markers) or through prior manual abstraction by tumor registrars (select tumor-based markers). For test results stored in scanned image files (particularly germline and tumor marker tests), information on which test was performed and test results was not readily accessible in an electronic format. CONCLUSION: Even in health care systems with sophisticated electronic health records, there were few codified data elements available for evaluating precision cancer medicine test use and results at the population level. Health care organizations should establish standards for electronic reporting of precision medicine tests to expedite cancer research and facilitate the implementation of precision medicine approaches.


Assuntos
Registros Eletrônicos de Saúde , Neoplasias/epidemiologia , Biomarcadores Tumorais , Coleta de Dados , Atenção à Saúde , Gerenciamento Clínico , Humanos , Biópsia Líquida , Técnicas de Diagnóstico Molecular , Neoplasias/diagnóstico , Neoplasias/etiologia , Neoplasias/terapia , Medicina de Precisão , Vigilância em Saúde Pública , Pesquisa , Estados Unidos/epidemiologia
4.
Oncologist ; 22(2): 165-172, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28179574

RESUMO

Endpoints related to tumor progression are commonly used in clinical trials of novel therapeutic agents for neuroendocrine tumors (NETs). Whether improved tumor control translates into improved overall survival (OS), however, is uncertain. We assessed associations between tumor progression endpoints and OS in observational cohorts of patients with advanced neuroendocrine tumors treated with somatostatin analogs or with everolimus. We identified 440 patients with advanced NET who had received treatment with single-agent somatostatin analogs and 109 patients treated with everolimus, all of whom were treated at our institution and were evaluable for both tumor progression and survival. We assessed associations between progression-free survival (PFS) and OS by using the Kendall tau test, and we assessed associations between tumor progression and OS by using a landmark analysis. In the 440 patients treated with somatostatin analogs, we observed a significant correlation between PFS and OS by using the Kendall tau test (0.31; p < .0001). Additionally, the development of progressive disease was associated with OS in a landmark analysis, at landmark times of 6, 12, 18, and 24 months. In the 109 patients treated with everolimus, we similarly observed a significant correlation between PFS and OS by using the Kendall tau test (0.44; p < .0001) and associations between progressive disease and OS by using a landmark analysis at 3, 6, and 12 months. In these observational cohorts of patients with metastatic NET treated with single-agent somatostatin analogs or everolimus, longer times to disease progression and longer PFS were both associated with improved OS. Our findings support the continued use of disease progression endpoints in NET clinical trials. The Oncologist 2017;22:165-172Implications for Practice: Clinical trials in patients with advanced neuroendocrine tumors have used progression-free survival as a primary endpoint. While there is a general assumption that slowing or halting tumor growth is beneficial, little direct evidence links improvements in progression endpoints to improvements in overall survival. This study assessed associations between tumor progression endpoints and overall survival in observational cohorts of patients with advanced neuroendocrine tumor treated with somatostatin analogs or everolimus. Longer times to disease progression and improved progression-free survival were both associated with improved overall survival. The findings support the continued use of tumor progression endpoints in clinical trials for neuroendocrine tumors.


Assuntos
Tumores Neuroendócrinos/diagnóstico , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Análise de Sobrevida
5.
Pancreas ; 45(10): 1386-1393, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27622342

RESUMO

OBJECTIVE: Somatostatin receptors (SSTRs), products of gene superfamily SSTR1-5, are commonly expressed in neuroendocrine tumors (NETs). Somatostatin analogs (SSAs) bind to SSTRs and are used as therapeutic agents in patients with advanced NETs. We hypothesized that tumor SSTR expression status would be associated with clinical outcomes in NET. METHODS: Expression of the 5 SSTRs was evaluated by immunohistochemistry, using tissue microarrays comprising 173 primary NETs, 24 matched metastases, and 22 metastatic NETs from 195 patients. Cox proportional hazards regression analysis was used to assess the association of SSTR expression status (high vs low) with clinical outcomes, adjusting for potential confounders. RESULTS: High expression of SSTR2 was associated with longer overall survival (OS) in the cohort overall (multivariate hazard ratio, 0.42; 95% confidence interval, 0.21-0.84; P = 0.013). In a subgroup of patients with metastatic small intestine NET treated with SSAs and evaluable for progression, SSTR2 expression was associated with both longer progression-free survival (PFS) and OS. No associations with PFS or OS were observed with expression of other SSTRs. CONCLUSIONS: Our study demonstrated that expression of SSTR2, but not other SSTRs, is associated with longer OS. In patients treated with SSAs, expression of SSTR2 is associated with longer PFS survival.


Assuntos
Tumores Neuroendócrinos , Intervalo Livre de Doença , Expressão Gênica , Humanos , Receptores de Somatostatina , Somatostatina
6.
Endocr Relat Cancer ; 23(8): 587-94, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27492634

RESUMO

The etiology of neuroendocrine tumors remains poorly defined. Although neuroendocrine tumors are in some cases associated with inherited genetic syndromes, such syndromes are rare. The majority of neuroendocrine tumors are thought to be sporadic. We performed a genome-wide association study (GWAS) to identify potential genetic risk factors for sporadic neuroendocrine tumors. Using germline DNA from blood specimens, we genotyped 909,622 SNPs using the Affymetrix 6.0 GeneChip, in a cohort comprising 832 neuroendocrine tumor cases from Dana-Farber Cancer Institute and Massachusetts General Hospital and 4542 controls from the Harvard School of Public Health. An additional 241 controls from Dana-Farber Cancer Institute were used for quality control. We assessed risk associations in the overall cohort, and in neuroendocrine tumor subgroups. We identified no potential risk associations in the cohort overall. In the small intestine neuroendocrine tumor subgroup, comprising 293 cases, we identified risk associations with three SNPs on chromosome 12, all in strong LD. The three SNPs are located upstream of ELK3, a transcription factor implicated in angiogenesis. We did not identify clear risk associations in the bronchial or pancreatic neuroendocrine subgroups. This large-scale study provides initial evidence that presumed sporadic small intestine neuroendocrine tumors may have a genetic etiology. Our results provide a basis for further exploring the role of genes implicated in this analysis, and for replication studies to confirm the observed associations. Additional studies to evaluate potential genetic risk factors for sporadic pancreatic and bronchial neuroendocrine tumors are warranted.


Assuntos
Neoplasias Brônquicas/genética , Neoplasias Intestinais/genética , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
7.
J Clin Oncol ; 31(27): 3418-25, 2013 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-23980085

RESUMO

PURPOSE: Clinical studies have implicated the mechanistic target of rapamycin (serine/threonine kinase; MTOR) pathway in the regulation of neuroendocrine tumor (NET) growth. We explored whether expression of MTOR pathway components has prognostic significance in NET patients. PATIENTS AND METHODS: We evaluated immunohistochemical expression of MTOR and phospho (p) -MTOR; its downstream targets RPS6KB1, RPS6, and EIF4EBP1; and its upstream regulators, in a cohort of 195 archival neuroendocrine tumors. We correlated expression levels with clinical outcomes, after adjusting for other prognostic variables. RESULTS: We observed anticipated correlations between expression of upstream components of the MTOR pathway and their downstream targets. Expression of PIK3CA, MTOR, or p-EIF4EBP1 was associated with high MKI67 (Ki-67) labeling index. We failed to identify clinical correlations associated with expression of the upstream regulators TSC1, TSC2, AKT, p-AKT, PDPK1, PTEN, PIK3R1, or PIK3CA. In contrast, high expression of MTOR or its activated downstream targets p-RPS6KB1, p-RPS6, or p-EIF4EBP1 was associated with adverse clinical outcomes. CONCLUSION: Our observations suggest that expression of MTOR or its downstream targets may be adverse prognostic factors in neuroendocrine tumors.


Assuntos
Tumores Neuroendócrinos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/genética , Prognóstico , Serina-Treonina Quinases TOR/biossíntese , Serina-Treonina Quinases TOR/genética
8.
Endocr Relat Cancer ; 20(2): 187-96, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23319495

RESUMO

The rarity of neuroendocrine tumors (NET) has contributed to a paucity of large epidemiologic studies of patients with this condition. We characterized presenting symptoms and clinical outcomes in a prospective database of over 900 patients with NET. We used data from patient questionnaires and the medical record to characterize presenting symptoms, disease-free survival (DFS), and overall survival (OS). The majority of patients in this database had gastroenteropancreatic NET. The median duration of patient-reported symptoms before diagnosis was 3.4 months; 19.5% reported durations from 1 to 5 years, 2.5% from 5 to 10 years, and 2% >10 years. The median DFS among patients with resected small bowel NET or pancreatic NET (panNET) was 5.8 and 4.1 years respectively. After correcting for left truncation bias, the median OS was 7.9 years for advanced small bowel NET and 3.9 years for advanced panNET. Chromogranin A (CGA) above twice the upper limit of normal was associated with shorter survival times (hazard ratios 2.8 (1.9, 4.0) P<0.001) in patients with metastatic disease, regardless of tumor subtype. Our data suggest that while most NET patients are diagnosed soon after symptom onset, prolonged symptom duration before diagnosis is a prominent feature of this disease. Though limited to observations from a large referral center, our observations confirm the prognostic value of CGA and suggest that median survival durations may be shorter than that reported in other institutional databases.


Assuntos
Tumores Neuroendócrinos/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromogranina A/sangue , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/epidemiologia , Prognóstico , Recidiva , Adulto Jovem
9.
Int J Cancer ; 130(6): 1338-46, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21544809

RESUMO

Urinary metabolites of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides, termed total NNAL, have recently been shown to be good predictors of lung cancer risk, years before diagnosis. We sought to determine the contribution of several genetic polymorphisms to total NNAL output and inter-individual variability. The study subjects were derived from the Harvard/Massachusetts General Hospital Lung cancer case-control study. We analyzed 87 self-described smokers (35 lung cancer cases and 52 controls), with urine samples collected at time of diagnosis (1992-1996). We tested 82 tagging SNPs in 16 genes related to the metabolism of NNK to total NNAL. Using weighted case status least squares regression, we tested for the association of each SNP with square-root (sqrt) transformed total NNAL (pmol per mg creatinine), controlling for age, sex, sqrt packyears and sqrt nicotine (ng per mg creatinine). After a sqrt transformation, nicotine significantly predicted a 0.018 (0.014, 0.023) pmol/mg creatinine unit increase in total NNAL for every ng/mg creatinine increase in nicotine at p < 10E-16. Three HSD11B1 SNPs and AKR1C4 rs7083869 were significantly associated with decreasing total NNAL levels: HSD11B1 rs2235543 (p = 4.84E-08) and rs3753519 (p = 0.0017) passed multiple testing adjustment at FDR q = 1.13E-05 and 0.07 respectively, AKR1C4 rs7083869 (p = 0.019) did not, FDR q = 0.51. HSD11B1 and AKR1C4 enzymes are carbonyl reductases directly involved in the single step reduction of NNK to NNAL. The HSD11B1 SNPs may be correlated with the functional variant rs13306401 and the AKR1C4 SNP is correlated with the enzyme activity reducing variant rs17134592, L311V.


Assuntos
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Nitrosaminas/metabolismo , Piridinas/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Adulto , Idoso , Estudos de Casos e Controles , Creatinina/urina , Feminino , Humanos , Individualidade , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/urina , Masculino , Pessoa de Meia-Idade , Nicotina/urina , Nitrosaminas/urina , Oxirredutases/genética , Polimorfismo de Nucleotídeo Único , Piridinas/urina , Fumar/genética , Fumar/metabolismo , Poluição por Fumaça de Tabaco
10.
Cancer ; 118(3): 804-11, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21751195

RESUMO

BACKGROUND: Gastroesophageal reflux disease (GERD), higher body mass index (BMI), smoking, and genetic variants in angiogenic pathway genes have been individually associated with increased risk of esophageal adenocarcinoma. However, how angiogenic gene polymorphisms and environmental factors jointly affect esophageal adenocarcinoma development remains unclear. METHODS: By using a case-only design (n = 335), the authors examined interactions between 141 functional/tagging angiogenic single nucleotide polymorphisms (SNPs) and environmental factors (GERD, BMI, smoking) in modulating esophageal adenocarcinoma risk. Gene-environment interactions were assessed by a 2-step approach. First, the authors applied random forest to screen for important SNPs that had either main or interaction effects. Second, they used case-only logistic regression to assess the effects of gene-environment interactions on esophageal adenocarcinoma risk, adjusting for covariates and false-discovery rate. RESULTS: Random forest analyses identified 3 sets of SNPs (17 SNPs-GERD, 26 SNPs-smoking, and 34 SNPs-BMI) that had the highest importance scores. In subsequent logistic regression analyses, interactions between 2 SNPs (rs2295778 of HIF1AN, rs13337626 of TSC2) and GERD, 2 SNPs (rs2295778 of HIF1AN, rs2296188 of VEGFR1) and smoking, and 7 SNPs (rs2114039 of PDGRFA, rs2296188 of VEGFR1, rs11941492 of VEGFR1, rs17708574 of PDGFRB, rs7324547 of VEGFR1, rs17619601 of VEGFR1, and rs17625898 of VEGFR1) and BMI were significantly associated with esophageal adenocarcinoma development (all false-discovery rates ≤0.10). Moreover, these interactions tended to have SNP dose-response effects for increased esophageal adenocarcinoma risk with increasing number of combined risk genotypes. CONCLUSIONS: These findings suggest that genetic variations in angiogenic genes may modify esophageal adenocarcinoma susceptibility through interactions with environmental factors in an SNP dose-response manner.


Assuntos
Adenocarcinoma/etiologia , Proteínas Angiogênicas/genética , Neoplasias Esofágicas/etiologia , Interação Gene-Ambiente , Polimorfismo de Nucleotídeo Único/genética , Transdução de Sinais , Índice de Massa Corporal , DNA de Neoplasias/genética , Feminino , Refluxo Gastroesofágico/etiologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Fatores de Risco , Fumar
11.
Carcinogenesis ; 32(8): 1216-22, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21606320

RESUMO

Genetic risk factors for sporadic neuroendocrine tumors (NET) are poorly understood. We tested risk associations in patients with sporadic NET and non-cancer controls, using a custom array containing 1536 single-nucleotide polymorphisms (SNPs) in 355 candidate genes. We identified 18 SNPs associated with NET risk at a P-value <0.01 in a discovery set of 261 cases and 319 controls. Two of these SNPs were found to be significantly associated with NET risk in an independent replication set of 235 cases and 113 controls, at a P value ≤0.05. An SNP in interleukin 12A (IL12A rs2243123), a gene implicated in inflammatory response, replicated with an adjusted odds ratio (95% confidence interval) (aOR) = 1.47 (1.03, 2.11) P-trend = 0.04. A second SNP in defender against cell death, (DAD1 rs8005354), a gene that modulates apoptosis, replicated at aOR = 1.43 (1.02, 2.02) P-trend = 0.04. Consistent with our observations, a pathway analysis, performed in the discovery set, suggested that genetic variation in inflammatory pathways or apoptosis pathways is associated with NET risk. Our findings support further investigation of the potential role of IL12A and DAD1 in the etiology of NET.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Biomarcadores Tumorais/genética , Subunidade p35 da Interleucina-12/genética , Proteínas de Membrana/genética , Tumores Neuroendócrinos/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Prognóstico , Fatores de Risco , Adulto Jovem
12.
Neoplasia ; 13(4): 386-92, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21472143

RESUMO

There is an increasing incidence of esophageal adenocarcinoma (EA) among younger people in the western populations. However, the association between genetic polymorphisms and the age of EA onset is unclear. In this study, 1330 functional/tagging single-nucleotide polymorphisms (SNPs) from 354 cancer-related genes were genotyped in 335 white EA patients. Twenty important SNPs that have the highest importance scores and lowest classification error rate were identified by the random forest algorithm to be associated with early onset of EA (age ≤ 55 years). Subsequent logistic regression analysis indicated that 10 SNPs (rs2070744 of NOS3, rs720321 of BCL2, rs17757541 of BCL2, rs11775256 of TNFRSF10A, rs1035142 of CASP8, rs2236302 of MMP14, rs4740363 of ABL1, rs696217 of GHRL, rs2445762 of CYP19A1, and rs11941492 of VEGFR2/KDR) were significantly associated with early onset of EA (≤55 vs >55 years, all P < .05 after adjusting for co-variates and false discovery rate). Among them, five SNPs in the NOS3, BCL2, TNFRSF10A, and CASP8 genes were known to be involved in apoptosis processes. In Kaplan-Meier analyses, rs2070744 of NOS3, rs720321 of BCL2, and rs1035142 of CASP8 were also significantly associated with early onset of EA. Moreover, there was a higher risk of developing EA at a younger age when one had more risk genotypes. In conclusion, polymorphisms in cancer-related genes, especially those in the apoptotic pathway, play an important role in the development of younger-aged EA in a dose-response manner.


Assuntos
Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Genes Neoplásicos/genética , Polimorfismo de Nucleotídeo Único , Adenocarcinoma/complicações , Adenocarcinoma/epidemiologia , Adolescente , Adulto , Idade de Início , Estudos de Casos e Controles , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/epidemiologia , Feminino , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/epidemiologia , Refluxo Gastroesofágico/genética , Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/fisiologia , Fumar/efeitos adversos , Fumar/epidemiologia , Fumar/genética , Adulto Jovem
13.
Carcinogenesis ; 32(4): 502-6, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21212151

RESUMO

How genetic variations in apoptosis pathway interact with environmental factors to contribute to esophageal adenocarcinoma (EA) risk has not been comprehensively investigated. We conducted a case-only analysis in 335 Caucasian EA patients that were genotyped for 242 single nucleotide polymorphisms (SNPs) in 43 apoptotic genes. Gene-environment interactions were assessed using a two-step approach. First, random forest algorithm was used to screen for the potential interacting markers. Next, we used case-only logistic regression model to estimate the effects of gene-environment interactions on EA risk. Four SNPs (PERP rs648802; PIK3CA rs4855094, rs7644468 and TNFRSF1A rs4149579) had significant interaction with gastroesophageal reflux disease (GERD). The presence of variant alleles in TP53BP1 rs560191, CASP7 rs7907519 or BCL2 rs12454712 enhanced the risk of smoking by 2.08-2.58 times [interaction odds ratio (ORi)=2.08-2.58, adjusted P-value (Padj)=0.02-0.04]. Compared with patients carrying ≤1 risk genotype, the risk of GERD on EA was increased in persons with two (ORi=1.89, Padj=0.016) or ≥3 (ORi=4.30, Padj<0.0001) risk genotypes. Compared with cases with ≤1 risk genotype, smoking-associated EA risk increased by 3.15 times when ≥2 risk genotypes were present (ORi=3.15, Padj<0.0001). In conclusion, interactions among apoptotic SNPs and GERD or smoking play an important role in EA development.


Assuntos
Adenocarcinoma/etiologia , Apoptose , Neoplasias Esofágicas/etiologia , Polimorfismo de Nucleotídeo Único , Fumar/efeitos adversos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Caspase 7/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Feminino , Refluxo Gastroesofágico/complicações , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Risco
14.
Carcinogenesis ; 31(7): 1259-63, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20453000

RESUMO

The incidence of esophageal adenocarcinoma (EA) has been increasing rapidly, particularly among white males, over the past few decades in the USA. However, the etiology of EA and the striking male predominance is not fully explained by known risk factors. To identify susceptible genes for EA risk, we conducted a pathway-based candidate gene association study on 335 Caucasian EA cases and 319 Caucasian controls. A total of 1330 single-nucleotide polymorphisms (SNPs) selected from 354 genes were analyzed using an Illumina GoldenGate assay. The genotyped common SNPs include missense and exonic SNPs, SNPs within untranslated regions and 2 kb 5' of the gene, and tagSNPs for genes with little functional information available. Logistic regression adjusted for potential confounders was used to assess the genetic effect of each SNP on EA risk. We also tested gene-gender interactions using the likelihood ratio tests. We found that the genetic variants in the apoptosis pathway were significantly associated with EA risk after correcting for multiple comparisons. SNPs of rs3127075 in Caspase-7 (CASP7) and rs4661636 in Caspase-9 (CASP9) genes that play a critical role in apoptosis were found to be associated with an increased risk of EA. A protective effect of SNP rs572483 in the progesterone receptor (PGR) gene was observed among women carrying the variant G allele [adjusted odds ratio (OR) = 0.19; 95% confidence interval (CI) = 0.08-0.46] but was not observed among men (adjusted OR = 1.38; 95% CI = 0.95-2.00). In conclusion, this study suggests that the genetic variants of CASP7 and CASP9 in the apoptosis pathway may be important predictive markers for EA susceptibility and that PGR in the sex hormone signaling pathway may be associated with the gender differences in EA risk.


Assuntos
Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Estudos de Associação Genética , Polimorfismo de Nucleotídeo Único , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Caspase 7/genética , Caspase 9/genética , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
15.
Carcinogenesis ; 30(5): 793-8, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19321798

RESUMO

The matrix metalloproteinase (MMP) family degrade extracellular matrix and mediate pathways including apoptosis, angiogenesis and immunity. We studied the association between four MMP polymorphisms within three MMP genes and esophageal adenocarcinoma (EA) risk and prognosis. A total of 313 EA cases and 455 age and gender frequency-matched controls were genotyped for MMP1 1G/2G, MMP3 6A/5A, MMP12 -82A/G and MMP12 1082A/G. The association between individual MMP polymorphisms and EA risk was evaluated using regression models and adjusted for age, gender, adult body mass index and smoking status. Haplotype analysis was performed to investigate the combined effect of all four linked MMP polymorphisms and EA risk. The MMP1 and MMP3 polymorphisms were associated with increased EA risk: MMP1 1G/2G and 2G/2G had adjusted odds ratios of 1.46 [95% confidence interval 1.0-2.1; P = 0.04] and adjusted odds ratio 1.83 (1.2-2.8; P = 0.005), respectively, whereas MMP3 6A/5A had adjusted odds ratio 1.40 (95% confidence interval 1.0-2.1; P = 0.09) and MMP3 5A/5A had 1.61 (95% confidence interval 1.0-2.5; P = 0.03). Two MMP haplotypes [MMP1-MMP3-MMP12 (-82) 2G-5A-A (adjusted odds ratio 1.36, 95% confidence interval 1.0-1.8; P = 0.03) and 2G-5A-G (adjusted odds ratio 1.70, 95% confidence interval 1.1-2.6; P = 0.01)] were also associated with increased EA risk. The relationship between BE cases with the same set of controls was similar. No association was identified between the MMP polymorphisms and overall survival or progression free survival of patients with EA. MMP1, MMP3 and possibly MMP12 -82A/G polymorphisms and their haplotypes are associated with increased EA risk.


Assuntos
Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Polimorfismo Genético , Adenocarcinoma/enzimologia , Adenocarcinoma/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Intervalos de Confiança , Neoplasias Esofágicas/enzimologia , Neoplasias Esofágicas/epidemiologia , Família , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/enzimologia , Neoplasias Nasofaríngeas/genética , Razão de Chances , Prognóstico , Grupos Raciais/genética , Valores de Referência , Fatores de Risco , Fumar/epidemiologia , Inquéritos e Questionários , Adulto Jovem
16.
Eur J Cancer ; 45(8): 1443-9, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19223177

RESUMO

Published data regarding the association between 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and prostate cancer risk have been conflicting. To derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between MTHFR C677T and A1298C polymorphisms and prostate cancer risk. Six studies including 3511 cases and 2762 controls described C677T genotypes, among which four articles totalling 838 cases and 1121 controls described A1298C genotypes, were involved in this meta-analysis. Overall meta-analysis indicated that the 677T allele was more likely to exert a protective effect on prostate cancer risk (OR=0.81, 95% CI: 0.68-0.98) with a recessive genetic model. No association was found for the 677CT genotype and the 677TT mutant homozygote with prostate cancer risk compared with 677CC, with OR=1.13 (95% CI: 0.88-1.45) and OR=0.85 (95% CI: 0.71-1.03), respectively. No evidence of an association of MTHFR A1298C polymorphism with prostate cancer was found. This meta-analysis supports that the C677T of the MTHFR gene is a low-penetrance susceptibility gene for prostate cancer, and might provide protective effects against prostate cancer risk.


Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Genótipo , Humanos , Masculino , População Branca/genética
17.
Carcinogenesis ; 29(11): 2147-52, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18757527

RESUMO

Apoptosis is important for targeting cancer cells for destruction. Various single-nucleotide polymorphisms (SNPs) in apoptotic genes have been associated with increased risks in lung cancer, particularly FAS -1377 G>A (rs2234767), FASLG -844 C>T (rs763110), IL1B +3954 C>T Phe105Phe (rs1143634) and BAT3 Ser625Pro (rs1052486). We studied the association of these SNPs with non-small cell lung cancer (NSCLC) in a large case-control study (N = 4263: 2644 cases and 1619 controls). No associations with NSCLC were observed in the main effects analysis for all four SNPs, adjusting for age, gender, smoking status, pack-years and years since smoking cessation. In subjects under age 60, for FASLG -844 C>T polymorphism, CT compared with the CC genotype, was significantly associated with increased risk of NSCLC, adjusted odds ratio (aOR) = 1.58 (1.22, 2.05), P = 0.0006 and TT aOR = 1.45 (1.01, 2.04), P = 0.04. In contrast, for those over age 60, the CT aOR = 0.91 (0.73, 1.13), P = 0.37 and TT aOR = 0.86 (0.64, 1.16), P = 0.32. The P-value for the age-genotype interaction was 0.004. For the IL1B +3954 C>T polymorphism, compared with the CC genotype, TT showed significant associations in former smokers and in men but tests of interaction were not significant (P(smoking) = 0.24, P(gender) = 0.17). No interactions were observed for FAS -1377 G>A and BAT3 Ser625Pro polymorphisms. Our findings indicate that age and smoking may modify the association of the FASLG -844 and IL1B + 3954 SNPs with the risk of NSCLC.


Assuntos
Fatores Etários , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Fumar , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Proteína Ligante Fas/genética , Humanos , Interleucina-1beta/genética , Pessoa de Meia-Idade , Receptor fas/genética
18.
Am J Hum Genet ; 79(4): 695-701, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16960805

RESUMO

Waldenstrom macroglobulinemia (WM), a distinctive subtype of non-Hodgkin lymphoma that features overproduction of immunoglobulin M (IgM), clearly has a familial component; however, no susceptibility genes have yet been identified. We performed a genomewide linkage analysis in 11 high-risk families with WM that were informative for linkage, for a total of 122 individuals with DNA samples, including 34 patients with WM and 10 patients with IgM monoclonal gammopathy of undetermined significance (IgM MGUS). We genotyped 1,058 microsatellite markers (average spacing 3.5 cM), performed both nonparametric and parametric linkage analysis, and computed both two-point and multipoint linkage statistics. The strongest evidence of linkage was found on chromosomes 1q and 4q when patients with WM and with IgM MGUS were both considered affected; nonparametric linkage scores were 2.5 (P=.0089) and 3.1 (P=.004), respectively. Other locations suggestive of linkage were found on chromosomes 3 and 6. Results of two-locus linkage analysis were consistent with independent effects. The findings from this first linkage analysis of families at high risk for WM represent important progress toward identifying gene(s) that modulate susceptibility to WM and toward understanding its complex etiology.


Assuntos
Predisposição Genética para Doença , Genoma Humano , Macroglobulinemia de Waldenstrom/genética , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 4 , Família , Feminino , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Modelos Genéticos , Linhagem
19.
J Natl Cancer Inst ; 97(13): 998-1007, 2005 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-15998953

RESUMO

BACKGROUND: Melanoma risk factors include fair pigmentation, multiple nevi, low DNA repair capacity, and CDKN2A or CDK4 mutations. Variants of the melanocortin-1 receptor (MC1R) gene have been associated with fair pigmentation and melanoma risk, and a polymorphism of the Agouti Signaling Protein (ASIP) gene has been associated with dark pigmentation. We examined MC1R and ASIP genotypes in relation to phenotypic characteristics, sporadic and familial melanoma risk, and melanoma thickness as an indicator of disease progression in a Mediterranean population. METHODS: We studied 267 melanoma patients and 382 control subjects from a case-control study and a family study in northeastern Italy. Host factors were assessed by physical examination, questionnaire, spectrophotometer, and minimal erythema dose measurement. MC1R was sequenced, ASIP was genotyped, and DNA repair capacity was measured by the host-cell reactivation assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression models. Effect modification of the association between MC1R and melanoma risk by phenotypic characteristics and DNA repair capacity was also assessed. All statistical tests were two-sided. RESULTS: Carrying MC1R variant alleles was associated with a two- to fourfold increase in risk of both sporadic and familial melanoma compared with carrying wild-type MC1R, particularly in individuals carrying multiple variant alleles (OR = 3.9; 95% CI = 3.3 to 4.6). This association was stronger in individuals with fewer additional risk factors (those with dark skin or few nevi). MC1R variant allele carriers were also three to four times more likely than were non-carriers to have thick melanomas. The ASIP polymorphism was not associated with pigmentation, nevi, or melanoma risk. CONCLUSIONS: MC1R was associated with melanoma risk and progression in a Mediterranean population, particularly in the absence of other strong risk factors, such as freckling or many nevi.


Assuntos
Reparo do DNA , Peptídeos e Proteínas de Sinalização Intercelular/genética , Melanoma/epidemiologia , Melanoma/genética , Receptor Tipo 1 de Melanocortina/genética , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Proteína Agouti Sinalizadora , Estudos de Casos e Controles , Intervalos de Confiança , Inibidor p16 de Quinase Dependente de Ciclina/genética , Progressão da Doença , Feminino , Frequência do Gene , Genótipo , Humanos , Itália/epidemiologia , Masculino , Região do Mediterrâneo/epidemiologia , Melanoma/patologia , Pessoa de Meia-Idade , Nevo/complicações , Razão de Chances , Polimorfismo Genético , Fatores de Risco , Análise de Sequência de DNA , Neoplasias Cutâneas/patologia , Pigmentação da Pele , Raios Ultravioleta
20.
Toxicology ; 207(2): 191-202, 2005 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-15596250

RESUMO

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is highly toxic in experimental animals, and is known to induce cytochrome P450 (CYP) gene expression. We investigated the effect of CYP1A1 and CYP1B1 variant genotypes and haplotypes on CYP1A1 and CYP1B1 mRNA expression and ethoxyresorufin-O-deethylase (EROD) activity in lymphocytes from 121 subjects from the Seveso population, Italy, accidentally exposed to TCDD in 1976. The 3'UTR 3801T>C and I462V variants of CYP1A1 were present in 16% and 6% of the subjects, respectively. The frequency of CYP1B1 variants was 85.2% for L432V, 49.6% for R48G and A119S, and 28.7% for N453S. There was complete linkage disequilibrium (LD) among the CYP1B1 variant loci (D'=-1) and high LD among the CYP1A1 loci (D'=0.86). Gene expression measured by RT-PCR did not vary by CYP1B1 genotype in uncultured lymphocytes. However, when lymphocytes were treated in vitro with 10 nM TCDD, CYP1B1 and CYP1A1 mRNA expression was strongly induced and modified by CYP variant alleles. Specifically, the CYP1B1*3 haplotype (L432V) was associated with increased CYP1B1 mRNA expression (P=0.03), following an additive model; the CYP1A1 I462V polymorphism was positively, although not significantly, associated with CYP1A1 expression. The CYP1B1*3 variant may have affected CYP1B1 expression in subjects highly and acutely exposed to dioxin at the time of the accident. Although based on small number of subjects, a slight increase in eczema (P=0.05, n=8) and urticaria (P=0.02, n=2) was observed 20 years after the accident in subjects carrying the CYP1B1*3 allele. Genetic variation in cytochrome P450 induction may identify subjects with variable responsiveness to TCDD and potentially increased risk of disease.


Assuntos
Hidrocarboneto de Aril Hidroxilases/biossíntese , Citocromo P-450 CYP1A1/biossíntese , Poluentes Ambientais/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Dibenzodioxinas Policloradas/farmacologia , Hidrocarboneto de Aril Hidroxilases/genética , Células Cultivadas , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1 , Poluentes Ambientais/toxicidade , Indução Enzimática/efeitos dos fármacos , Feminino , Genótipo , Haplótipos , Humanos , Itália , Leucócitos Mononucleares/enzimologia , Masculino , Dibenzodioxinas Policloradas/toxicidade , RNA/biossíntese
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