A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population

<p>Abstract</p> <p>Background</p> <p>In recent years, numerous studies have assessed the prevalence of germline mutations in <it>BRCA1 </it>and <it>BRCA2 </it>genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of <it>BRCA1-2 </it>mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of <it>BRCA1-2 </it>germline mutations was also evaluated.</p> <p>Methods</p> <p>Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for <it>BRCA1-2 </it>mutations by DHPLC analysis and DNA sequencing. Association of <it>BRCA1 </it>and <it>BRCA2 </it>mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test.</p> <p>Results and Conclusion</p> <p>Overall, 8 <it>BRCA1 </it>and 5 <it>BRCA2 </it>deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in <it>BRCA2 </it>gene. The geographical distribution of <it>BRCA1-2 </it>mutations was related to three specific large areas of Sardinia, reflecting its ancient history: <it>a</it>) the Northern area, linguistically different from the rest of the island (where a <it>BRCA2 c.8764_8765delAG </it>mutation with founder effect was predominant); <it>b</it>) the Middle area, land of the ancient Sardinian population (where <it>BRCA2 </it>mutations are still more common than <it>BRCA1 </it>mutations); and <it>c</it>) the South-Western area, with many Phoenician and Carthaginian locations (where <it>BRCA1 </it>mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of <it>BRCA1-2 </it>germline mutations.</p

european journal of cancer

Medroxyprogesterone acetate (MPA) is widely used in oncology both in the treatment of hormone-related cancers and as supportive therapy in anorexia/cachexia syndrome (ACS), but conclusive data are not yet available to explain its anticachectic effect. ACS is characterised by weight loss, changes in metabolism, reduction of appetite, nausea and vomiting. Several cytokines, mainly interleukin (IL)-1, IL-2, IL-6 and tumour necrosis factor alpha (TNF alpha), are involved in the pathogenesis of ACS. Additionally, nausea and vomiting can be mediated by factors inducing serotonin (5-HT) production and/or release by pleiotropic cells including activated T lymphocytes. In the present study, we report the effect of MPA on peripheral blood mononuclear cells (PBMC) from 10 cancer patients in advanced stage of disease (6 head and neck, 2 colon, 1 lung and 1 ovary). The proliferative response of PBMC to PHA, anti-CD3 monoclonal antibody (MAb) or recombinant IL-2 (rIL-2), the production of IL-1 beta, IL-2, IL-6, TNF alpha and 5-HT by PHA-stimulated PBMC and the expression of lymphocyte membrane-bound IL-2 receptor (IL-2R) subunities (CD25 and CD122) were studied. The addition of MPA significantly reduced the PBMC proliferative response to PHA and anti-CD3 MAb but not to rIL-2. MPA 0.2 microgram/ml was also capable of reducing the levels of IL-1 beta, IL-6, TNF alpha and 5-HT produced in culture by PHA-stimulated PBMC, whereas it did not induce any change in the percentage of PBMC expressing either CD25 or CD122 or both molecules after stimulation with PHA or anti-CD3 mAb

Medroxyprogesterone acetate reduces the in vitro production of cytokines and serotonin involved in anorexial/cachexia and emesis by peripheral blood mononuclear cells of cancer patients

Medroxyprogesterone acetate (MPA) is widely used in oncology both in the treatment of hormone-related cancers and as supportive therapy in anorexia/cachexia syndrome (ACS), but conclusive data are not yet available to explain its anticachectic effect. ACS is characterised by weight loss, changes in metabolism, reduction of appetite, nausea and vomiting. Several cytokines, mainly interleukin (IL)-1, IL-2, IL-6 and tumour necrosis factor α (TNFα), are involved in the pathogenesis of ACS. Additionally, nausea and vomiting can be mediated by factors inducing serotonin (5-HT) production and/or release by pleiotropic cells including activated T lymphocytes. In the present study, we report the effect of MPA on peripheral blood mononuclear cells (PBMC) from 10 cancer patients in advanced stage of disease (6 head and neck, 2 colon, 1 lung and 1 ovary). The proliferative response of PBMC to PHA, anti-CD3 monoclonal antibody (MAb) or recombinant IL-2 (rIL-2), the production of IL-1β, IL-2, IL-6, TNFα and 5-HT by PHA-stimulated PBMC and the expression of lymphocyte membrane-bound IL-2 receptor (IL-2R) subunities (CD25 and CD122) were studied. The addition of MPA significantly reduced the PBMC proliferative response to PHA and anti-CD3 MAb but not to rIL-2. MPA 0.2 μg/ml was also capable of reducing the levels of IL-1β, IL-6, TNFα and 5- HT produced in culture by PHA-stimulated PBMC, whereas it did not induce any change in the percentage of PBMC expressing either CD25 or CD122 or both molecules after stimulation with PHA or anti-CD3 mAb