p53 mutations in human cutaneous melanoma correlate with sun exposure but are not always involved in melanomagenesis

In melanoma, the relationship between sun exposure and the origin of mutations in either the N-ras oncogene or the p53 tumour-suppressor gene is not as clear as in other types of skin cancer. We have previously shown that mutations in the N-ras gene occur more frequently in melanomas originating from sun-exposed body sites, indicating that these mutations are UV induced. To investigate whether sun exposure also affects p53 in melanoma, we analysed 81 melanoma specimens for mutations in the p53 gene. The mutation frequency is higher than thus far reported: 17 specimens (21%) harbour one or more p53 mutations. Strikingly, 17 out of 22 mutations in p53 are of the C:G to T:A or CC:GG to TT:AA transitional type, strongly suggesting an aetiology involving UV exposure. Interestingly, the p53 mutation frequency in metastases was much lower than in primary tumours. In the case of metastases, a role for sun exposure was indicated by the finding that the mutations are present exclusively in skin metastases and not in internal metastases. Together with a relatively frequent occurrence of silent third-base pair mutations in primary melanomas, this indicates that the p53 mutations, at least in these tumours, have not contributed to melanomagenesis and may have originated after establishment of the primary tumour. 1999 Cancer Research Campaig

Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations

Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n = 626; HUNT2 n = 112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42–1.20); 0.94 (0.72–1.22); 1.12 (0.82–1.53) and 1.26 (0.79–2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant

Endogenous sex steroids and risk of cervical carcinoma : results from the EPIC study

Background: Epidemiologic data and animal models suggest that, despite the predominant role of human papillomavirus infection, sex steroid hormones are also involved in the etiology of invasive cervical carcinoma (ICC). Methods: Ninety-nine ICC cases, 121 cervical intraepithelial neoplasia grade 3 (CIN3) cases and 2 control women matched with each case for center, age, menopausal status and blood collection-related variables, were identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Circulating levels of testosterone (T) and estradiol (E(2)); dehydroepiandrosterone sulfate (DHEAS); progesterone (premenopausal women); and sex hormone-binding globulin (SHBG) were measured using immunoassays. Levels of free (f) T and E(2) were calculated from absolute concentrations of T, E(2), and SHBG. Odds ratios (ORs) and 95% confidence intervals (CI) were computed using regularized conditional logistic regression. Results: Among premenopausal women, associations with ICC were observed for fT (OR for highest vs. lowest tertile 5.16, 95% CI, 1.50-20.1). SHBG level was associated with a significant downward trend in ICC risk. T, E(2), fE(2), and DHEAS showed nonsignificant positive association with ICC. Progesterone was uninfluential. Among postmenopausal women, associations with ICC were found for T (OR 3.14; 95% CI, 1.21-9.37), whereas E(2) and fT showed nonsignificant positive association. SHBG level was unrelated to ICC risk in postmenopausal women. No associations between any hormone and CIN3 were detected in either pre- or postmenopausal women. Conclusions: Our findings suggest for the first time that T and possibly E(2) may be involved in the etiology of ICC. Impact: The responsiveness of cervical tumors to hormone modulators is worth exploring. Cancer Epidemiol Biomarkers Prev; 20(12); 2532-40. (C) 2011 AACR

High-Anxious Individuals Show Increased Chronic Stress Burden, Decreased Protective Immunity, and Increased Cancer Progression in a Mouse Model of Squamous Cell Carcinoma

In spite of widespread anecdotal and scientific evidence much remains to be understood about the long-suspected connection between psychological factors and susceptibility to cancer. The skin is the most common site of cancer, accounting for nearly half of all cancers in the US, with approximately 2–3 million cases of non-melanoma cancers occurring each year worldwide. We hypothesized that a high-anxious, stress-prone behavioral phenotype would result in a higher chronic stress burden, lower protective-immunity, and increased progression of the immuno-responsive skin cancer, squamous cell carcinoma. SKH1 mice were phenotyped as high- or low-anxious at baseline, and subsequently exposed to ultraviolet-B light (1 minimal erythemal dose (MED), 3 times/week, 10-weeks). The significant strengths of this cancer model are that it uses a normal, immunocompetent, outbred strain, without surgery/injection of exogenous tumor cells/cell lines, and produces lesions that resemble human tumors. Tumors were counted weekly (primary outcome), and tissues collected during early and late phases of tumor development. Chemokine/cytokine gene-expression was quantified by PCR, tumor-infiltrating helper (Th), cytolytic (CTL), and regulatory (Treg) T cells by immunohistochemistry, lymph node T and B cells by flow cytometry, adrenal and plasma corticosterone and tissue vascular-endothelial-growth-factor (VEGF) by ELISA. High-anxious mice showed a higher tumor burden during all phases of tumor development. They also showed: higher corticosterone levels (indicating greater chronic stress burden), increased CCL22 expression and Treg infiltration (increased tumor-recruited immuno-suppression), lower CTACK/CCL27, IL-12, and IFN-γ gene-expression and lower numbers of tumor infiltrating Th and CTLs (suppressed protective immunity), and higher VEGF concentrations (increased tumor angiogenesis/invasion/metastasis). These results suggest that the deleterious effects of high trait anxiety could be: exacerbated by life-stressors, accentuated by the stress of cancer diagnosis/treatment, and mediate increased tumor progression and/or metastasis. Therefore, it may be beneficial to investigate the use of chemotherapy-compatible anxiolytic treatments immediately following cancer diagnosis, and during cancer treatment/survivorship

The presence of Legionella species in watersystems supplied with tapwater in the Netherlands

Legionella's werden geisoleerd uit warm watervoorzieningen, water van koeltorens, water van luchtbevochtigers en incidenteel uit drinkwater zelf. In 32% van de onderzochte objecten werden, uit water met een temperawtuur varierend van 6 graden C tot en met 59 graden C, legionella's geisoleerd overwegend (75%) in concentraties kleiner dan 10 c.f.u./ml. In deze objecten werden nergens gevallen van legionellose onderkend. De in dit onderzoek voor het eerst geconstateerde besmettingen van luchtbevochtigers met legionellae worden als ongewenst gekwalificeerd.DGM/DWB-D /Trouwborst

Public health genomics : What are the opportunities for prevention?

In Nederland wordt op het genoom gebaseerde kennis en technologie nog weinig toegepast in de publieke gezondheidszorg. De ontwikkelingen op dit vakgebied, dat public health genomics wordt genoemd, gaan ook in Nederland langzamer dan verwacht. Deskundigen hebben hier verschillende verklaringen voor, waaronder de biologische complexiteit van het genoom en de interacties met de omgeving, en de vaak lage voorspellende waarde van genetische variaties voor chronische ziekten. Daarnaast ervaren deskundigen de trage besluitvorming en maatschappelijke discussies over nieuwe mogelijkheden op het gebied van public health genomics als vertragend. Toch zijn er veelbelovende ontwikkelingen voor toekomstige toepassingen van public health genomics. Dit geldt met name voor ziektepreventie, bijvoorbeeld het gebruiken van genetische risicoprofielen bij kankerscreening, het toepassen van prenatale testen die meer zekerheid en minder risico's bieden dan de huidige testen, en het screenen van paren met een kinderwens op dragerschap van erfelijke aandoeningen. Van genomics-toepassingen bij gezondheidsbevordering zijn minder hoge verwachtingen. Zo lijkt het communiceren van genetische risicoinformatie over ziekten als diabetes of hart- en vaatziekten maar beperkte toegevoegde waarde te hebben bij leefstijlinterventies. In opdracht van ZonMw heeft het RIVM de stand van zaken van public health genomics in Nederland en de kansen voor preventie in kaart gebracht. Het onderzoek bestond uit literatuurinventarisatie, deskundigenconsultatie en een viertal casestudies. Voor de deskundigenconsultatie werden deskundigen in Nederland op het gebied van public health genomics, of een gerelateerd vakgebied, uitgenodigd om aan een online discussieplatform deel te nemen. Hierbij konden zij reageren op stellingen over huidige toepassingen en toekomstverwachtingen van public health genomics.In the Netherlands, applications of genomics in public health are still rather scanty. Progress in public health genomics is lagging behind expectations. Experts in the field of public health genomics mentioned several contributing factors, including: biological complexity, low predictive value, slow decision-making and public debate. However, there are still promising developments for applications of public health genomics in the future. This holds especially for disease prevention, for example: risk stratification in cancer screening, non-invasive prenatal testing, and preconception carrier screening. With respect to applications of genomics in health promotion, expectations are more modest. This is illustrated by the limited additional value of genetic risk information about non-communicable diseases to the effectiveness of lifestyle interventions. ZonMw commissioned RIVM to explore the state of the art of public health genomics in the Netherlands with special emphasis to the opportunities for disease prevention and health promotion. The study consisted of a literature survey, an expert consultation, and four case studies. For the expert consultation, Dutch public health genomics experts were invited to participate in an online discussion forum, where people could respond to statements about current applications and future prospects in relation to public health genomics.ZonM