Oral microbiome and risk of malignant esophageal lesions in a high-risk area of China: A nested case-control study.

OBJECTIVE: We aimed to prospectively evaluate the association of oral microbiome with malignant esophageal lesions and its predictive potential as a biomarker of risk. METHODS: We conducted a case-control study nested within a population-based cohort with up to 8 visits of oral swab collection for each subject over an 11-year period in a high-risk area for esophageal cancer in China. The oral microbiome was evaluated with 16S ribosomal RNA (rRNA) gene sequencing in 428 pre-diagnostic oral specimens from 84 cases with esophageal lesions of severe squamous dysplasia and above (SDA) and 168 matched healthy controls. DESeq analysis was performed to identify taxa of differential abundance. Differential oral species together with subject characteristics were evaluated for their potential in predicting SDA risk by constructing conditional logistic regression models. RESULTS: A total of 125 taxa including 37 named species showed significantly different abundance between SDA cases and controls (all P<0.05 & false discovery rate-adjusted Q<0.10). A multivariate logistic model including 11 SDA lesion-related species and family history of esophageal cancer provided an area under the receiver operating characteristic curve (AUC) of 0.89 (95% CI, 0.84-0.93). Cross-validation and sensitivity analysis, excluding cases diagnosed within 1 year of collection of the baseline specimen and their matched controls, or restriction to screen-endoscopic-detected or clinically diagnosed case-control triads, or using only bacterial data measured at the baseline, yielded AUCs>0.84. CONCLUSIONS: The oral microbiome may play an etiological and predictive role in esophageal cancer, and it holds promise as a non-invasive early warning biomarker for risk stratification for esophageal cancer screening programs.

Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors.

Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4 × 10(-6)) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1 × 10(-4)). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ≥ 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3 × 10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.

Breast cancer receptor status and stage at diagnosis in over 1,200 consecutive public hospital patients in Soweto, South Africa: a case series.

INTRODUCTION: Estimates of the proportion of estrogen receptor negative (ERN) and triple-negative (TRN) breast cancer from sub-Saharan Africa are variable and include high values. Large studies of receptor status conducted on non-archival tissue are lacking from this region. METHODS: We identified 1218 consecutive women (91% black) diagnosed with invasive breast cancer from 2006­2012 at a public hospital in Soweto, South Africa. Immunohistochemistry based ER, progesterone receptor (PR) and human epidermal factor 2 (HER2) receptors were assessed at diagnosis on pre-treatment biopsy specimens. Mutually adjusted associations of receptor status with stage, age, and race were examined using risk ratios (RRs). ER status was compared with age-stratified US Surveillance Epidemiology and End Results program (SEER) data. RESULTS: 35% (95% confidence interval (CI): 32-38) of tumors were ERN, 47% (45-52) PRN, 26% (23-29) HER2P and 21% (18-23) TRN. Later stage tumors were more likely to be ERN and PRN (RRs 1.9 (1.1-2.9) and 2.0 (1.3-3.1) for stage III vs. I) but were not strongly associated with HER2 status. Age was not strongly associated with ER or PR status, but older women were less likely to have HER2P tumors (RR, 0.95 (0.92-0.99) per 5 years). During the study, stage III + IV tumors decreased from 66% to 46%. In black women the percentage of ERN (37% (34-40)) and PRN tumors (48% (45-52)) was higher than in non-black patients (22% (14-31) and 34% (25-44), respectively, P = 0.004 and P = 0.02), which remained after age and stage adjustment. Age-specific ERN proportions in black South African women were similar to those of US black women, especially for women diagnosed over age 50. CONCLUSION: Although a greater proportion of black than non-black South African women had ER-negative or TRN breast cancer, in all racial groups in this study breast cancer was predominantly ER-positive and was being diagnosed at earlier stages over time. These observations provide initial indications that late-stage aggressive breast cancers may not be an inherent feature of the breast cancer burden across Africa.

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer.

INTRODUCTION: Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS: More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS: The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS: With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.

Sexual behavior and HPV infection in British women, by postal questionnaires and telephone interviews.

Sexually transmitted human papillomaviruses (HPVs), most frequently HPV 16, are the primary cause of cervical carcinogenesis. The aim of this study was to evaluate the relationship between sexual behavior and prevalence and acquisition of HPV infection among British women attending regular cervical screening who responded to postal questionnaires and/or telephone interviews. A total of 1,880 women who had been tested for HPV in the ARTISTIC (A Randomized Trial In Screening To Improve Cytology) trial were randomized to three methods of data collection: group 1 (questionnaire including sexual history, no interview), group 2 (questionnaire excluding sexual history, short interview including sexual history), and group 3 (questionnaire and long interview including sexual history in both). Questions on sexual history included age at first sexual intercourse, sexually transmitted diseases, lifetime (total and regular) sexual partners, and number of partners in the last 5 years (total and new). Demographics, reproductive, cervical screening, and smoking history were also collected in questionnaires. The overall participation rate was 35%. There was good agreement (87.4-95.5%) on sexual behavior answers in questionnaires and interviews in women in group 3 and no significant differences between data obtained by questionnaire or interview. Odds ratios (OR) for both HPV prevalence and acquisition increased consistently with increasing numbers of lifetime sexual partners, regular partners, and new partners in the last 5 years (recent partners). No significant association was found for other characteristics investigated. The effect of recent sexual partners on HPV acquisition (OR for 2+ recent partners: 4.4, 95% CI: 1.7-11.2) was stronger than that of earlier (> 5 years ago) partners (OR for 2+ earlier partners: 2.2, 95% CI: 0.7-6.7) suggesting that most incident HPV infections are newly acquired rather than recurrent.

Identification of genetic variants that influence circulating IGF1 levels: a targeted search strategy.

An important class of genetic variants that affect disease susceptibility may lie within regulatory elements that influence gene expression. Regulatory sequences are difficult to identify and may be distant from the genes they regulate, but many lie within evolutionarily conserved regions (ECRs). We used comparative genomics to identify 12 ECRs up to 75 kb 5' to and within introns of IGF1. These were screened by high-resolution melting curve analysis, and 18 single-nucleotide polymorphisms (SNPs) were identified, including five novel variants. We analysed two large population-based series of healthy women to test the nine SNPs with minor allele frequency (MAF) >1% within ECRs. Three of the nine SNPs within ECRs (rs35455143, rs35765817 and rs3839984) were significantly associated with circulating IGF1 levels in a multivariate analysis (P 70 kb 5' of IGF1. Two (rs35455143 and rs35765817) are in strong LD with each other and appear to have opposite effects on circulating IGF1. Our results on a subset of other SNPs in or near IGF1 were consistent with previously reported associations with IGF1 levels, although only one (rs35767: P = 0.05) was statistically significant. We believe that this is the first systematic study of an association between a phenotype and SNPs within ECRs extending over a large region adjacent to a gene. Targeting ECRs appears to be a useful strategy for identifying a subset of potentially functional non-coding regulatory SNPs.

Mammographic density and markers of socioeconomic status: a cross-sectional study.

BACKGROUND: Socioeconomic status (SES) is known to be positively associated with breast cancer risk but its relationship with mammographic density, a marker of susceptibility to breast cancer, is unclear. This study aims to investigate whether mammographic density varies by SES and to identify the underlying anthropometric, lifestyle and reproductive factors leading to such variation. METHODS: In a cross-sectional study of mammographic density in 487 pre-menopausal women, SES was assessed from questionnaire data using highest achieved level of formal education, quintiles of Census-derived Townsend scores and urban/rural classification of place of residence. Mammographic density was measured on digitised films using a computer-assisted method. Linear regression models were fitted to assess the association between SES variables and mammographic density, adjusting for correlated variables. RESULTS: In unadjusted models, percent density was positively associated with SES, with an absolute difference in percent density of 6.3% (95% CI 1.6%, 10.5%) between highest and lowest educational categories, and of 6.6% (95% CI -0.7%, 12.9%) between highest and lowest Townsend quintiles. These associations were mainly driven by strong negative associations between these SES variables and lucent area and were attenuated upon adjustment for body mass index (BMI). There was little evidence that reproductive factors explained this association. SES was not associated with the amount of dense tissue in the breast before or after BMI adjustment. The effect of education on percent density persisted after adjustment for Townsend score. Mammographic measures did not vary according to urban/rural place of residence. CONCLUSIONS: The observed SES gradients in percent density paralleled known SES gradients in breast cancer risk. Although consistent with the hypothesis that percent density may be a mediator of the SES differentials in breast cancer risk, the SES gradients in percent density were mainly driven by the negative association between SES and BMI. Nevertheless, as density affects the sensitivity of screen-film mammography, the higher percent density found among high SES women would imply that these women have a higher risk of developing cancer but a lower likelihood of having it detected earlier.

Birth size and breast cancer risk: re-analysis of individual participant data from 32 studies.

BACKGROUND: Birth size, perhaps a proxy for prenatal environment, might be a correlate of subsequent breast cancer risk, but findings from epidemiological studies have been inconsistent. We re-analysed individual participant data from published and unpublished studies to obtain more precise estimates of the magnitude and shape of the birth size-breast cancer association. METHODS AND FINDINGS: Studies were identified through computer-assisted and manual searches, and personal communication with investigators. Individual participant data from 32 studies, comprising 22,058 breast cancer cases, were obtained. Random effect models were used, if appropriate, to combine study-specific estimates of effect. Birth weight was positively associated with breast cancer risk in studies based on birth records (pooled relative risk [RR] per one standard deviation [SD] [= 0.5 kg] increment in birth weight: 1.06; 95% confidence interval [CI] 1.02-1.09) and parental recall when the participants were children (1.02; 95% CI 0.99-1.05), but not in those based on adult self-reports, or maternal recall during the woman's adulthood (0.98; 95% CI 0.95-1.01) (p for heterogeneity between data sources = 0.003). Relative to women who weighed 3.000-3.499 kg, the risk was 0.96 (CI 0.80-1.16) in those who weighed < 2.500 kg, and 1.12 (95% CI 1.00-1.25) in those who weighed > or = 4.000 kg (p for linear trend = 0.001) in birth record data. Birth length and head circumference from birth records were also positively associated with breast cancer risk (pooled RR per one SD increment: 1.06 [95% CI 1.03-1.10] and 1.09 [95% CI 1.03-1.15], respectively). Simultaneous adjustment for these three birth size variables showed that length was the strongest independent predictor of risk. The birth size effects did not appear to be confounded or mediated by established breast cancer risk factors and were not modified by age or menopausal status. The cumulative incidence of breast cancer per 100 women by age 80 y in the study populations was estimated to be 10.0, 10.0, 10.4, and 11.5 in those who were, respectively, in the bottom, second, third, and top fourths of the birth length distribution. CONCLUSIONS: This pooled analysis of individual participant data is consistent with birth size, and in particular birth length, being an independent correlate of breast cancer risk in adulthood.

Ethnic variations in mammographic density: a British multiethnic longitudinal study.

It is not known whether the 20-30% lower breast cancer incidence rates in first-generation South Asian and Afro-Caribbean women relative to Caucasian women in the United Kingdom are reflected in mammographic density. The authors conducted a United Kingdom population-based multiethnic study of mammographic density at ages 50-64 years in 645 women. Data on breast cancer risk factors were obtained using a questionnaire/telephone interview. Threshold percent density was assessed on 5,277 digitized mammograms taken in 1995-2004 and was analyzed using multilevel models. Both ethnic minorities were characterized by more protective breast cancer risk factor distributions than Caucasians, such as later menarche, shorter stature, higher parity, earlier age at first birth, and less use of hormone therapy, but they had a higher mean body mass index; the last four factors were associated with lower mammographic density. Age-adjusted percent mammographic densities in Afro-Caribbeans and South Asians were 5.6% (95% confidence interval (CI): 3.5, 7.5) and 5.9% (95% CI: 3.6, 8.0) lower, respectively, than in Caucasians. Lower densities were partly attributed to higher body mass index, less use of hormone therapy, and a protective reproductive history, but these factors did not account entirely for ethnic differences, since fully adjusted mean densities were 1.3% (95% CI: -1.3, 3.7) and 3.8% (95% CI: 1.1, 6.3) lower, respectively. Ethnic differences in mammographic density are consistent with those for breast cancer risk.

Lifestyle of UK commercial aircrews relative to air traffic controllers and the general population.

INTRODUCTION: Commercial aircrews are exposed to potential occupational hazards and, recently, epidemiological studies have examined their morbidity and mortality relative to the general population. Aircrews are, however, likely to differ from the general population in several respects which may affect the validity of such comparisons. METHODS: A cohort of 17,990 commercial aircrews was identified through the United Kingdom (UK) Civil Aviation Authority medical records and is being followed for morbidity and mortality. Demographic, lifestyle, reproductive, and medical characteristics of commercial aircrews were compared with those of: 1) UK air traffic control officers (ATCOs; N = 3386) identified in a similar way as aircrews; and 2) estimates for the UK general population. RESULTS: Aircrews and ATCOs had similar characteristics, except that sex-age-adjusted prevalences for current smoking, obesity, and hypertension were statistically significantly higher in the latter. Both aircrews and ATCOs differed considerably from the general population with, for instance, much lower sex-age-adjusted prevalences of current smoking, obesity, and hypertension but higher levels of regular physical exercise. Age-adjusted fertility rates among female aircrews and ATCOs were only one-third of those in the general population. These differences were slightly attenuated when comparisons with the general population were restricted to its highest socio-economic stratum. DISCUSSION: The differences between aircrews and the general population are consistent with a strong "healthy worker effect." Aircrews and ATCOs undergo a similar employment selection process and thus taking the latter as the reference population, in addition to the general population, will help to minimize the "healthy worker effect" and gain insight into its biases.

Breast MRI segmentation for density estimation: Do different methods give the same results and how much do differences matter?

PURPOSE: To compare two methods of automatic breast segmentation with each other and with manual segmentation in a large subject cohort. To discuss the factors involved in selecting the most appropriate algorithm for automatic segmentation and, in particular, to investigate the appropriateness of overlap measures (e.g., Dice and Jaccard coefficients) as the primary determinant in algorithm selection. METHODS: Two methods of breast segmentation were applied to the task of calculating MRI breast density in 200 subjects drawn from the Avon Longitudinal Study of Parents and Children, a large cohort study with an MRI component. A semiautomated, bias-corrected, fuzzy C-means (BC-FCM) method was combined with morphological operations to segment the overall breast volume from in-phase Dixon images. The method makes use of novel, problem-specific insights. The resulting segmentation mask was then applied to the corresponding Dixon water and fat images, which were combined to give Dixon MRI density values. Contemporaneously acquired T1 - and T2 -weighted image datasets were analyzed using a novel and fully automated algorithm involving image filtering, landmark identification, and explicit location of the pectoral muscle boundary. Within the region found, fat-water discrimination was performed using an Expectation Maximization-Markov Random Field technique, yielding a second independent estimate of MRI density. RESULTS: Images are presented for two individual women, demonstrating how the difficulty of the problem is highly subject-specific. Dice and Jaccard coefficients comparing the semiautomated BC-FCM method, operating on Dixon source data, with expert manual segmentation are presented. The corresponding results for the method based on T1 - and T2 -weighted data are slightly lower in the individual cases shown, but scatter plots and interclass correlations for the cohort as a whole show that both methods do an excellent job in segmenting and classifying breast tissue. CONCLUSIONS: Epidemiological results demonstrate that both methods of automated segmentation are suitable for the chosen application and that it is important to consider a range of factors when choosing a segmentation algorithm, rather than focus narrowly on a single metric such as the Dice coefficient.

Polymorphisms and circulating levels in the insulin-like growth factor system and risk of breast cancer: a systematic review.

We reviewed all English-language articles on associations among circulating levels of the insulin-like growth factors (IGF) and their binding proteins (IGFBP), polymorphisms in their genes, and breast cancer risk. In premenopausal women, five of eight IGF-I studies and four of six IGFBP-3 studies of circulating levels found that women in the highest quantile had more than twice the risk of developing breast cancer of those in the lowest, although in some this effect was only apparent at young ages. In postmenopausal women, however, there was no consistent effect. A simple sequence length polymorphism 1 kb 5' to IGF-I was examined in relation to circulating levels of IGF-I (12 studies) or breast cancer risk (4 studies), but there was no convincing evidence of any effect. For an A/C polymorphism 5' to IGFBP-3, all three studies were consistent with a modest effect on circulating levels, but no evidence of a direct effect on breast cancer risk was seen in the only relevant study. Variation within the reference range of IGF-I and IGFBP-3 may confer only modest increases in breast cancer risk, and any single polymorphism may only account for a small proportion of that variation. Nevertheless, population attributable fractions for high circulating levels of IGF-I and IGFBP-3 and for common genetic variants could be substantial. Further large studies, or combined analysis of data from existing studies, are needed to quantify these effects more precisely.

Trajetória de Mulheres Rastreadas para o Câncer de Mama na Rede Pública de Saúde / Trajectory of Breast Cancer Screened Women in Unified Health System / Trayectoria de Mujeres Rastreadas para el Cáncer de Mama en la Red Pública de Salud

Introdução: Conhecer os tempos entre as etapas do programa de rastreamento é importante para acompanhar as ações de controle de câncer. Objetivo: Estimar o intervalo de tempo entre o resultado suspeito de malignidade pela mamografia e o início do primeiro tratamento, e identificar fatores associados ao seu início, entre mulheres rastreadas para câncer de mama, nos serviços do Sistema Único de Saúde (SUS) do município do Rio de Janeiro. Método: Registros do Sistema de Informação do Controle do Câncer de Mama para mulheres de 40-69 anos, com uma mamografia de rastreamento efetuada em julho-dezembro/2010, com resultados suspeitos (BI-RADS® 4 ou 5), foram relacionados com os Sistemas de Informação Hospitalar, Ambulatorial e de Mortalidade para 2010-2012. O tempo foi estimado pelo método de Kaplan-Meier, e seus determinantes identificados pela regressão de Cox. Resultados: Entre 158 mulheres com mamografia alterada, foram identificados registros de 66 (41,8%) casos de câncer de mama. Destes, 12,1% tinham informações sobre biópsias prévias. O tempo mediano entre a mamografia e o início do tratamento foi de 206 dias, sendo menor para mulheres entre 40-49 anos (138 dias) do que para as mais idosas (190 para mulheres de 50-59 anos; 234 dias para mulheres de 60-69 anos) (Log-rank, p<0,05). Mulheres que repetiram mamografia apresentaram maior atraso (hazard ratio: 0,36; intervalo de confiança de 95% 0,19-0,72). Conclusão: Há poucas biópsias registradas no SUS e longo tempo até o início de tratamento, mesmo quando as mamografias são solicitadas por hospitais especializados, demonstrando necessidade de o SUS melhorar o seguimento de mulheres com mamografia suspeita.

Introduction: Knowing the times between the steps of a screening program is important to track the cancer control actions. Objective: Estimate the time interval between the suspected result of malignant mammography and the beginning of the first treatment, and to identify associated factors with its onset, among women screened for breast cancer, in services of the Unified Health System (SUS) in the city of Rio de Janeiro. Method: The records of the Information System of Breast Cancer Control for women aged 40-69 years, with a screening mammography carried out in july-december/2010, and whose results revealed suspicious (BI-RADS® 4 or 5) were related to Hospital, Outpatient and Mortality Information Systems for 2010-12. The time was estimated by Kaplan-Meier method, and its determinants were identified through Cox regression. Results: 158 women with altered mammography, records were identified, with breast cancer diagnosis, in the other databases for 66 (41.8%). Of these, 12.1% had information on biopsies. The median time between mammography and the start of treatment was 206 days, being lower for women aged 40-49 years (138 days) than for older women (190 for women aged 50-59; 234 days for women of 60-69 years) (Log rank, p<0.05). Women who repeated the mammography (hazard ratio: 0.36; 95% confidence interval 0.19-0.72) presented a longer time. Conclusion: There are few biopsies registered in the SUS and long time until the beginning of treatment, even when mammographies are requested by specialized hospitals, which demonstrates the need for SUS to improve the follow-up of women with suspected mammography.

Introducción: Conocer los tiempos entre las etapas de programa de rastreo es importante para controlar las acciones de control del cáncer. Objetivo:Estimar el intervalo de tiempo entre resultado sospechoso de malignidad de la mamografía y inicio del primer tratamiento, y identificar factores asociados, entre mujeres rastreadas para cáncer de mama, en servicios del Sistema Único de Salud (SUS), municipio de Río de Janeiro. Método:Registros del Sistema de Información del Control del Cáncer de Mama para mujeres de 40-69 años, con una mamografía de rastreo efectuada en julio-diciembre/2010, cuyos resultados revelaron alteraciones sospechosas (BI-RADS® 4 o 5) relacionados con Sistemas de Información Hospitalaria, Ambulatorial y de Mortalidad para 2010-12. El tiempo fue estimado pelo método Kaplan-Meier, y sus determinantes identificados por la regresión de Cox. Resultados: Entre 158 mujeres con mamografía alterada, fueron identificados registros, con diagnóstico de cáncer de mama, en otras bases para 66 (41,8%). Dellas, 12,1% tenía informaciones sobre biopsias. Tiempo medio entre la mamografía y inicio del tratamiento fue de 206 días, siendo menor para mujeres entre 40-49 años (138 días) que para ancianas (190 para mujeres de 50-59 años, 234 días para mujeres de 60-a 69 años) (Log-rank, p <0,05). Mujeres que repitió la mamografía (hazard ratio: 0,36, intervalo de confianza del 95% 0,19-0,72) presentaron mayor tiempo. Conclusión:Hay pocas biopsias registradas en SUS y largo tiempo hasta el inicio del tratamiento, incluso cuando las mamografías son solicitadas por hospitales especializados, demostrando la necesidad del SUS de mejorar el seguimiento de mujeres con mamografía sospechosa

Common variants in ZNF365 are associated with both mammographic density and breast cancer risk.

High-percent mammographic density adjusted for age and body mass index is one of the strongest risk factors for breast cancer. We conducted a meta analysis of five genome-wide association studies of percent mammographic density and report an association with rs10995190 in ZNF365 (combined P = 9.6 × 10(-10)). Common variants in ZNF365 have also recently been associated with susceptibility to breast cancer.

Maternal pelvic size not predictive of daughter's breast cancer or ovarian cancer in a large Swedish cohort.

Recent studies from Finland reported that maternal pelvic size predicted daughters' breast and ovarian cancer, possibly because maternal pelvic size is a marker for in utero hormone exposure. We sought to replicate this association in 3,845 women born between 1915 and 1929 in Uppsala, Sweden, and followed from 1960 to 2002. Archived obstetric records provided the standard measures of maternal pelvic size (intercristal distance, interspinous distance, the intercristal-interspinous difference, and the external conjugate distance). The Swedish Cancer Registry ascertained cancer incidence, with 273 cohort members developing primary breast cancer, and 52 developing primary ovarian cancer during the follow-up period. There was no evidence (P > 0.1) of an association between any measure of maternal pelvic size and incidence of either breast or ovarian cancer. This was true both before and after adjustment for various characteristics of the women and their mothers, and in analyses stratified by age at diagnosis (<50 versus >or=50 years of age, as a proxy for premenopausal and postmenopausal ages). There was also no evidence of an association in subgroup analyses restricted specifically to those groups in which the Finnish data found the greatest effect. Our study is of comparable size to the Finnish studies and was highly powered (>99%) to detect effects of the magnitude they reported. Our nonreplication therefore casts doubt on the link between maternal pelvic size and risk of breast and ovarian cancer in the offspring.

Overseas sun exposure, nevus counts, and premature skin aging in young English women: a population-based survey.

A large number of melanocytic nevi is the strongest known risk factor for melanoma in whites, but its relationship to sun exposure overseas among young white women living in temperate climates is unclear. A total of 754 white English women aged 18-46 years were recruited into a cross-sectional study in 1997-2000 to investigate the effect of ultraviolet exposures on numbers of nevi and atypical nevi, and on skin aging as measured by microtopography. Having ever holidayed in hotter countries was associated with a greater age- and phenotype-adjusted mean number of whole-body nevi (percent increase=74; 95% confidence interval: 24, 144; P=0.001), particularly for holidays taken at ages 18-29 years and for counts of the trunk and lower limbs. Having ever lived overseas was not associated with nevus counts, but was inversely associated with number of atypical nevi (P=0.02). Skin aging was not associated with residence or holidays abroad. The association of holidays overseas with an increased nevus count in young white women, which was stronger in the anatomical sites intermittently exposed to sunlight, supports the hypothesis that intermittent sun exposure is of relevance in the etiology of nevi and, hence, melanoma. The findings are of public health relevance given the growing popularity of foreign holidays.

Vitamin D receptor gene polymorphisms, serum 25-hydroxyvitamin D levels, and melanoma: UK case-control comparisons and a meta-analysis of published VDR data.

We have carried out melanoma case-control comparisons for six vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) and serum 25-hydroxyvitamin D(3) levels in order to investigate the role of vitamin D in melanoma susceptibility. There was no significant evidence of an association between any VDR SNP and risk in 1028 population-ascertained cases and 402 controls from Leeds, UK. In a second Leeds case-control study (299 cases and 560 controls) the FokI T allele was associated with increased melanoma risk (odds ratio (OR) 1.42, 95% confidence interval (CI) 1.06-1.91, p=0.02). In a meta-analysis in conjunction with published data from other smaller data sets (total 3769 cases and 3636 controls), the FokI T allele was associated with increased melanoma risk (OR 1.19, 95% CI 1.05-1.35), and the BsmI A allele was associated with a reduced risk (OR 0.81, 95% CI 0.72-0.92), in each instance under a parsimonious dominant model. In the first Leeds case-control comparison cases were more likely to have a higher body mass index (BMI) than controls (p=0.007 for linear trend). There was no evidence of a case-control difference in serum 25-hydroxyvitamin D(3) levels. In 1043 incident cases from the first Leeds case-control study, a single estimation of serum 25-hydroxyvitamin D(3) level taken at recruitment was inversely correlated with Breslow thickness (p=0.03 for linear trend). These data provide evidence to support the view that vitamin D and VDR may have a small but potentially important role in melanoma susceptibility, and putatively a greater role in disease progression.

Association of a common AKAP9 variant with breast cancer risk: a collaborative analysis.

Data from several studies have suggested that polymorphisms in A-kinase anchoring proteins (AKAPs), which are key components of signal transduction, contribute to carcinogenesis. To evaluate the impact of AKAP variants on breast cancer risk, we genotyped six nonsynonymous single-nucleotide polymorphisms that were predicted to be deleterious and found two (M463I, 1389G>T and N2792S, 8375A>G) to be associated with an allele dose-dependent increase in risk of familial breast cancer in a German population. We extended the analysis of AKAP9 M463I, which is in strong linkage disequilibrium with AKAP9 N2792S, to 9523 breast cancer patients and 13770 healthy control subjects from seven independent European and Australian breast cancer studies. All statistical tests were two-sided. The collaborative analysis confirmed the association of M463I with increased breast cancer risk. Among all breast cancer patients, the combined adjusted odds ratio (OR) of breast cancer for individuals homozygous for the rare allele TT (frequency = 0.19) compared with GG homozygotes was 1.17 (95% confidence interval [CI] = 1.08 to 1.27, P = .0003), and the OR for TT homozygotes plus GT heterozygotes compared with GG homozygotes was 1.10 (95% CI = 1.04 to 1.17, P = .001). Among the combined subset of 2795 familial breast cancer patients, the respective ORs were 1.27 (95% CI = 1.12 to 1.45, P = .0003) and 1.16 (95% CI = 1.06 to 1.27, P = .001).