RESUMEN
Statins have been associated with an increased risk of keratinocyte carcinoma but data are limited and conflicting. Statins are hypothesized to contribute to KC through immunomodulation. A whole-population case-control study of the Icelandic population was conducted using the Icelandic Cancer Registry and Icelandic Prescription Medicine Register. These are high-quality registers which include all cancer diagnoses, as well as every prescription in the country. Cases included all first-time histologically confirmed diagnoses of (BCC), in situ squamous cell carcinoma (SCCis) and invasive SCC between 2003 and 2017. Each case was paired with 10 age- and sex-matched controls. Multivariate conditional logistic regression analysis was performed. Four thousand seven hundred patients with BCC, 1167 patients with SCCis and 1013 patients with invasive SCC were identified and paired with 47,292, 11,961 and 10,367 controls, respectively. Overall statin use was associated with an increased risk of invasive SCC and SCCis but not BCC (adjusted OR [95% CI]: 1.29 [1.11-1.50]; 1.43 [1.24-1.64]; 1.03 [0.95-1.12], respectively). Subgroup analysis demonstrated that statins were significantly associated with invasive SCC and SCCis in patients over 60, but not in those under 60. Atorvastatin was only associated with an increased risk of SCCis; whereas, simvastatin was associated with an increased risk of both invasive SCC and SCCis. This whole-population study of Iceland demonstrates that statin exposure is associated with increased risk of SCC, but not BCC, in a low UV environment. The reasons are unclear, but our results may suggest that individuals receiving atorvastatin and simvastatin have differing levels of baseline keratinocyte cancer risk or that properties of a statin other than 'statin intensity' affect association with SCC.
Asunto(s)
Carcinoma Basocelular , Carcinoma de Células Escamosas , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Neoplasias Cutáneas , Atorvastatina , Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Islandia/epidemiología , Simvastatina , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Metformin has anticarcinogenic properties and is also known to inhibit the sonic hedgehog pathway, but population-based studies analyzing the potential protective effect for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are needed. OBJECTIVES: To delineate the association between metformin use and invasive SCC, SCC in situ (SCCis), and BCC. METHODS: A population-based case-control study design was employed using all 6880 patients diagnosed in Iceland between 2003-2017 with first-time BCC, SCCis, or invasive SCC, and 69,620 population controls. Multivariate odds ratios (ORs) were calculated using conditional logistic regression. RESULTS: Metformin was associated with a lower risk of developing BCC (OR, 0.71; 95% confidence interval [CI], 0.61-0.83), even at low doses. No increased risk of developing SCC was observed. SCCis risk was mildly elevated in the 501-1500 daily dose unit category (OR, 1.40; 95% CI, 1.00-1.96). LIMITATIONS: This study was retrospective in nature with the inability to adjust for ultraviolet exposure, Fitzpatrick skin type, and comorbidities. CONCLUSION: Metformin is associated with decreased risk of BCC development, even at low doses. Metformin might have potential as a chemoprotective agent for patients at high risk of BCC, although this will need confirmation in future studies.
Asunto(s)
Carcinoma Basocelular/epidemiología , Metformina/uso terapéutico , Neoplasias Cutáneas/epidemiología , Anciano , Anciano de 80 o más Años , Carcinoma Basocelular/patología , Carcinoma Basocelular/prevención & control , Estudios de Casos y Controles , Femenino , Proteínas Hedgehog/antagonistas & inhibidores , Proteínas Hedgehog/metabolismo , Humanos , Islandia/epidemiología , Masculino , Metformina/farmacología , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Piel/efectos de los fármacos , Piel/patología , Piel/efectos de la radiación , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/prevención & control , Rayos Ultravioleta/efectos adversosRESUMEN
BACKGROUND: Population-based studies analyzing hydrochlorothiazide's (HCTZ's) effect on keratinocyte carcinoma, and particularly invasive squamous cell carcinoma (SCC), are lacking. OBJECTIVES: To characterize the association between HCTZ use and invasive SCC, SCC in situ (SCCis), and basal cell carcinoma (BCC). METHODS: This population-based case-control study included all 6880 patients diagnosed with first-time BCC, SCCis, and invasive SCC between 2003 and 2017 in Iceland and 69,620 population controls. Conditional logistic regression analyses were used to calculate multivariate odds ratios (ORs) for keratinocyte carcinoma associated with HCTZ use. RESULTS: A cumulative HCTZ dose above 37,500 mg was associated with increased risk of invasive SCC (OR, 1.69; 95% confidence interval [CI], 1.04-2.74). Users of HCTZ also had an increased risk of SCCis (OR, 1.24; 95% CI, 1.01-1.52) and BCC (OR, 1.14; 95% CI, 1.02-1.29). LIMITATIONS: Limitations include this study's retrospective nature with the resulting inability to adjust for ultraviolet exposure, Fitzpatrick skin type, and comorbidities. CONCLUSIONS: High cumulative exposure to HCTZ is associated with the development of keratinocyte carcinoma and, most importantly, invasive SCC. Sun protective behaviors alone may not eliminate the carcinogenic potential of HCTZ.
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Antihipertensivos/efectos adversos , Carcinoma Basocelular/epidemiología , Carcinoma de Células Escamosas/epidemiología , Hidroclorotiazida/efectos adversos , Neoplasias Cutáneas/epidemiología , Anciano , Anciano de 80 o más Años , Carcinogénesis/efectos de los fármacos , Carcinoma Basocelular/inducido químicamente , Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Islandia/epidemiología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Piel/efectos de los fármacos , Piel/patología , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/patología , Factores de TiempoAsunto(s)
Carcinoma Basocelular/epidemiología , Carcinoma de Células Escamosas/epidemiología , Neoplasias Cutáneas/epidemiología , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Adalimumab/uso terapéutico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Etanercept/uso terapéutico , Femenino , Humanos , Islandia/epidemiología , Infliximab/uso terapéutico , Masculino , Persona de Mediana Edad , Sistema de Registros , Factores de Riesgo , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: The natural history of breast cancer among BRCA2 carriers has not been clearly established. In a previous study from Iceland, positive ER status was a negative prognostic factor. We sought to identify factors that predicted survival after invasive breast cancer in an expanded cohort of BRCA2 carriers. METHODS: We studied 608 women with invasive breast cancer and a pathogenic BRCA2 mutation (variant) from four Nordic countries. Information on prognostic factors and treatment was retrieved from health records and by analysis of archived tissue specimens. Hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression. RESULTS: About 77% of cancers were ER-positive, with the highest proportion (83%) in patients under 40 years. ER-positive breast cancers were more likely to be node-positive (59%) than ER-negative cancers (34%) (P < 0.001). The survival analysis included 584 patients. Positive ER status was protective in the first 5 years from diagnosis (multivariate HR = 0.49; 95% CI 0.26-0.93, P = 0.03); thereafter, the effect was adverse (HR = 1.91; 95% CI 1.07-3.39, P = 0.03). The adverse effect of positive ER status was limited to women who did not undergo endocrine treatment (HR = 2.36; 95% CI 1.26-4.44, P = 0.01) and patients with intact ovaries (HR = 1.99; 95% CI 1.11-3.59, P = 0.02). CONCLUSIONS: The adverse effect of a positive ER status in BRCA2 carriers with breast cancer may be contingent on exposure to ovarian hormones.
Asunto(s)
Proteína BRCA2/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Receptores de Estrógenos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Persona de Mediana Edad , Mutación , Países Escandinavos y NórdicosRESUMEN
Obesity, often assessed at one point in time, is an established risk factor of several types of cancer, however, associations with cumulative exposure to obesity across the life course are not well understood. We investigated the relationship between combined measures of duration and intensity of premenopausal overweight and obesity and the incidence of postmenopausal breast, endometrial, and colorectal cancers in Icelandic women. Body mass index (BMI) trajectories between ages 20 and 50 of 88,809 women from the Cancer Detection Clinic Cohort were predicted using growth curve models. Indicators of overweight and obesity duration and intensity were computed and their association with risk of postmenopausal breast, endometrial, and colorectal cancers was examined using multivariate Cox models for subjects followed-up beyond the age of 50 (n = 67,488). During a mean follow-up of 17 years, incident events of 3,016 postmenopausal breast, 410 endometrial and 987 colorectal cancers were ascertained. Each 0.1 kg/m2 per year increase in BMI between ages 20 and 50 was positively associated with risks of postmenopausal breast, endometrium and colorectal cancers with hazard ratios equal to 1.09 (95% Confidence Interval (CI):1.04-1.13), 1.31 (95% CI: 1.18-1.44) and 1.10 (95% CI: 1.00-1.21), respectively. Compared to women who were never obese, cumulative BMI × years of obesity were linearly positively associated with risk of endometrial cancer, whereas the association with breast cancer was initially positive, but leveled off with increasing cumulative BMI × years. Cumulative exposure to obesity may provide additional insights into the etiology of cancer and should be considered in future studies that assess obesity-cancer relationships.
Asunto(s)
Neoplasias de la Mama/epidemiología , Neoplasias Colorrectales/epidemiología , Neoplasias Endometriales/epidemiología , Obesidad/epidemiología , Sobrepeso/epidemiología , Adulto , Índice de Masa Corporal , Neoplasias de la Mama/etiología , Neoplasias Colorrectales/etiología , Neoplasias Endometriales/etiología , Femenino , Humanos , Islandia/epidemiología , Persona de Mediana Edad , Análisis Multivariante , Obesidad/complicaciones , Sobrepeso/complicaciones , Posmenopausia , Premenopausia , Adulto JovenRESUMEN
Obesity is a risk factor for colorectal cancer. Yet, some research indicates that weight-reducing bariatric surgery also increases colorectal cancer risk. Our study was undertaken because current evidence examining bariatric surgery and risk of colorectal cancer is limited and inconsistent. This population-based cohort study included adults with a documented obesity diagnosis in Denmark, Finland, Iceland, Norway or Sweden in 1980-2015. The incidence of colorectal cancer in participants with obesity who had and had not undergone bariatric surgery was compared to the incidence in the corresponding background population by calculating standardized incidence ratios (SIR) with 95% confidence intervals (CI). Additionally, operated and nonoperated participants with obesity were compared using multivariable Cox regression, providing hazard ratios (HR) with 95% CIs adjusted for confounders. Among 502,772 cohort participants with an obesity diagnosis, 49,931(9.9%) underwent bariatric surgery. The overall SIR of colon cancer was increased after bariatric surgery (SIR 1.56; 95% CI 1.28-1.88), with higher SIRs ≥10 years postsurgery. The overall HR of colon cancer in operated compared to nonoperated participants was 1.13 (95% CI 0.92-1.39) and 1.55 (95% CI 1.04-2.31) 10-14 years after bariatric surgery. Bariatric surgery did not significantly increase the risk of rectal cancer (SIR 1.14, 95% CI 0.83-1.52; HR 1.08, 95% CI 0.79-1.49), but the risk estimates increased with longer follow-up periods. Our study suggests that bariatric surgery is associated with an increased risk of colon cancer, while the support for an increased risk of rectal cancer was weaker.
Asunto(s)
Cirugía Bariátrica/efectos adversos , Neoplasias del Colon/epidemiología , Obesidad/cirugía , Neoplasias del Recto/epidemiología , Adulto , Anciano , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Finlandia/epidemiología , Humanos , Islandia/epidemiología , Incidencia , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Suecia/epidemiología , Adulto JovenRESUMEN
Background: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population. Methods: Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database. Results: The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele. Conclusions: K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress.
Asunto(s)
Carcinoma de Células Escamosas/genética , Genes BRCA2 , Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , Neoplasias Cutáneas/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Alelos , Genotipo , Humanos , Islandia/epidemiología , Mutación , Países Bajos/epidemiología , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: The impact of an inherited BRCA2 mutation on the prognosis of women with breast cancer has not been well documented. We studied the effects of oestrogen receptor (ER) status, other prognostic factors and treatments on survival in a large cohort of BRCA2 mutation carriers. METHODS: We identified 285 breast cancer patients with a 999del5 BRCA2 mutation and matched them with 570 non-carrier patients. Clinical information was abstracted from patient charts and pathology records and supplemented by evaluation of tumour grade and ER status using archived tissue specimens. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression. The effects of various therapies were studied in patients treated from 1980 to 2012. RESULTS: Among mutation carriers, positive ER status was associated with higher risk of death than negative ER status (HR=1.94; 95% CI=1.22-3.07, P=0.005). The reverse association was seen for non-carriers (HR=0.71; 95% CI: 0.51-0.97; P=0.03). CONCLUSIONS: Among BRCA2 carriers, ER-positive status is an adverse prognostic factor. BRCA2 carrier status should be known at the time when treatment decisions are made.
Asunto(s)
Neoplasias de la Mama/genética , Estrógenos , Genes BRCA2 , Mutación , Neoplasias Hormono-Dependientes/genética , Síndromes Neoplásicos Hereditarios/genética , Receptores de Estrógenos/análisis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/química , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Femenino , Humanos , Islandia/epidemiología , Masculino , Persona de Mediana Edad , Neoplasias Hormono-Dependientes/química , Neoplasias Hormono-Dependientes/mortalidad , Neoplasias Hormono-Dependientes/terapia , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/genética , Síndromes Neoplásicos Hereditarios/mortalidad , Síndromes Neoplásicos Hereditarios/terapia , Pronóstico , Modelos de Riesgos Proporcionales , Resultado del Tratamiento , Adulto JovenRESUMEN
It is not well known to what extent carrying a BRCA2 mutation affects the survival of women with breast cancer and prognostic factors among BRCA2-positive women warrant investigation. Using a record linkage approach we compared the long-term survival in carriers and noncarriers of an inherited BRCA2 founder mutation (999del5), and sought to identify prognostic factors among the BRCA2 mutation-positive subset, including markers of genetic instability (aneuploidy) and mitotic activity (S-phase fraction). We established the genetic status of 2,967 Icelandic breast cancer patients (215 mutation carriers and 2,752 noncarriers) diagnosed from 1955 to 2004, representing 72 % of all cases diagnosed in the country during this period. Tumour ploidy and S-phase fraction were assessed on tumour cells by DNA flow cytometry. Prognostic factors were assessed blindly with respect to mutation status. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival by BRCA2 status, using Cox regression. After a median follow-up of 9.5 years, BRCA2 mutation carriers had a higher risk of death from breast cancer than noncarriers (HR 1.64, 95 % CI 1.24-2.16, p < 0.001). The risk increase was restricted to women with diploid tumours (HR 3.03, 95 % CI 1.91-4.79, p < 0.001). Among breast cancer patients with aneuploid tumours, survival of carriers was similar to that of noncarriers (HR 0.76, 95 % CI 0.41-1.41, p = 0.38). Increased tumour size and a positive nodal status predicted worse prognosis in all patients, whereas the highly correlated prognostic factors diploidy, low proliferative activity and a positive estrogen receptor status had reverse effects in mutation carriers and noncarriers. Breast cancer patients who carry the Icelandic founder BRCA2 mutation have inferior long-term survival than noncarriers, but the adverse prognosis is restricted to mutation carriers with diploid, slowly proliferating tumours.
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Proteína BRCA2/genética , Neoplasias de la Mama/genética , Diploidia , Análisis de Supervivencia , Adulto , Anciano , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Mutación , PronósticoRESUMEN
INTRODUCTION: The nationwide Icelandic Cancer Registry (ICR) was established in 1954 and has been extensively used for research from the outset although formal quality assessment of the registry database has not previously been undertaken. In this paper we report the first formal evaluation of the comparability, validity, timeliness and completeness of the ICR. MATERIAL AND METHODS: Data from the ICR for the period 1955-2009 (41 994 cancer diagnoses) were used, applying established quantitative and semi-quantitative methods. In order to evaluate the completeness of the ICR, record linkage was performed between the ICR and the population-based Hospital Discharge Registry to identify potential missing cases for tumour diagnoses in 2000 and 2001. RESULTS: The registration is in accordance with internationally accepted standards. It has high validity, but random variation in rates is prominent in this small population. Record linkage with the Hospital Discharge Registry revealed that in addition to the 2459 cancers registered in 2000-2001, 21 cases were missing, indicating 99.15% completeness. Tumours of the central nervous system constituted 71%, and haematological malignancies 19% of these missing entries. DISCUSSION: The ICR has high completeness, validity and timeliness and is comparable to the cancer registries of the other Nordic Countries. As cancer registries have many important roles, it is of great importance that their data are at all times as complete and valid as possible. Thus the ICR aims to constantly improve and update the data gathering process.
Asunto(s)
Neoplasias/epidemiología , Sistema de Registros/normas , Distribución por Edad , Clasificación/métodos , Certificado de Defunción , Europa (Continente)/epidemiología , Femenino , Humanos , Islandia/epidemiología , Incidencia , Masculino , Neoplasias/clasificación , Neoplasias/mortalidad , Neoplasias Primarias Desconocidas/epidemiología , Reproducibilidad de los Resultados , Proyectos de Investigación , Distribución por Sexo , Factores de TiempoRESUMEN
Triple-negative breast cancer (TNBC) occurs in approximately 15% of all breast cancer patients, and the incidence of TNBC is greatly increased in BRCA1 mutation carriers. This study aimed to assess the impact of BRCA1 promoter methylation with respect to breast cancer subtypes in sporadic disease. Tissue microarrays (TMAs) were constructed representing tumors from 303 patients previously screened for BRCA1 germline mutations, of which a subset of 111 sporadic tumors had previously been analyzed with respect to BRCA1 methylation. Additionally, a set of eight tumors from BRCA1 mutation carriers were included on the TMAs. Expression analysis was performed on TMAs by immunohistochemistry (IHC) for BRCA1, pRb, p16, p53, PTEN, ER, PR, HER2, CK5/6, EGFR, MUC1 and Ki-67. Data on BRCA1 aberrations and IHC expression was examined with respect to breast cancer-specific survival. The results demonstrate that CpG island hypermethylation of BRCA1 significantly associates with the basal/triple-negative subtype. Low expression of pRb, and high/intense p16, were associated with BRCA1 promoter hypermethylation, and the same effects were seen in BRCA1 mutated tumors. The expression patterns of BRCA1, pRb, p16 and PTEN were highly correlated, and define a subgroup of TNBCs characterized by BRCA1 aberrations, high Ki-67 (≥ 40%) and favorable disease outcome. In conclusion, our findings demonstrate that epigenetic inactivation of the BRCA1 gene associates with RB/p16 dysfunction in promoting TNBCs. The clinical implications relate to the potential use of targeted treatment based on PARP inhibitors in sporadic TNBCs, wherein CpG island hypermethylation of BRCA1 represents a potential marker of therapeutic response.
Asunto(s)
Proteína BRCA1/genética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Metilación de ADN , Proteína de Retinoblastoma/genética , Neoplasias de la Mama/metabolismo , Islas de CpG/genética , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Humanos , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Regiones Promotoras GenéticasRESUMEN
Earlier menarche correlates with shorter adult height and higher childhood body fat. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 × 10(-14)). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height, did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass index (BMI) and 5 of those associated with earlier AAM.
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Envejecimiento/fisiología , Cromosomas Humanos Par 6/genética , Variación Genética , Estudio de Asociación del Genoma Completo , Menarquia/genética , Polimorfismo de Nucleótido Simple/genética , Tejido Adiposo/anatomía & histología , Adulto , Antropometría/métodos , Secuencia de Bases , Estatura/genética , Índice de Masa Corporal , Mapeo Cromosómico , Dinamarca , Femenino , Humanos , Islandia , Países Bajos , Transcripción GenéticaRESUMEN
According to the leading hypothesis on testicular cancer (TC) etiology exposure to a specific pattern of steroid hormones in utero, in particular, to high levels of estrogens and low levels of androgens is the major determinant of TC risk in the offspring. We performed a case-referent study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal endogenous steroid hormones with regard to the risk of TC. TC cases and referents were aged between 0 and 25 years. For each case-index mother pair, three or four matched referent-referent mother pairs were identified using national population registries. First trimester or early second trimester sera were retrieved from the index mothers of 73 TC cases and 286 matched referent mothers, and were tested for dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG). Offspring of mothers with high DHEAS levels had a significantly decreased risk of TC (OR for highest vs. lowest DHEAS quartile, 0.18 (95% CI 0.06-0.58). In contrast, offspring of mothers with high androstenedione levels had an increased risk of TC (OR 4.1; 95% CI 1.2-12.0). High maternal total estradiol level also tended to be associated with an increased risk of TC in the offspring (OR 32; 95% CI 0.98-1,090). We report the first direct evidence that interplay of maternal steroid hormones in the early pregnancy is important in the etiology of TC in the offspring.
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Hormonas Esteroides Gonadales/sangre , Efectos Tardíos de la Exposición Prenatal/epidemiología , Neoplasias Testiculares/epidemiología , Adolescente , Adulto , Androstenodiona/sangre , Estudios de Casos y Controles , Niño , Preescolar , Sulfato de Deshidroepiandrosterona/sangre , Estradiol/sangre , Estrona/sangre , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , Medición de Riesgo , Factores de Riesgo , Globulina de Unión a Hormona Sexual/análisis , Testosterona/sangre , Adulto JovenRESUMEN
Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 x 10(-7). This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Obesidad/genética , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , Secuencia de Bases , Índice de Masa Corporal , Peso Corporal/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Regulación de la Expresión Génica , Genoma Humano/genética , Humanos , Obesidad/complicaciones , Carácter Cuantitativo HeredableRESUMEN
During recent decades the incidence of testicular cancer (TC) has increased rapidly around the world. Associated exogenous etiological factors might therefore be identifiable. We performed a case-control study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of congenital or neonatal infections with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) as risk factors of TC in the offspring. For each case-index mother pair, three or four matched control-control mother pairs were identified using national population registries. First trimester sera were retrieved from the index mothers of 66 TC cases and 258 matched control mothers, and were tested for antibodies to EBV and CMV. High level of maternal EBV IgG antibodies was associated with significantly increased risk of TC in the offspring (odds ratio (OR), 2.50; 95% confidence interval (CI), 1.15, 5.40), especially with risk of non-seminoma TC (OR, 2.73; 950% CI, 1.25, 5.99) and non-seminoma TC diagnosed under 8 years of age (OR, 2.72; 95% CI, 1.05, 7.04). In contrast, offspring of CMV IgG-seropositive mothers had a decreased risk of TC diagnosed under 8 years of age (OR, 0.35; 95% CI, 0.14, 0.89). Our results suggest that EBV and CMV infections may be associated with TC.
Asunto(s)
Infecciones por Citomegalovirus/epidemiología , Citomegalovirus/crecimiento & desarrollo , Infecciones por Virus de Epstein-Barr/epidemiología , Herpesvirus Humano 4/crecimiento & desarrollo , Neoplasias Testiculares/virología , Adolescente , Adulto , Anticuerpos Antivirales/sangre , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/virología , Ensayo de Inmunoadsorción Enzimática , Infecciones por Virus de Epstein-Barr/sangre , Infecciones por Virus de Epstein-Barr/virología , Europa (Continente)/epidemiología , Femenino , Humanos , Inmunoglobulina G/sangre , Transmisión Vertical de Enfermedad Infecciosa , Masculino , Persona de Mediana Edad , Embarazo , Estudios Seroepidemiológicos , Neoplasias Testiculares/epidemiología , Adulto JovenRESUMEN
Adult human height is one of the classical complex human traits. We searched for sequence variants that affect height by scanning the genomes of 25,174 Icelanders, 2,876 Dutch, 1,770 European Americans and 1,148 African Americans. We then combined these results with previously published results from the Diabetes Genetics Initiative on 3,024 Scandinavians and tested a selected subset of SNPs in 5,517 Danes. We identified 27 regions of the genome with one or more sequence variants showing significant association with height. The estimated effects per allele of these variants ranged between 0.3 and 0.6 cm and, taken together, they explain around 3.7% of the population variation in height. The genes neighboring the identified loci cluster in biological processes related to skeletal development and mitosis. Association to three previously reported loci are replicated in our analyses, and the strongest association was with SNPs in the ZBTB38 gene.
Asunto(s)
Estatura/genética , Ligamiento Genético , Genoma Humano , Polimorfismo de Nucleótido Simple , Adulto , Desarrollo Óseo/genética , Proteínas de Unión al ADN/genética , Femenino , Frecuencia de los Genes , Humanos , Masculino , Mitosis/genética , Proteínas Represoras/genéticaRESUMEN
UNLABELLED: Earlier studies have shown that cancer risk is related to educational level in many countries. The relationship between education and cancer risk has not been studied in the small, but ethnically homogenous, Icelandic population postulated to be outstanding as regards social equity. MATERIAL AND METHODS: We conducted a follow-up study of a cohort of 60,194 males and 58,505 females aged 20-64 at census 1981 in Iceland. Information on education from the census was classified into three educational groups and linked with the population-based Icelandic Cancer Registry. Standardized incidence ratios (SIRs) were calculated for the period 1982 to 2004. RESULTS: We found a significant association between educational level and cancer risk. Among males with academic education, the SIR was elevated for prostate cancer (SIR=1.17, 95% CI 1.05-1.30) and melanoma (SIR=1.41, 95% CI 1.00-1.93) and lowered for cancers of the lung (SIR=0.72, 95% CI 0.59-0.87) and stomach (SIR=0.67, 95% CI 0.48-0.90). Women with academic education had an increased risk of breast cancer (SIR=1.19, 95% CI 1.07-1.33) and a decreased risk of lung cancer (SIR=0.49, 95% CI 0.36-0.65). Increasing educational level was associated with a lowered risk of cervical cancer (p trend=0.017). DISCUSSION: The association between education and cancer incidence seen in this study resembles observations from other countries and probably reflects concordance between social status and certain risk factors for cancer. Our study confirms health-related socioeconomic differences in Iceland and must be taken into account when programmes for health promotion are planned.