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1.
Artigo em Inglês | MEDLINE | ID: mdl-33716034

RESUMO

CONTEXT: Insomnia is a common problem affecting cancer survivors. While effective nonpharmacological treatments are available, it is unknown whether individual genetic characteristics influence treatment response. OBJECTIVES: We conducted an exploratory analysis of genetic associations with insomnia treatment response in a randomized trial of cognitive behavioral therapy for insomnia (CBT-I) vs. acupuncture in a heterogeneous group of cancer survivors. METHODS: We successfully genotyped 136 participants for 11 genetic variants. Successful treatment response was defined as a reduction in Insomnia Severity Index score of at least eight points from baseline to week 8. We used Fisher exact tests to evaluate associations between genotype and treatment success for each treatment arm, for an alpha level of 0.05 with unadjusted and Holm-Bonferroni-adjusted P-values. RESULTS: We found that more carriers of COMT rs4680-A alleles responded to acupuncture compared to the GG carriers (63.6% vs. 27.8%, P = 0.013). More carriers of the NFKB2 rs1056890 CC genotype also responded to acupuncture compared to TT or CT carriers (72.2% vs. 38.9%, P = 0.009). There were no significant differences found between any of the tested gene variants and CBT-I response. None of the results remained statistically significant after adjustment for multiple testing. CONCLUSION: In cancer survivors, specific variants in the COMT and NFKB2 genes are potentially associated with response to acupuncture but not to CBT-I. Confirming these preliminary results will help inform precision insomnia management for cancer survivors.

2.
Acupunct Med ; : 964528421999395, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33752446

RESUMO

INTRODUCTION: Decreased brain-derived neurotrophic factor (BDNF) is associated with poor sleep. This study examined the effects of acupuncture versus cognitive behavioral therapy for insomnia (CBT-I) on serum BDNF and sleep outcomes in cancer survivors with insomnia. METHODS: This was an exploratory analysis of a randomized clinical trial (n = 160) comparing acupuncture versus CBT-I for cancer survivors with insomnia. Interventions were delivered over 8 weeks. Outcomes were assessed at baseline and week 8. Serum BDNF was evaluated with enzyme-linked immunosorbent assay (ELISA). Sleep was evaluated with the insomnia severity index and consensus sleep diary. Pearson correlations between BDNF and sleep outcomes were calculated. Data analysis was limited to 87 survivors who provided serum samples. RESULTS: Among 87 survivors, the mean age was 61.9 (SD: 11.4) years, 51.7% were women, and 24.1% were non-White. Mean serum BDNF did not significantly increase in acupuncture (n = 50) or CBT-I (n = 37) groups. When analysis was restricted to patients with low baseline BDNF (i.e. levels below the sample median of 47.1 ng/mL), the acupuncture group (n = 22) demonstrated a significant 7.2 ng/mL increase in mean serum BDNF (P = 0.03), whereas the CBT-I group (n = 21) demonstrated a non-significant 2.9 ng/mL increase (P = 0.28). Serum BDNF was not significantly correlated with sleep outcomes (all P > 0.05). CONCLUSION: Among cancer survivors with insomnia and low baseline BDNF, acupuncture significantly increased serum BDNF levels; however, the clinical significance of this finding requires further investigation.Trial registration no. NCT02356575 (ClinicalTrials.gov).

3.
J Urol ; : 101097JU0000000000001571, 2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33356484

RESUMO

PURPOSE: Cigarette smoking is a risk factor for developing nonmuscle invasive bladder cancer, and continued smoking exposure after diagnosis may increase the likelihood of adverse clinical outcomes. We compare self-reported vs biochemically verified nicotine exposure to determine the accuracy of self-report among recently diagnosed nonmuscle invasive bladder cancer patients. MATERIALS AND METHODS: This cross-sectional analysis consisted of 517 nonmuscle invasive bladder cancer patients who contributed a urine or saliva specimen the same day as self-reporting their smoking, use of e-cigarettes, nicotine replacement therapy and whether they lived with a smoker. Cotinine, the primary metabolite of nicotine, was used as an objective biomarker of recent nicotine exposure. RESULTS: The prevalence of high, low and no cotinine exposure was 13%, 54% and 33%, respectively. Overall, 7.3% of patients (38/517) reported being a current cigarette smoker, while 13% (65/517) had cotinine levels consistent with active smoking exposure. Of these 65 patients 27 denied current smoking, resulting in a sensitivity of self-reported current smoking of 58%. After considering other sources of nicotine exposure such as e-cigarettes, cigars, nicotine replacement therapy and living with a smoker, the sensitivity was higher, at 82%. Nearly all patients with low cotinine denied any smoking-related exposure. CONCLUSIONS: Our findings suggest either biochemical verification with cotinine or additional questions about other sources of nicotine are needed to accurately identify nonmuscle invasive bladder cancer patients who have smoking-related exposures. Accurate classification of active and passive smoking exposure is essential to allow clinicians to advise cessation and help researchers estimate the association between post-diagnosis smoking-related exposure and nonmuscle invasive bladder cancer recurrence risk.

4.
Hum Mutat ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33169439

RESUMO

PALB2 has been identified as a breast and pancreatic cancer susceptibility gene. Utilizing a targeted sequencing approach, we discovered two novel germline missense PALB2 variants c.191C>T and c.311C>T, encoding p.Ser64Leu and p.Pro104Leu, respectively, in individuals in a pancreatic cancer registry. No missense PALB2 variants from familial pancreatic cancer patients, and few PALB2 variants overall, have been functionally characterized. Given the known role of PALB2, we tested the impact of p.Ser64Leu and p.Pro104Leu variants on DNA damage responses. Neither p.Ser64Leu nor p.Pro104Leu had clear effects on interactions with BRCA1 and KEAP1, which are mediated by adjacent motifs in PALB2. However, both variants are associated with defective recruitment of PALB2, and the RAD51 recombinase downstream, to DNA damage foci. Further, p.Ser64Leu and p.Pro104Leu both largely compromise DNA double-strand break-initiated homologous recombination, and confer increased cellular sensitivity to ionizing radiation (IR) and the poly (ADP-ribose) polymerase (PARP) inhibitor Olaparib. Taken together, our results represent the first demonstration of functionally deleterious PALB2 missense variants associated with familial pancreatic cancer and of deleterious variants in the N-terminus outside of the coiled-coil domain. Further, our results suggest the possibility of personalized treatments, using IR or PARP inhibitor, of pancreatic and other cancers that carry a deleterious PALB2 variant. This article is protected by copyright. All rights reserved.

5.
Cancer Epidemiol Biomarkers Prev ; 29(11): 2203-2210, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32856602

RESUMO

BACKGROUND: Scalp and neck (SN) melanoma confers a worse prognosis than melanoma of other sites but little is known about its determinants. We aimed to identify associations between SN melanoma and known risk genes, phenotypic traits, and sun exposure patterns. METHODS: Participants were cases from the Western Australian Melanoma Health Study (n = 1,200) and the Genes, Environment, and Melanoma Study (n = 3,280). Associations between risk factors and SN melanoma, compared with truncal and arm/leg melanoma, were investigated using binomial logistic regression. Facial melanoma was also compared with the trunk and extremities, to evaluate whether associations were subregion specific, or reflective of the whole head/neck region. RESULTS: Compared with other sites, increased odds of SN and facial melanoma were observed in older individuals [SN: OR = 1.28, 95% confidence interval (CI) = 0.92-1.80, P trend = 0.016; Face: OR = 4.57, 95% CI = 3.34-6.35, P trend < 0.001] and those carrying IRF4-rs12203592*T (SN: OR = 1.35, 95% CI = 1.12-1.63, P trend = 0.002; Face: OR = 1.29, 95% CI = 1.10-1.50, P trend = 0.001). Decreased odds were observed for females (SN: OR = 0.49, 95% CI = 0.37-0.64, P < 0.001; Face: OR = 0.66, 95% CI = 0.53-0.82, P < 0.001) and the presence of nevi (SN: OR = 0.66, 95% CI = 0.49-0.89, P = 0.006; Face: OR = 0.65, 95% CI = 0.52-0.83, P < 0.001). CONCLUSIONS: Differences observed between SN melanoma and other sites were also observed for facial melanoma. Factors previously associated with the broader head and neck region, notably older age, may be driven by the facial subregion. A novel finding was the association of IRF4-rs12203592 with both SN and facial melanoma. IMPACT: Understanding the epidemiology of site-specific melanoma will enable tailored strategies for risk factor reduction and site-specific screening campaigns.

6.
Hum Mutat ; 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32643855

RESUMO

We hypothesized that human genes differ by their sensitivity to ultraviolet (UV) exposure. We used somatic mutations detected by genome-wide screens in melanoma and reported in the Catalog Of Somatic Mutations In Cancer. As a measure of UV sensitivity, we used the number of silent mutations generated by C>T transitions in pyrimidine dimers of a given transcript divided by the number of potential sites for this type of mutations in the transcript. We found that human genes varied by UV sensitivity by two orders of magnitude. We noted that the melanoma-associated tumor suppressor gene CDKN2A was among the top five most UV-sensitive genes in the human genome. Melanoma driver genes have a higher UV-sensitivity compared with other genes in the human genome. The difference was more prominent for tumor suppressors compared with oncogene. The results of this study suggest that differential sensitivity of human transcripts to UV light may explain melanoma specificity of some driver genes. Practical significance of the study relates to the fact that differences in UV sensitivity among human genes need to be taken into consideration whereas predicting melanoma-associated genes by the number of somatic mutations detected in a given gene.

7.
Brain Imaging Behav ; 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32710338

RESUMO

Cancer-related cognitive dysfunction is an important issue for breast cancer survivors. Previous research has identified both cross-sectional and longitudinal alterations in brain function related to cancer status and treatment. In this study, we prospectively collected functional magnetic resonance imaging data in breast cancer cases treated with adjuvant chemotherapy and in controls with no cancer history during a working memory task. Data and blood specimens were collected immediately prior to the start of treatment (baseline) and following completion of treatment (follow-up), and at yoked intervals for controls. In secondary analysis we assessed the levels of oxidative DNA damage in peripheral blood lymphocytes of cases and controls using the Comet assay. A significant group*time interaction revealed reduced deactivation in the superior frontal gyrus in the controls at follow-up, in contrast to cases, who exhibited similar magnitude of deactivation at baseline and follow-up. Working memory performance indicated a significant improvement in the controls at follow-up, and no change in performance in cases. In secondary analyses, oxidative DNA damage levels were elevated in the cases at follow-up compared to controls, but no associations were found between the Comet assay variables and functional imaging at either time-point or group. In light of previous reports on task induced deactivations, our findings reflect continuing effortful processing at follow-up in the breast cancer group, with relatively less effortful processing in the control group given the reduced novelty and practice effects from the baseline to follow-up.

8.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1784-1791, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32546605

RESUMO

BACKGROUND: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. METHODS: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. RESULTS: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10-6) was observed in the meta-analysis (P GxE = 1.2 ×10-6, P Joint = 4.2 ×10-7). CONCLUSIONS: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. IMPACT: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

9.
Medicine (Baltimore) ; 99(21): e20085, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481275

RESUMO

INTRODUCTION: Chronic pain is a leading cause of disability and remains under-treated in nearly half of patients with cancer. The opioid crisis has highlighted an urgent public health need for effective nonpharmacological pain management. Electroacupuncture (EA) and Battlefield Acupuncture (BFA) represent nonpharmacological modalities used in clinical practice to manage pain; however, their effectiveness has not been rigorously evaluated in oncology settings. METHODS: We describe the design of a 3-arm, parallel, single-center, multisite randomized controlled trial that investigates EA and BFA versus usual-care wait-list control (WLC) for chronic musculoskeletal pain among 360 patients with diverse cancer types across various stages. The primary aim is to compare effects of EA and BFA versus WLC on pain, physical function, and co-morbid symptoms. The secondary aim is to examine the interaction between patient outcome expectancy and acupuncture modality (EA vs BFA) on pain reduction. The tertiary aim is to evaluate the association between genetic polymorphisms and responses to acupuncture. Patients will be randomized in a 2:2:1 ratio to EA:BFA:WLC. Acupuncture groups will receive weekly treatments over 10 weeks. WLC will receive usual care over the same evaluation period as the acupuncture groups. The primary endpoint will be the change in average pain intensity score from baseline to week 12. We will collect validated patient-reported outcomes and blood/saliva samples at multiple timepoints over 24 weeks. DISCUSSION: Our findings will advance nonpharmacological pain management in oncology and inform personalized treatment approaches that integrate individuals' expectations and genetic biomarkers to deliver "precision" acupuncture to cancer patients with chronic pain. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02979574.


Assuntos
Terapia por Acupuntura/métodos , Sobreviventes de Câncer , Dor Crônica/terapia , Dor Musculoesquelética/terapia , Manejo da Dor/métodos , Adulto , Humanos , Medição da Dor/métodos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Menopause ; 27(8): 913-917, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32217888

RESUMO

OBJECTIVE: Because hot flashes are a common symptom experienced by women with breast cancer, we sought to explore genetic predictors associated with response to acupuncture for the treatment of hot flashes. METHODS: Using data from our completed randomized controlled trial (Clinicaltrials.gov identifier: NCT01005108) on hot flashes among breast cancer survivors who provided biomarker collection (N = 108), we extracted and assayed DNA for single nucleotide polymorphisms in genes involved in neurotransmission, thermoregulation, and inflammation (ADORA1, COMT, TCL1A, and TRPV1). For our primary outcome we classified individuals with a 50% or more reduction in their hot flash composite score at the end of treatment as responders. We used Fisher exact test to identify individual and combined single nucleotide polymorphisms associated with treatment response. RESULTS: Among women (N = 57) who received acupuncture treatment (electro or sham), we found that women who were carriers of at least one of these six genotypes (ADORA1 rs41264025-GA or rs16851029-GG or rs12744240-GT, COMT rs6269-GA, TCL1A rs2369049-GG, and TRPV1 rs8065080-TT) were more likely to respond to acupuncture for hot flashes than noncarriers (70.3% vs 37.5%, P = 0.035). These six genotypes were not associated with response in women (N = 51) who received pharmacological hot flash treatment (gabapentin or placebo pill; 37.5% vs 37.5%, P = 1.0). CONCLUSIONS: In this exploratory, proof of concept study, we identified six genotypes that may predict response to acupuncture for hot flashes in breast cancer survivors. If confirmed by future studies, these findings may inform the development of personalized acupuncture for managing hot flashes.

12.
JAMA Netw Open ; 2(9): e1912259, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31560388

RESUMO

Importance: Radiation therapy for breast cancer is associated with increased risk of a second primary contralateral breast cancer, but the genetic factors modifying this association are not well understood. Objective: To determine whether a genetic risk score comprising single nucleotide polymorphisms in the nonhomologous end-joining DNA repair pathway is associated with radiation-associated contralateral breast cancer. Design, Setting, and Participants: This case-control study included a case group of women with contralateral breast cancer that was diagnosed at least 1 year after a first primary breast cancer who were individually matched to a control group of women with unilateral breast cancer. Inclusion criteria were receiving a first invasive breast cancer diagnosis prior to age 55 years between 1985 and 2008. Women were recruited through 8 population-based cancer registries in the United States, Canada, and Denmark as part of the Women's Environment, Cancer, and Radiation Epidemiology Studies I (November 2000 to August 2004) and II (March 2010 to December 2012). Data analysis was conducted from July 2017 to August 2019. Exposures: Stray radiation dose to the contralateral breast during radiation therapy for the first breast cancer. A novel genetic risk score comprised of genetic variants in the nonhomologous end-joining DNA repair pathway was considered the potential effect modifier, dichotomized as high risk if the score was above the median of 74 and low risk if the score was at or below the median. Main Outcomes and Measures: The main outcome was risk of contralateral breast cancer associated with stray radiation dose stratified by genetic risk score, age, and latency. Results: A total of 5953 women were approached for study participation, and 3732 women (62.7%) agreed to participate. The median (range) age at first diagnosis was 46 (23-54) years. After 5 years of latency or more, among women who received the first diagnosis when they were younger than 40 years, exposure to 1.0 Gy (to convert to rad, multiply by 100) or more of stray radiation was associated with a 2-fold increased risk of contralateral breast cancer compared with women who were not exposed (rate ratio, 2.0 [95% CI, 1.1-3.6]). The risk was higher among women with a genetic risk score above the median (rate ratio, 3.0 [95% CI, 1.1-8.1]), and there was no association among women with a genetic risk score below the median (rate ratio, 1.3 [95% CI, 0.5-3.7]). Among younger women with a high genetic risk score, the attributable increased risk for contralateral breast cancer associated with stray radiation dose was 28%. Conclusions and Relevance: This study found an increased risk of contralateral breast cancer that was attributable to stray radiation exposure among women with a high genetic risk score and who received a first breast cancer diagnosis when they were younger than 40 years after 5 years or more of latency. This genetic risk score may help guide treatment and surveillance for women with breast cancer.


Assuntos
Neoplasias da Mama/radioterapia , Neoplasias Induzidas por Radiação/patologia , Segunda Neoplasia Primária/induzido quimicamente , Radioterapia/efeitos adversos , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/genética , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco
13.
Neuro Oncol ; 21(10): 1297-1309, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31123752

RESUMO

BACKGROUND: Patients with brain tumors treated with radiotherapy (RT) and chemotherapy (CT) often experience cognitive dysfunction. We reported that single nucleotide polymorphisms (SNPs) in the APOE, COMT, and BDNF genes may influence cognition in brain tumor patients. In this study, we assessed whether genes associated with late-onset Alzheimer's disease (LOAD), inflammation, cholesterol transport, dopamine and myelin regulation, and DNA repair may influence cognitive outcome in this population. METHODS: One hundred and fifty brain tumor patients treated with RT ± CT or CT alone completed a neurocognitive assessment and provided a blood sample for genotyping. We genotyped genes/SNPs in these pathways: (i) LOAD risk/inflammation/cholesterol transport, (ii) dopamine regulation, (iii) myelin regulation, (iv) DNA repair, (v) blood-brain barrier disruption, (vi) cell cycle regulation, and (vii) response to oxidative stress. White matter (WM) abnormalities were rated on brain MRIs. RESULTS: Multivariable linear regression analysis with Bayesian shrinkage estimation of SNP effects, adjusting for relevant demographic, disease, and treatment variables, indicated strong associations (posterior association summary [PAS] ≥ 0.95) among tests of attention, executive functions, and memory and 33 SNPs in genes involved in: LOAD/inflammation/cholesterol transport (eg, PDE7A, IL-6), dopamine regulation (eg, DRD1, COMT), myelin repair (eg, TCF4), DNA repair (eg, RAD51), cell cycle regulation (eg, SESN1), and response to oxidative stress (eg, GSTP1). The SNPs were not significantly associated with WM abnormalities. CONCLUSION: This novel study suggests that polymorphisms in genes involved in aging and inflammation, dopamine, myelin and cell cycle regulation, and DNA repair and response to oxidative stress may be associated with cognitive outcome in patients with brain tumors.


Assuntos
Neoplasias Encefálicas/genética , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/terapia , Cognição/efeitos dos fármacos , Cognição/efeitos da radiação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Radioterapia/efeitos adversos , Adulto Jovem
14.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1238-1245, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31015203

RESUMO

BACKGROUND: Pancreatic cancer is the fourth-leading cause of cancer death in both men and women in the United States. The currently identified common susceptibility loci account for a small fraction of estimated heritability. We sought to estimate overall heritability of pancreatic cancer and partition the heritability by variant frequencies and functional annotations. METHODS: Analysis using the genome-based restricted maximum likelihood method (GREML) was conducted on Pancreatic Cancer Case-Control Consortium (PanC4) genome-wide association study (GWAS) data from 3,568 pancreatic cancer cases and 3,363 controls of European Ancestry. RESULTS: Applying linkage disequilibrium- and minor allele frequency-stratified GREML (GREML-LDMS) method to imputed GWAS data, we estimated the overall heritability of pancreatic cancer to be 21.2% (SE = 4.8%). Across the functional groups (intronic, intergenic, coding, and regulatory variants), intronic variants account for most of the estimated heritability (12.4%). Previously identified GWAS loci explained 4.1% of the total phenotypic variation of pancreatic cancer. Mutations in hereditary pancreatic cancer susceptibility genes are present in 4% to 10% of patients with pancreatic cancer, yet our GREML-LDMS results suggested these regions explain only 0.4% of total phenotypic variance for pancreatic cancer. CONCLUSIONS: Although higher than previous studies, our estimated 21.2% overall heritability may still be downwardly biased due to the inherent limitation that the contribution of rare variants in genes with a substantive overall impact on disease are not captured when applying these commonly used methods to imputed GWAS data. IMPACT: Our work demonstrated the importance of rare and common variants in pancreatic cancer risk.


Assuntos
Neoplasias Pancreáticas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia
16.
Cancer Epidemiol ; 58: 25-32, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30445228

RESUMO

BACKGROUND: There is inadequate evidence to determine whether there is an effect of alcohol consumption on lung cancer risk. We conducted a pooled analysis of data from the International Lung Cancer Consortium and the SYNERGY study to investigate this possible association by type of beverage with adjustment for other potential confounders. METHODS: Twenty one case-control studies and one cohort study with alcohol-intake data obtained from questionnaires were included in this pooled analysis (19,149 cases and 362,340 controls). Adjusted odds ratios (OR) or hazard ratios (HR) with corresponding 95% confidence intervals (CI) were estimated for each measure of alcohol consumption. Effect estimates were combined using random or fixed-effects models where appropriate. Associations were examined for overall lung cancer and by histological type. RESULTS: We observed an inverse association between overall risk of lung cancer and consumption of alcoholic beverages compared to non-drinkers, but the association was not monotonic. The lowest risk was observed for persons who consumed 10-19.9 g/day ethanol (OR vs. non-drinkers = 0.78; 95% CI: 0.67, 0.91), where 1 drink is approximately 12-15 g. This J-shaped association was most prominent for squamous cell carcinoma (SCC). The association with all lung cancer varied little by type of alcoholic beverage, but there were notable differences for SCC. We observed an association with beer intake (OR for ≥20 g/day vs nondrinker = 1.42; 95% CI: 1.06, 1.90). CONCLUSIONS: Whether the non-monotonic associations we observed or the positive association between beer drinking and squamous cell carcinoma reflect real effects await future analyses and insights about possible biological mechanisms.


Assuntos
Adenocarcinoma/epidemiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Carcinoma de Células Escamosas/epidemiologia , Neoplasias Pulmonares/epidemiologia , Adenocarcinoma/etiologia , Idoso , Bebidas Alcoólicas/efeitos adversos , Carcinoma de Células Escamosas/etiologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Inquéritos e Questionários
17.
Breast Cancer Res ; 20(1): 149, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30526633

RESUMO

BACKGROUND: Tamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown. METHODS: Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5-0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS. RESULTS: Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20-55% reduced RR of CBC (AS = 2, RR = - 0.81, 95% CI 0.62-1.06; AS = 1.5, RR = 0.45, 95% CI 0.30-0.68; and AS = 1, RR = 0.55, 95% CI 0.40-0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59-1.96; and AS = 0, RR = 1.17, 95% CI 0.58-2.35) (p for homogeneity = - 0.02). CONCLUSION: This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP2D6/genética , Segunda Neoplasia Primária/genética , Tamoxifeno/uso terapêutico , Adulto , Idoso , Antineoplásicos Hormonais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/prevenção & controle , Variantes Farmacogenômicos/genética , Polimorfismo de Nucleotídeo Único , Tamoxifeno/metabolismo , Resultado do Tratamento
18.
Melanoma Res ; 28(5): 380-389, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29975213

RESUMO

Factors influencing melanoma survival include sex, age, clinical stage, lymph node involvement, as well as Breslow thickness, presence of tumor-infiltrating lymphocytes based on histological analysis of primary melanoma, mitotic rate, and ulceration. Identification of genes whose expression in primary tumors is associated with these key tumor/patient characteristics can shed light on molecular mechanisms of melanoma survival. Here, we show results from a gene expression analysis of formalin-fixed paraffin-embedded primary melanomas with extensive clinical annotation. The Cancer Genome Atlas data on primary melanomas were used for validation of nominally significant associations. We identified five genes that were significantly associated with the presence of tumor-infiltrating lymphocytes in the joint analysis after adjustment for multiple testing: IL1R2, PPL, PLA2G3, RASAL1, and SGK2. We also identified two genes significantly associated with melanoma metastasis to the regional lymph nodes (PIK3CG and IL2RA), and two genes significantly associated with sex (KDM5C and KDM6A). We found that LEF1 was significantly associated with Breslow thickness and CCNA2 and UBE2T with mitosis. RAD50 was the gene most significantly associated with survival, with a higher level of expression associated with worse survival.


Assuntos
Expressão Gênica/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Melanoma/mortalidade , Melanoma/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida
19.
J Invest Dermatol ; 138(11): 2398-2404, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29753029

RESUMO

BRAF and NRAS mutations arise early in melanoma development, but their associations with low-penetrance melanoma susceptibility loci remain unknown. In the Genes, Environment and Melanoma Study, 1,223 European-origin participants had their incident invasive primary melanomas screened for BRAF/NRAS mutations and germline DNA genotyped for 47 single-nucleotide polymorphisms identified as low-penetrant melanoma-risk variants. We used multinomial logistic regression to simultaneously examine each single-nucleotide polymorphism's relationship to BRAF V600E, BRAF V600K, BRAF other, and NRAS+ relative to BRAF-/NRAS- melanoma adjusted for study features. IRF4 rs12203592*T was associated with BRAF V600E (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.43-0.79) and V600K (OR = 0.65, 95% CI = 0.41-1.03), but not BRAF other or NRAS+ melanoma. A global test of etiologic heterogeneity (Pglobal = 0.001) passed false discovery (Pglobal = 0.0026). PLA2G6 rs132985*T was associated with BRAF V600E (OR = 1.32, 95% CI = 1.05-1.67) and BRAF other (OR = 1.82, 95% CI = 1.11-2.98), but not BRAF V600K or NRAS+ melanoma. The test for etiologic heterogeneity (Pglobal) was 0.005. The IRF4 rs12203592 associations were slightly attenuated after adjustment for melanoma-risk phenotypes. The PLA2G6 rs132985 associations were independent of phenotypes. IRF4 and PLA2G6 inherited genotypes may influence melanoma BRAF/NRAS subtype development.


Assuntos
GTP Fosfo-Hidrolases/genética , Genótipo , Fosfolipases A2 do Grupo VI/genética , Fatores Reguladores de Interferon/genética , Melanoma/genética , Proteínas de Membrana/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco
20.
Int J Cancer ; 143(4): 823-830, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29524207

RESUMO

Background parenchymal enhancement (BPE) is the degree to which normal breast tissue enhances on contrast-enhanced magnetic resonance imaging (MRI). MRI-density is a volumetric measure of breast density that is highly correlated with mammographic density, an established breast cancer risk factor. Endogenous estrogen concentrations are positively associated with postmenopausal breast cancer risk and BPE has been shown to be sensitive to hormonal exposures. The objective of our study was to examine the relationship between BPE and MRI-density and serum hormone concentrations in postmenopausal women. This was a study of cancer-free postmenopausal women undergoing contrast-enhanced breast MRI (N = 118). At the time of MRI all women completed a self-administered questionnaire and blood samples were collected for hormone analyses. Serum concentrations of estrone (E1), estradiol (E2) and bioavailable E2 were examined by category of BPE and MRI-density. Compared to women with "minimal" BPE, those who had "marked" BPE had significantly higher serum concentrations of E1, E2 and bioavailable E2 (90% increase, ptrend across all categories = 0.001; 150% increase, ptrend = 0.001; and 158% increase, ptrend = 0.001, respectively). These associations were only affected to a minor extent by adjustment for BMI and other variables. After adjustment for BMI, no significant associations between MRI-density and serum E1, E2 and bioavailable E2 were observed. Serum estrogen concentrations were significantly positively associated with BPE. Our study provides further evidence of the hormone-sensitive nature of BPE, indicating a potential role for BPE as an imaging marker of endogenous and exogenous hormonal exposures in the breast.


Assuntos
Densidade da Mama , Meios de Contraste , Estradiol/sangue , Estrona/sangue , Imagem por Ressonância Magnética/métodos , Pós-Menopausa/sangue , Disponibilidade Biológica , Índice de Massa Corporal , Feminino , Humanos , Pessoa de Meia-Idade , Inquéritos e Questionários
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