The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions.

Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).

The ambulatory monitoring documents a more elevated blood pressure regimen (pre-hypertension) in normotensives with endothelial dysfunction.

PURPOSE: The present study investigates the blood pressure (BP) 24-h values in normotensives with and without endothelial dysfunction (ED). The scope is to detect differences in BP regimen supporting the hypothesis that the ED is associated with vasopressant effects that can cause a condition of "pre-hypertension". MATERIALS AND METHODS: Thirty-eight normotensives were investigated in their endothelial function by mean of the non-invasive post-ischemic brachial artery vasodilation test (endothelium-dependent vasomotricity). Their were also automatically and non-invasively monitored in their systolic (S) and diastolic (D) BP over the 24-h period in order to confirm that they were not hypertensive. RESULTS: Eight of the investigated normotensives were found to show an ED. A significantly higher daily mean level as well as a more prominent nychtohemeral variability in SBP and DBP 24-h values were observed in the normotensives with ED as compared to the normotensives without ED. The higher BP regimen in the normotensives with ED was found to maintain a circadian rhythm. However, a significant amplification the second harmonic component, with a 12-h period, was observed. The different structure of the BP 24-h pattern in the normotensives with ED was confirmed by the detection of additional ultradian components at the linear-in-period spectral analysis. CONCLUSIONS: The present study documented a significant elevation of BP 24-h values in normotensives with ED that is the reflex of consistent changes in the frequency organization of the BP circadian pattern. The elevation of BP regimen suggests that the ED is associated with vasopressant effects even in normotensives. Such a condition of higher BP in normotensives with ED can be regarded as a status of "pre-hypertension".

Higher blood pressure load (baric impact) in normotensives with endothelial dysfunction: a paraphysiological status of "pre-hypertension".

PURPOSE: The present study investigated the blood pressure (BP) load (L), namely Baric Impact (BI), in normotensives with and without endothelial dysfunction (ED). The aim was to detect baric differences supporting the thesis that the ED is associated with vasopressant effects that are responsible for a paraphysiological condition of higher BP (pre-hypertension) even in normotensives. MATERIALS AND METHODS: Thirty-eight normotensives were investigated in their endothelium-dependent vasomotricity by mean of the non-invasive post-ischemic brachial artery vasodilation test. Additionally, their underwent a non-invasive ambulatory (A) BP monitoring (M) over the 24-h span in order to confirm that they were not hypertensive. The ABPM served also to compute the systolic (S) and diastolic (D) BI. RESULTS: The ED was detected in eight normotensives of the investigated group. These cases with ED were found to show a significantly higher SBI and DBI as compared to the normotensives without ED. CONCLUSIONS: The significant elevation of the SBI and DBI in normotensives with ED is an evidence convincing that a dysfunctional endothelium is responsible for vasopressant effects that cause a paraphysiological status of "pre-hypertension".