RESUMO
PURPOSE: The leptin-signaling pathway and other genes involved in energy homeostasis (EH) have been examined in relation to breast cancer risk as well as to obesity. We test the hypothesis that genetic variation in EH genes influences survival after diagnosis with breast cancer and that body mass index (BMI) will modify that risk. METHODS: We evaluated associations between 10 EH genes and survival among 1,186 non-Hispanic white and 1,155 Hispanic/Native American women diagnosed with breast cancer. Percent Native American (NA) ancestry was determined from 104 ancestry-informative markers. Adaptive rank truncation product (ARTP) was used to determine gene and pathway significance. RESULTS: The overall EH pathway was marginally significant for all-cause mortality among women with low NA ancestry (P(ARTP) = 0.057). Within the pathway, ghrelin(GHRL) and leptin receptor (LEPR) were significantly associated with all-cause mortality (P(ARTP) = 0.035 and 0.007, respectively). The EH pathway was significantly associated with breast cancer-specific mortality among women with low NA ancestry (P(ARTP) = 0.038). Three genes cholecystokinin (CCK), GHRL, and LEPR were significantly associated with breast cancer-specific mortality among women with low NA ancestry (P(ARTP) = 0.046,0.015, and 0.046, respectively), while neuropeptide Y (NPY) was significantly associated with breast cancer-specific mortality among women with higher NA ancestry(P(ARTP) = 0.038). BMI did not modify these associations. CONCLUSIONS: Our data support our hypothesis that certain EH genes influence survival after diagnosis with breast cancer; associations appear to be most important among women with low NA ancestry.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Metabolismo Energético/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Colecistocinina/genética , Feminino , Genótipo , Hispânico ou Latino/genética , Homeostase/genética , Humanos , Pessoa de Meia-Idade , Neuropeptídeo Y/genética , Receptores de Grelina/genética , Receptores para Leptina/genética , Fatores de Risco , Transdução de Sinais/genética , População Branca/genética , Adulto JovemRESUMO
PURPOSE: There is suggestive but limited evidence for a relationship between meat intake and breast cancer (BC) risk. Few studies included Hispanic women. We investigated the association between meats and fish intake and BC risk among Hispanic and NHW women. METHODS: The study included NHW (1,982 cases and 2,218 controls) and the US Hispanics (1,777 cases and 2,218 controls) from two population-based case-control studies. Analyses considered menopausal status and percent Native American ancestry. We estimated pooled ORs combining harmonized data from both studies, and study- and race-/ethnicity-specific ORs that were combined using fixed or random effects models, depending on heterogeneity levels. RESULTS: When comparing highest versus lowest tertile of intake, among NHW we observed an association between tuna intake and BC risk (pooled OR 1.25; 95 % CI 1.05-1.50; trend p = 0.006). Among Hispanics, we observed an association between BC risk and processed meat intake (pooled OR 1.42; 95% CI 1.18-1.71; trend p < 0.001), and between white meat (OR 0.80; 95% CI 0.67-0.95; trend p = 0.01) and BC risk, driven by poultry. All these findings were supported by meta-analysis using fixed or random effect models and were restricted to estrogen receptor-positive tumors. Processed meats and poultry were not associated with BC risk among NHW women; red meat and fish were not associated with BC risk in either race/ethnic groups. CONCLUSIONS: Our results suggest the presence of ethnic differences in associations between meat and BC risk that may contribute to BC disparities.
Assuntos
Neoplasias da Mama/epidemiologia , Hispânico ou Latino/estatística & dados numéricos , População Branca/estatística & dados numéricos , Adulto , Idoso , Animais , Neoplasias da Mama/etnologia , Estudos de Casos e Controles , Feminino , Peixes , Humanos , Carne , Pessoa de Meia-Idade , Aves Domésticas , Carne Vermelha , Fatores de RiscoRESUMO
Inflammation, hormones and energy-related factors have been associated with colorectal cancer (CRC) and it has been proposed that convergence and interactions of these factors importantly influence CRC risk. We have previously hypothesized that genetic variation in the CHIEF (convergence of hormones, inflammation and energy-related factors) pathway would influence risk of CRC. In this paper, we utilize an Adaptive Rank Truncation Product (ARTP) statistical method to determine the overall pathway significance and then use that method to identify the key elements within the pathway associated with disease risk. Data from two population-based case-control studies of colon (n = 1555 cases and 1956 controls) and rectal (n = 754 cases and 959 controls) cancer were used. We use ARTP to estimate pathway and gene significance and polygenic scores based on ARTP findings to further estimate the risk associated with the pathway. Associations were further assessed based on tumor molecular phenotype. The CHIEF pathway was statistically significant for colon cancer (P(ARTP)= 0.03) with the most significant interferons (P(ARTP) = 0.0253), JAK/STAT/SOCS (P(ARTP) = 0.0111), telomere (P(ARTP) = 0.0399) and transforming growth factor ß (P(ARTP) = 0.0043) being the most significant subpathways for colon cancer. For rectal cancer, interleukins (P(ARTP) = 0.0235) and selenoproteins (P ARTP = 0.0047) were statistically significant although the pathway overall was of borderline significance (P(ARTP) = 0.06). Interleukins (P(ARTP) = 0.0456) and mitogen-activated protein kinase (P(ARTP) = 0.0392) subpathways were uniquely significant for CpG island methylator phenotype-positive colon tumors. Increasing number of at-risk alleles was significantly associated with both colon [odds ratio (OR) = 6.21, 95% confidence interval (CI): 4.72, 8.16] and rectal (OR = 7.82, 95% CI: 5.26, 11.62) cancer. We conclude that elements of the CHIEF pathway are important for CRC risk.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Polimorfismo de Nucleotídeo Único/genética , Transdução de Sinais , Adulto , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Interferons/genética , Janus Quinase 1/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Fatores de Risco , Fator de Transcrição STAT1/genética , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/genética , Telômero/genética , Fator de Crescimento Transformador beta/genética , Estados Unidos/epidemiologiaRESUMO
Mitogen-activated protein kinases (MAPK) are integration points for multiple biochemical signals. We evaluated 13 MAPK genes with breast cancer risk and determined if diet and lifestyle factors mediated risk. Data from 3 population-based case-control studies conducted in Southwestern United States, California, and Mexico included 4183 controls and 3592 cases. Percent Indigenous American (IA) ancestry was determined from 104 ancestry informative markers. The adaptive rank truncated product (ARTP) was used to determine the significance of each gene and the pathway with breast cancer risk, by menopausal status, genetic ancestry level, and estrogen receptor (ER)/progesterone receptor (PR) strata. MAP3K9 was associated with breast cancer overall (P(ARTP) = 0.02) with strongest association among women with the highest IA ancestry (P(ARTP) = 0.04). Several SNPs in MAP3K9 were associated with ER+/PR+ tumors and interacted with dietary oxidative balance score (DOBS), dietary folate, body mass index (BMI), alcohol consumption, cigarette smoking, and a history of diabetes. DUSP4 and MAPK8 interacted with calories to alter breast cancer risk; MAPK1 interacted with DOBS, dietary fiber, folate, and BMI; MAP3K2 interacted with dietary fat; and MAPK14 interacted with dietary folate and BMI. The patterns of association across diet and lifestyle factors with similar biological properties for the same SNPs within genes provide support for associations.
Assuntos
Neoplasias da Mama/genética , Dieta/estatística & dados numéricos , Estilo de Vida , Proteínas Quinases Ativadas por Mitógeno/genética , Adulto , Idoso , Índice de Massa Corporal , Neoplasias da Mama/etnologia , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Gorduras na Dieta/metabolismo , Fibras na Dieta/metabolismo , Fosfatases de Especificidade Dupla/genética , Ingestão de Energia/genética , Feminino , Ácido Fólico/metabolismo , Disparidades nos Níveis de Saúde , Humanos , MAP Quinase Quinase Quinase 2 , MAP Quinase Quinase Quinases/genética , Menopausa/genética , México/epidemiologia , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 14 Ativada por Mitógeno/genética , Proteína Quinase 8 Ativada por Mitógeno/genética , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Polimorfismo de Nucleotídeo Único/genética , Grupos Populacionais/genética , Receptores de Estrogênio/sangue , Receptores de Progesterona/sangue , Sistema de Registros , Fatores de Risco , São Francisco , Sudoeste dos Estados UnidosRESUMO
Angiogenesis is essential for tumor development and progression. Genetic variation in angiogenesis-related genes may influence breast carcinogenesis. We evaluated dietary factors associated with oxidative balance, DDIT4 (one SNP), FLT1 (35 SNPs), HIF1A (four SNPs), KDR (19 SNPs), MPO (one SNP), NOS2A (15 SNPs), TEK (40 SNPs) and VEGFA (eight SNPs) and breast cancer risk among Hispanic (2,111 cases and 2,597 controls) and non-Hispanic white (1,481 cases and 1,586 controls) women in the Breast Cancer Health Disparities Study. Adaptive rank truncated product (ARTP) analysis was used to determine gene and pathway significance with breast cancer. TEK was associated with breast cancer overall (pARTP = 0.03) and with breast cancer survival (pARTP = 0.01). KDR was of borderline significance overall (pARTP = 0.07), although significantly associated with breast cancer in both low and intermediate Native American (NA) ancestry groups (pARTP = 0.02) and estrogen receptor (ER)+/progesterone receptor (PR)- tumor phenotype (pARTP = 0.008). Both VEGFA and NOS2A were associated with ER-/PR- tumor phenotype (pARTP = 0.01 and pARTP = 0.04, respectively). FLT1 was associated with breast cancer survival among those with low NA ancestry (pARTP = 0.009). With respect to diet, having a higher dietary oxidative balance score (DOBS) was significantly associated with lower breast cancer risk [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.64-0.84], with the strongest associations observed for women with the highest NA ancestry (OR 0.44, 95% CI 0.30-0.65). We observed few interactions between DOBS and angiogenesis-related genes. Our data suggest that dietary factors and genetic variation in angiogenesis-related genes contribute to breast cancer carcinogenesis.
Assuntos
Neoplasias da Mama/epidemiologia , Dieta , Neovascularização Patológica/genética , Estresse Oxidativo , Adulto , Idoso , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/genética , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/genética , Peroxidase/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in immune function and cell growth; genetic variation in this pathway could influence breast cancer risk. We examined 12 genes in the JAK/STAT/SOCS signaling pathway with breast cancer risk and mortality in an admixed population of Hispanic (2,111 cases, 2,597 controls) and non-Hispanic white (1,481 cases, 1,585 controls) women. Associations were assessed by Indigenous American (IA) ancestry. After adjustment for multiple comparisons, JAK1 (three of ten SNPs) and JAK2 (4 of 11 SNPs) interacted with body mass index (BMI) among pre-menopausal women, while STAT3 (four of five SNPs) interacted significantly with BMI among post-menopausal women to alter breast cancer risk. STAT6 rs3024979 and TYK2 rs280519 altered breast cancer-specific mortality among all women. Associations with breast cancer-specific mortality differed by IA ancestry; SOCS1 rs193779, STAT3 rs1026916, and STAT4 rs11685878 associations were limited to women with low IA ancestry, and associations with JAK1 rs2780890, rs2254002, and rs310245 and STAT1 rs11887698 were observed among women with high IA ancestry. JAK2 (5 of 11 SNPs), SOCS2 (one of three SNPs), and STAT4 (2 of 20 SNPs) interacted with cigarette smoking status to alter breast cancer-specific mortality. SOCS2 (one of three SNPs) and all STAT3, STAT5A, and STAT5B SNPs significantly interacted with use of aspirin/NSAIDs to alter breast cancer-specific mortality. Genetic variation in the JAK/STAT/SOCS pathway was associated with breast cancer-specific mortality. The proportion of SNPs within a gene that significantly interacted with lifestyle factors lends support for the observed associations.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Biomarcadores Tumorais/genética , Neoplasias da Mama/mortalidade , Disparidades em Assistência à Saúde , Polimorfismo de Nucleotídeo Único/genética , Fumar/efeitos adversos , Adulto , Idoso , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Estudos de Casos e Controles , Interações Medicamentosas , Feminino , Seguimentos , Predisposição Genética para Doença , Hispânico ou Latino , Humanos , Janus Quinase 1/genética , Janus Quinase 2/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Fator de Transcrição STAT1/genética , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/genética , Taxa de Sobrevida , População BrancaRESUMO
Angiogenesis is essential for tumor progression. Vascular endothelial growth factor (VEGFA) and its receptors 1 (FLT1) and 2 (KDR), have been identified as major mediators of this process. We hypothesized that genetic variation in FLT1 (38 SNPs), KDR (22 SNPS), and VEGFA (11 SNPs) would be associated with colon and rectal cancer development and survival. Data from a case-control study of 1555 colon cancer cases and 1956 controls and 754 rectal cancer cases and 959 controls were used. An adaptive rank truncation product (ARTP), based on 10,000 permutations, was used to determine the statistical significance of the candidate genes and angiogenesis pathway. Based on ARTP results, FLT1 was significantly associated with risk of colon cancer (P(ARTP) = 0.045) and VEGFA was significantly associated with rectal cancer (P(ARTP) = 0.036). After stratifying by tumor molecular subtype, SNP associations observed for colon cancer were: VEGFA rs2010963 with CIMP+ colon tumors; FLT1 rs4771249 and rs7987649 with TP53; FLT1 rs3751397, rs7337610, rs7987649, and rs9513008 and KDR rs10020464, rs11941492, and rs12498529 with MSI+ and CIMP+/KRAS2-mutated tumors. FLT1 rs2296189 and rs600640 were associated with CIMP+ rectal tumors and FLT1 rs7983774 was associated with TP53-mutated rectal tumors. Four SNPs in FLT1 were associated with colon cancer survival while three SNPs in KDR were associated with survival after diagnosis with rectal cancer. Aspirin/NSAID use, smoking cigarettes, and BMI modified the associations. These findings suggest the importance of inflammation and angiogenesis in the etiology of colorectal cancer and that genetic and lifestyle factors may be targets for modulating disease risk.
Assuntos
Neoplasias Colorretais/etiologia , Polimorfismo de Nucleotídeo Único/genética , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Inflamação/complicações , Inflamação/genética , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neovascularização Patológica , Fenótipo , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Utah/epidemiologiaRESUMO
The TGF-ß signaling pathway regulates cellular proliferation and differentiation. We evaluated genetic variation in this pathway, its association with breast cancer survival, and survival differences by genetic ancestry and self-reported ethnicity. The Breast Cancer Health Disparities Study includes participants from the 4-Corners Breast Cancer Study (n = 1,391 cases) and the San Francisco Bay Area Breast Cancer Study (n = 946 cases) who have been followed for survival. We evaluated 28 genes in the TGF-ß signaling pathway using a tagSNP approach. Adaptive rank truncated product (ARTP) was used to test the gene and pathway significance by Native American (NA) ancestry and by self-reported ethnicity (non-Hispanic white (NHW) and Hispanic/NA). Genetic variation in the TGF-ß signaling pathway was associated with overall breast cancer survival (P ARTP = 0.05), especially for women with low NA ancestry (P ARTP = 0.007) and NHW women (P ARTP = 0.006). BMP2, BMP4, RUNX1, and TGFBR3 were significantly associated with breast cancer survival overall (P ARTP = 0.04, 0.02, 0.002, and 0.04, respectively). Among women with low NA, ancestry associations were as follows: BMP4 (P ARTP = 0.007), BMP6 (P ARTP = 0.001), GDF10 (P ARTP = 0.05), RUNX1 (P ARTP = 0.002), SMAD1 (P ARTP = 0.05), and TGFBR2 (P ARTP = 0.02). A polygenic risk model showed that women with low NA ancestry and high numbers of at-risk alleles had twice the risk of dying from breast cancer as did women with high NA ancestry. Our data suggest that genetic variation in the TGF-ß signaling pathway influences breast cancer survival. Associations were similar when the analyses were stratified by genetic ancestry or by self-reported ethnicity.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Fator de Crescimento Transformador beta/genética , Adulto , Idoso , Estudos de Casos e Controles , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Feminino , Predisposição Genética para Doença , Disparidades em Assistência à Saúde , Hispânico ou Latino/genética , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , São Francisco/epidemiologia , Transdução de Sinais/genética , Análise de Sobrevida , Fator de Crescimento Transformador beta/metabolismo , População Branca/genéticaRESUMO
INTRODUCTION: MAPK genes are activated by a variety of factors related to growth factors, hormones, and environmental stress. METHODS: We evaluated associations between 13 MAPK genes and survival among 1,187 nonHispanic White and 1,155 Hispanic/Native American (NA) women diagnosed with breast cancer. We assessed the influence of diet, lifestyle, and genetic ancestry on these associations. Percent NA ancestry was determined from 104 Ancestry Informative Markers. Adaptive rank truncation product (ARTP) was used to determine gene and pathway significance. RESULTS: Associations were predominantly observed among women with lower NA ancestry. Specifically, the mitogen-activated protein kinases (MAPK) pathway was associated with all-cause mortality (P ARTP = 0.02), but not with breast cancer-specific mortality (P ARTP = 0.10). However, MAP2K1 and MAP3K9 were associated with both breast cancer-specific and all-cause mortality. MAPK12 (P ARTP = 0.05) was only associated with breast cancer-specific mortality, and MAP3K1 (P ARTP = 0.02) and MAPK1 (P ARTP = 0.05) were only associated with all-cause mortality. Among women with higher NA ancestry, MAP3K2 was significantly associated with all-cause mortality (P ARTP = 0.04). Several diet and lifestyle factors, including alcohol consumption, caloric intake, dietary folate, and cigarette smoking, significantly modified the associations with MAPK genes and all-cause mortality. CONCLUSIONS: Our study supports an association between MAPK genes and survival after diagnosis with breast cancer, especially among women with low NA ancestry. The interaction between genetic variation in the MAPK pathway with diet and lifestyle factors for all women supports the important role of these factors for breast cancer survivorship.
Assuntos
Neoplasias da Mama/mortalidade , Dieta , Predisposição Genética para Doença/genética , Disparidades nos Níveis de Saúde , Estilo de Vida , Proteínas Quinases Ativadas por Mitógeno/genética , Adulto , Idoso , Neoplasias da Mama/etiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , Etnicidade/genética , Feminino , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sobrevida , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Telomeres are involved in maintaining genomic stability. Previous studies have linked both telomere length (TL) and telomere-related genes with cancer. We evaluated associations between telomere-related genes, TL, and breast cancer risk in an admixed population of US non-Hispanic white (1,481 cases, 1,586 controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based on their genetic ancestry. TL-related genes assessed were MEN1, MRE11A, RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2. Longer TL was associated with increased breast cancer risk [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women with high Indigenous American ancestry. Several TL-related single nucleotide polymorphisms had modest association with breast cancer risk overall, including TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95); TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24); TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93); TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24); TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several differences in association were detected by hormone receptor status of tumors. Most notable were associations with TERT rs2736118 (ORadj 6.18, 95% CI 2.90, 13.19) with estrogen receptor negative/progesterone receptor positive (ER-/PR+) tumors and TERT rs2735940 (ORadj 0.73, 95% CI 0.59, 0.91) with ER-/PR- tumors. These data provide support for an association between TL and TL-related genes and risk of breast cancer. The association may be modified by hormone receptor status and genetic ancestry.
Assuntos
Neoplasias da Mama/genética , Estudos de Associação Genética , Telomerase/genética , Homeostase do Telômero/genética , Telômero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Instabilidade Genômica , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Fatores de RiscoRESUMO
Interleukins are a group of cytokines that contribute to growth and differentiation, cell migration, and inflammatory and anti-inflammatory responses by the immune system. In our study, we examined genetic variation in genes from various anti-inflammatory and proinflammatory interleukins to determine association with colon and rectal cancer risk and overall survival. Data from two population-based incident studies of colon cancer (1,555 cases and 1,956 controls) and rectal cancer (754 cases and 954 controls) were used. After controlling for multiple comparisons, single nucleotide polymorphisms (SNPs) from four genes, IL3, IL6R, IL8, IL15, were associated with increased colon cancer risk, and CXCR1 and CXCR2 were significantly associated with increased rectal cancer risk. Only SNPs from genes within the IL-8 pathway (IL8, CXCR1 and CXCR2) showed a significant association with both colon and rectal cancer risk. Several SNPs interacted significantly with IL8 and IFNG SNPs and with aspirin/non-steroidal anti-inflammatory drug (NSAID), cigarette smoking, estrogen use and BMI. For both colon and rectal cancer, increasing numbers of risk alleles were associated with increased hazard of death from cancer; the estimated hazard of death for colon cancer for the highest category of risk alleles was 1.74 (95% confidence interval [CI] 1.18-2.56) and 1.96 (95% CI 1.28-2.99) for rectal cancer. These data suggest that interleukin genes play a role in risk and overall survival for colon and rectal cancer.
Assuntos
Neoplasias do Colo/genética , Neoplasias do Colo/mortalidade , Interleucinas/genética , Neoplasias Retais/genética , Neoplasias Retais/mortalidade , Adulto , Idoso , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Biomarcadores Tumorais/genética , Índice de Massa Corporal , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Interferon gama/genética , Interleucina-15/genética , Interleucina-3/genética , Interleucina-8/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-6/genética , Receptores de Interleucina-8A/genética , Receptores de Interleucina-8B/genética , Risco , Fatores de Risco , Transdução de Sinais/genética , FumarRESUMO
Growth factors (GF) stimulate cell proliferation through binding to cell membrane receptors and are thought to be involved in cancer risk and survival. We examined how genetic variation in epidermal growth factor (EGF), neuregulin 2 (NRG2), ERBB2 (HER2/neu), fibroblast growth factors 1 and 2 (FGF1 and FGF2) and its receptor 2 (FGFR2), and platelet-derived growth factor B (PDGFB) independently and collectively influence breast cancer risk and survival. We analyzed data from the Breast Cancer Health Disparities Study which includes Hispanic (2,111 cases, 2,597 controls) and non-Hispanic white (1,481 cases, 1,586 controls) women. Adaptive rank-truncated product (ARTP) analysis was conducted to determine gene significance. Odds ratios (OR) and 95 % confidence intervals were obtained from conditional logistic regression models to estimate breast cancer risk and Cox proportional hazard models were used to estimate hazard ratios (HR) of dying from breast cancer. We assessed Native American (NA) ancestry using 104 ancestry informative markers. We observed few significant associations with breast cancer risk overall or by menopausal status other than for FGFR2 rs2981582. This SNP was significantly associated with ER+/PR+ (OR 1.66, 95 % CI 1.37-2.00) and ER+/PR- (OR 1.54, 95 % CI 1.03-2.31) tumors. Multiple SNPs in FGF1, FGF2, and NRG2 significantly interacted with multiple SNPs in EGFR, ERBB2, FGFR2, and PDGFB, suggesting that breast cancer risk is dependent on the collective effects of genetic variants in other GFs. Both FGF1 and ERBB2 significantly influenced overall survival, especially among women with low levels of NA ancestry (P ARTP = 0.007 and 0.003, respectively). Our findings suggest that genetic variants in growth factors signaling appear to influence breast cancer risk through their combined effects. Genetic variation in ERBB2 and FGF1 appear to be associated with survival after diagnosis with breast cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Peptídeos e Proteínas de Sinalização Intercelular/genética , Adulto , Idoso , Estudos de Casos e Controles , Fator de Crescimento Epidérmico/genética , Feminino , Fator 1 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/genética , Genes erbB-2 , Genes sis , Hispânico ou Latino/genética , Humanos , Indígenas Norte-Americanos/genética , Pessoa de Meia-Idade , Fatores de Crescimento Neural/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , População Branca/genéticaRESUMO
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in immune function and cell growth. We evaluated the association between genetic variation in JAK1 (10 SNPs), JAK2 (9 SNPs), TYK2 (5 SNPs), suppressors of cytokine signaling (SOCS)1 (2 SNPs), SOCS2 (2 SNPs), STAT1 (16 SNPs), STAT2 (2 SNPs), STAT3 (6 SNPs), STAT4 (21 SNPs), STAT5A (2 SNPs), STAT5B (3 SNPs), STAT6 (4 SNPs) with risk of colorectal cancer. We used data from population-based case-control studies (colon cancer n = 1555 cases, 1,956 controls; rectal cancer n = 754 cases, 959 controls). JAK2, SOCS2, STAT1, STAT3, STAT5A, STAT5B, and STAT6 were associated with colon cancer; STAT3, STAT4, STAT6, and TYK2 were associated with rectal cancer. Given the biological role of the JAK/STAT-signaling pathway and cytokines, we evaluated interaction with IFNG, TNF, and IL6; numerous statistically significant associations after adjustment for multiple comparisons were observed. The following statistically significant interactions were observed: TYK2 with aspirin/NSAID use; STAT1, STAT4, and TYK2 with estrogen status; and JAK2, STAT2, STAT4, STAT5A, STAT5B, and STAT6 with smoking status and colon cancer risk; JAK2, STAT6, and TYK2 with aspirin/NSAID use; JAK1 with estrogen status; STAT2 with cigarette smoking and rectal cancer. JAK2, SOCS1, STAT3, STAT5, and TYK2 were associated with colon cancer survival (hazard rate ratio (HRR) of 3.3 95% CI 2.01,5.42 for high mutational load). JAK2, SOCS1, STAT1, STAT4, and TYK2 were associated with rectal cancer survival (HRR 2.80 95% CI 1.63,4.80). These data support the importance of the JAK/STAT-signaling pathway in colorectal cancer and suggest targets for intervention.
Assuntos
Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Janus Quinases/metabolismo , Neoplasias Retais/genética , Neoplasias Retais/metabolismo , Fatores de Transcrição STAT/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Adulto , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Estudos de Casos e Controles , Neoplasias do Colo/mortalidade , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Janus Quinases/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de Estrogênio/metabolismo , Neoplasias Retais/mortalidade , Fatores de Transcrição STAT/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT4/metabolismo , Transdução de Sinais , Fumar/efeitos adversos , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/genética , Taxa de Sobrevida , TYK2 Quinase/genética , TYK2 Quinase/metabolismoRESUMO
Telomerase reverse transcriptase (TERT) is one of the main functional subunits of the telomerase enzyme, which functions to increase telomere length. Studies have suggested that TERT may be important to the etiology of colorectal cancer. In this study we evaluate seven TERT SNPs in 1555 incident colon cancer cases and 1956 matched controls and in 754 incident rectal cancer cases and 959 matched controls. We observed that two TERT SNPs were associated with colon cancer. TERT rs2736118 was associated with increased risk of colon cancer (OR = 1.31, 95% CI 1.02, 1.69) and TERT-CLPTM1L rs2853668 was inversely associated with colon cancer (OR = 0.71, 95% CI 0.55, 0.92). TERT-CLPTM1L rs2853668 also was inversely associated with rectal cancer (OR 0.62, 95% CI 0.43, 0.90). BMI interacted significantly with three TERT SNPs to alter risk of colon cancer. Those with the variant allele and who were obese had the greatest risk of colon cancer. TERT-CLPTM1L rs2853668 interacted significantly with aspirin/NSAID use, where those with the AA genotype had a much lower risk of colon cancer when using aspirin/NSAIDs than those with the other genotypes. Several TERT SNPs were uniquely associated with CIMP+ and MSI tumors. These data confirm earlier reports of the association between TERT-CLPTM1L and colon and rectal cancer. Our detection of a significant interaction with BMI for multiple TERT SNPs and unique associations with CIMP+ tumors enhance our understanding of TERT's role in colon carcinogenesis.
Assuntos
Transformação Celular Neoplásica/genética , Neoplasias do Colo/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Retais/genética , Telomerase/genética , Adulto , Idoso , Estudos de Casos e Controles , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/patologia , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Prognóstico , Neoplasias Retais/epidemiologia , Neoplasias Retais/patologia , Fatores de Risco , Telômero/genética , Utah/epidemiologiaRESUMO
Mitogen-activated protein kinase (MAPK) pathways regulate cellular functions including cell proliferation, differentiation, migration, and apoptosis. Associations between genes in the DUSP, ERK1/2, JNK, and p38 MAPK-signaling pathways and dietary factors associated with growth factors, inflammation, and oxidative stress and risk of colon and rectal cancer were evaluated. Data include colon cases (n = 1555) and controls (n = 1956) and rectal cases (n = 754) and controls (n = 959). Statistically significant interactions were observed for the MAPK-signaling pathways after adjustment for multiple comparisons. DUSP genes interacted with carbohydrates, mutagen index, calories, calcium, vitamin D, lycopene, dietary fats, folic acid, and selenium. MAPK1, MAPK3, MAPK1, and RAF1 within the ERK1/2 MAPK-signaling pathway interacted with dietary fats and cruciferous vegetables. Within the JNK MAPK-signaling pathway, interactions between MAP3K7 and protein, vitamin C, iron, folic acid, carbohydrates, and cruciferous vegetables; MAP3K10 and folic acid; MAP3K9 and lutein/zeaxanthin; MAPK8 and calcium; MAP3K3 and calcium and lutein; MAP3K1 and cruciferous vegetables. Interaction within the p38-signaling pathway included MAPK14 with calories, carbohydrates saturated fat, selenium, vitamin C; MAP3K2 and carbohydrates, and folic acid. These data suggest that dietary factors involved in inflammation and oxidative stress interact with MAPK-signaling genes to alter risk of colorectal cancer.
Assuntos
Neoplasias do Colo/genética , Dieta , Sistema de Sinalização das MAP Quinases , Neoplasias Retais/genética , Adulto , Idoso , Cálcio da Dieta/administração & dosagem , Carotenoides/administração & dosagem , Estudos de Casos e Controles , Neoplasias do Colo/prevenção & controle , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Ingestão de Energia , Feminino , Ácido Fólico/administração & dosagem , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Modelos Logísticos , Licopeno , Masculino , Pessoa de Meia-Idade , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Neoplasias Retais/prevenção & controle , Fatores de Risco , Selênio/administração & dosagem , Verduras/química , Vitamina D/administração & dosagem , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
Mitogen-activated protein kinase (MAPK) pathways regulate many cellular functions including cell proliferation, differentiation, migration and apoptosis. We evaluate genetic variation in the c-Jun-N-terminal kinases, p38, and extracellular regulated kinases 1/2 MAPK-signaling pathways and colon and rectal cancer risk using data from population-based case-control studies (colon: n = 1555 cases, 1956 controls; rectal: n = 754 cases, 959 controls). We assess 19 genes (DUSP1, DUSP2, DUSP4, DUSP6, DUSP7, MAP2K1, MAP3K1, MAP3K2, MAP3K3, MAP3K7, MAP3K9, MAP3K10, MAP3K11, MAPK1, MAPK3, MAPK8, MAPK12, MAPK14 and RAF1). MAP2K1 rs8039880 [odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.38, 0.83; GG versus AA genotype] and MAP3K9 rs11625206 (OR = 1.41, 95% CI = 1.14, 1.76; recessive model) were associated with colon cancer (P (adj) value < 0.05). DUSP1 rs322351 (OR = 1.43, 95% CI = 1.09, 1.88; TT versus CC) and MAPK8 rs10857561 (OR = 1.48, 95% CI 1.08, 2.03; AA versus GG/GA) were associated with rectal cancer (P (adj) < 0.05). Aspirin/non-steroidal anti-inflammatory drug, cigarette smoking and body mass index interacted with several genes to alter cancer risk. Genetic variants had unique associations with KRAS, TP53 and CIMP+ tumors. DUSP2 rs1724120 [hazard rate ratio (HRR) = 0.72, 95%CI = 0.54, 0.96; AA versus GG/GA), MAP3K10 rs112956 (HRR = 1.40, 95% CI = 1.10, 1.76; CT/TT versus CC) and MAP3K11 (HRR = 1.76, 95% CI 1.18, 2.62 TT versus GG/GT) influenced survival after diagnosis with colon cancer; MAP2K1 rs8039880 (HRR = 2.53, 95% CI 1.34, 4.79 GG versus AG/GG) and Raf1 rs11923427 (HRR = 0.59 95% CI = 0.40, 0.86; AA versus TT/TA) were associated with rectal cancer survival. These data suggest that genetic variation in the MAPK-signaling pathway influences colorectal cancer risk and survival after diagnosis. Associations may be modified by lifestyle factors that influence inflammation and oxidative stress.
Assuntos
Neoplasias do Colo/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Neoplasias Retais/genética , Adulto , Idoso , Anti-Inflamatórios não Esteroides/farmacologia , Estudos de Casos e Controles , Neoplasias do Colo/etiologia , Neoplasias do Colo/mortalidade , Feminino , Variação Genética , Genótipo , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Neoplasias Retais/etiologia , Neoplasias Retais/mortalidade , Fumar/efeitos adversosRESUMO
Breast cancer incidence rates are characterized by unique racial and ethnic differences. Native American ancestry has been associated with reduced breast cancer risk. We explore the biological basis of disparities in breast cancer risk in Hispanic and non-Hispanic white women by evaluating genetic variation in genes involved in inflammation, insulin and energy homeostasis in conjunction with genetic ancestry. Hispanic (2111 cases, 2597 controls) and non-Hispanic white (1481 cases, 1586 controls) women enrolled in the 4-Corner's Breast Cancer Study, the Mexico Breast Cancer Study and the San Francisco Bay Area Breast Cancer Study were included. Genetic admixture was determined from 104 ancestral informative markers that discriminate between European and Native American ancestry. Twenty-one genes in the CHIEF candidate pathway were evaluated. Higher Native American ancestry was associated with reduced risk of breast cancer (odds ratio = 0.79, 95% confidence interval 0.65, 0.95) but was limited to postmenopausal women (odds ratio = 0.66, 95% confidence interval 0.52, 0.85). After adjusting for genetic ancestry and multiple comparisons, four genes were significantly associated with breast cancer risk, NFκB1, NFκB1A, PTEN and STK11. Within admixture strata, breast cancer risk among women with low Native American ancestry was associated with IkBKB, NFκB1, PTEN and RPS6KA2, whereas among women with high Native American ancestry, breast cancer risk was associated with IkBKB, mTOR, PDK2, PRKAA1, RPS6KA2 and TSC1. Higher Native American ancestry was associated with reduced breast cancer risk. Breast cancer risk differed by genetic ancestry along with genetic variation in genes involved in inflammation, insulin, and energy homeostasis.
Assuntos
Neoplasias da Mama/genética , Metabolismo Energético/genética , Variação Genética , Hormônios/genética , Inflamação/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-IdadeRESUMO
Bone morphogenetic proteins (BMP) are part of the TGF-ß-signaling pathway; genetic variation in these genes may be involved in colorectal cancer. In this study, we evaluated the association between genetic variation in BMP1 (11 tagSNPs), BMP2 (5 tagSNPs), BMP4 (3 tagSNPs), BMPR1A (9 tagSNPs), BMPR1B (21 tagSNPs), BMPR2 (11 tagSNPs) and GDF10 (7 tagSNPs) with risk of colon and rectal cancer and tumor molecular phenotype. We used data from population-based case-control studies (colon cancer n = 1,574 cases, 1,970 controls; rectal cancer n = 791 cases, 999 controls). We observed that genetic variation in BMPR1A, BMPR1B, BMPR2, BMP2 and BMP4 was associated with risk of developing colon cancer, with 20 to 30% increased risk for most high-risk genotypes. A summary of high-risk genotypes showed over a twofold increase in colon cancer risk at the upper risk category (OR = 2.49 95% CI = 1.95, 3.18). BMPR2, BMPR1B, BMP2 and GDF10 were associated with rectal cancer. BMPR2 rs2228545 was associated with an almost twofold increased risk of rectal cancer. The risk associated with the highest category of the summary score for rectal cancer was 2.97 (95% CI = 1.87, 4.72). Genes in the BMP-signaling pathway were consistently associated with CIMP+ status in combination with both KRAS-mutated and MSI tumors. BMP genes interacted statistically significantly with other genes in the TGF-ß-signaling pathway, including TGFß1, TGFßR1, Smad 3, Smad 4 and Smad 7. Our data support a role for genetic variation in BMP-related genes in the etiology of colon and rectal cancer. One possible mechanism is via the TGF-ß-signaling pathway.
Assuntos
Proteínas Morfogenéticas Ósseas/genética , Neoplasias do Colo/genética , Variação Genética , Neoplasias Retais/genética , Adulto , Idoso , Estudos de Casos e Controles , Neoplasias do Colo/epidemiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Neoplasias Retais/epidemiologia , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismoRESUMO
BACKGROUND: The transforming growth factor-ß-signaling pathway has been identified as being involved in colorectal cancer. OBJECTIVE: The aim of this study was to determine how diet and lifestyle factors in combination with genetic variation in the transforming growth factor-ß-signaling pathway alters colorectal cancer risk. DESIGN: We used data from 2 population-based case-control studies. PATIENTS: Participants included patients with colon cancer (n = 1574) and controls (n = 1970) and patients with rectal cancer ( n = 791) and controls (n = 999). MAIN OUTCOME MEASURES: The primary outcomes measured were newly diagnosed cases of colon or rectal cancer. RESULTS: Colon and rectal cancer risk increased with the number of at-risk genotypes within the transforming growth factor-ß-signaling pathway (OR 3.68, 95% CI 2.74,4.94 for colon cancer; OR 3.89, 95% CI 2.66,5.69 for rectal cancer). A high at-risk lifestyle score also resulted in significant increased risk with number of at-risk lifestyle factors (OR 2.99, 95% CI 2.32,3.85 for colon cancer; OR 3.37, 95% CI 2.24,5.07 for rectal cancer). The combination of high-risk genotype and high-risk lifestyle results in the greatest increase in risk (OR 7.89, 95% CI 4.45,13.96 for colon cancer; OR 8.75, 95% CI 3.66,20.89 for rectal cancer). LIMITATIONS: The study results need validation in other large studies of colon and rectal cancer. CONCLUSIONS: In summary, our data suggest that there is increased colon and rectal cancer risk with increasing number of at-risk genotypes and at-risk lifestyle factors. Although the integrity of the pathway can be diminished by a number of high-risk genotypes, this risk can be offset, in part, by maintaining a healthy lifestyle.
Assuntos
Neoplasias do Colo/genética , DNA de Neoplasias/genética , Variação Genética , Estilo de Vida , Neoplasias Retais/genética , Fator de Crescimento Transformador alfa/genética , Adulto , Idoso , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/metabolismo , Feminino , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Neoplasias Retais/epidemiologia , Neoplasias Retais/metabolismo , Estudos Retrospectivos , Transdução de Sinais , Fator de Crescimento Transformador alfa/metabolismo , Estados Unidos/epidemiologiaRESUMO
Pro-oxidant and anti-oxidant genetic and lifestyle factors can contribute to an individual's level of oxidative stress. We hypothesize that diet, lifestyle and genetic factors work together to influence colon and rectal cancer through an oxidative balance mechanism. We evaluated nine markers for eosinophil peroxidase (EPX), two for myeloperoxidase (MPO), four for hypoxia-inducible factor-1A (HIFIA), and 16 for inducible nitric oxide synthase (NOS2A) in conjunction with dietary antioxidants, aspirin/NSAID use, and cigarette smoking. We used data from population-based case-control studies (colon cancer n=1555 cases, 1956 controls; rectal cancer n=754 cases, 959 controls). Only NOS2A rs2297518 was associated with colon cancer (OR 0.86 95% CI 0.74, 0.99) and EPX rs2302313 and MPO rs2243828 were associated with rectal cancer (OR 0.75 95% CI 0.59, 0.96; OR 0.81 95% CI 0.67, 0.99 respectively) for main effects. However, after adjustment for multiple comparisons we observed the following significant interactions for colon cancer: NOS2A and lutein, EPX and aspirin/NSAID use, and NOS2A (4 SNPs) and cigarette smoking. For rectal cancer we observed the following interactions after adjustment for multiple comparisons: HIF1A and vitamin E, NOS2A (3SNPs) with calcium; MPO with lutein; HIF1A with lycopene; NOS2A with selenium; EPX and NOS2A with aspirin/NSAID use; HIF1A, MPO, and NOS2A (3 SNPs) with cigarette smoking. We observed significant interaction between a composite oxidative balance score and a polygenic model for both colon (p interaction 0.0008) and rectal cancer (p=0.0018). These results suggest the need to comprehensively evaluate interactions to assess the contribution of risk from both environmental and genetic factors.