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Concept: BRCA2


Objective To evaluate the strength and validity of the evidence for the association between adiposity and risk of developing or dying from cancer.Design Umbrella review of systematic reviews and meta-analyses.Data sources PubMed, Embase, Cochrane Database of Systematic Reviews, and manual screening of retrieved references.Eligibility criteria Systematic reviews or meta-analyses of observational studies that evaluated the association between indices of adiposity and risk of developing or dying from cancer.Data synthesis Primary analysis focused on cohort studies exploring associations for continuous measures of adiposity. The evidence was graded into strong, highly suggestive, suggestive, or weak after applying criteria that included the statistical significance of the random effects summary estimate and of the largest study in a meta-analysis, the number of cancer cases, heterogeneity between studies, 95% prediction intervals, small study effects, excess significance bias, and sensitivity analysis with credibility ceilings.Results 204 meta-analyses investigated associations between seven indices of adiposity and developing or dying from 36 primary cancers and their subtypes. Of the 95 meta-analyses that included cohort studies and used a continuous scale to measure adiposity, only 12 (13%) associations for nine cancers were supported by strong evidence. An increase in body mass index was associated with a higher risk of developing oesophageal adenocarcinoma; colon and rectal cancer in men; biliary tract system and pancreatic cancer; endometrial cancer in premenopausal women; kidney cancer; and multiple myeloma. Weight gain and waist to hip circumference ratio were associated with higher risks of postmenopausal breast cancer in women who have never used hormone replacement therapy and endometrial cancer, respectively. The increase in the risk of developing cancer for every 5 kg/m(2) increase in body mass index ranged from 9% (relative risk 1.09, 95% confidence interval 1.06 to 1.13) for rectal cancer among men to 56% (1.56, 1.34 to 1.81) for biliary tract system cancer. The risk of postmenopausal breast cancer among women who have never used HRT increased by 11% for each 5 kg of weight gain in adulthood (1.11, 1.09 to 1.13), and the risk of endometrial cancer increased by 21% for each 0.1 increase in waist to hip ratio (1.21, 1.13 to 1.29). Five additional associations were supported by strong evidence when categorical measures of adiposity were included: weight gain with colorectal cancer; body mass index with gallbladder, gastric cardia, and ovarian cancer; and multiple myeloma mortality.Conclusions Although the association of adiposity with cancer risk has been extensively studied, associations for only 11 cancers (oesophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney) were supported by strong evidence. Other associations could be genuine, but substantial uncertainty remains. Obesity is becoming one of the biggest problems in public health; evidence on the strength of the associated risks may allow finer selection of those at higher risk of cancer, who could be targeted for personalised prevention strategies.

Concepts: Cancer, Breast cancer, Obesity, Menopause, Estrogen, Colorectal cancer, Hereditary nonpolyposis colorectal cancer, BRCA2


Over the last two decades, ovarian cancer mortality rates have levelled or declined. There are, however, persisting and substantial differences in ovarian cancer patterns and trends.

Concepts: Vitamin D, Metastasis, Mortality rate, Hereditary nonpolyposis colorectal cancer, BRCA2, Ovarian cancer


Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer.

Concepts: Epidemiology, Cancer, Breast cancer, Metastasis, Menopause, Estrogen, BRCA2, BRCA1


Discordant trends in the incidence of metastatic breast and prostate cancer since the widespread implementation of early-detection efforts may reflect distinct disease dynamics or may result from the different screening strategies used.

Concepts: Epidemiology, Cancer, Breast cancer, Metastasis, Prostate cancer, Radiation therapy, BRCA2, Screening


The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer but its role in protecting other tissues from DNA damage has not been explored. Here we show a new role for BRCA1 as a gatekeeper of cardiac function and survival. In mice, loss of BRCA1 in cardiomyocytes results in adverse cardiac remodelling, poor ventricular function and higher mortality in response to ischaemic or genotoxic stress. Mechanistically, loss of cardiomyocyte BRCA1 results in impaired DNA double-strand break repair and activated p53-mediated pro-apoptotic signalling culminating in increased cardiomyocyte apoptosis, whereas deletion of the p53 gene rescues BRCA1-deficient mice from cardiac failure. In human adult and fetal cardiac tissues, ischaemia induces double-strand breaks and upregulates BRCA1 expression. These data reveal BRCA1 as a novel and essential adaptive response molecule shielding cardiomyocytes from DNA damage, apoptosis and heart dysfunction. BRCA1 mutation carriers, in addition to risk of breast and ovarian cancer, may be at a previously unrecognized risk of cardiac failure.

Concepts: DNA, Cancer, Mutation, Heart, DNA repair, BRCA2, P53, BRCA1


Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

Concepts: Genetics, Cancer, Breast cancer, Oncology, Tumor, BRCA2, Breast, BRCA1


INTRODUCTION: Detection of asymptomatic adnexal tumours in postmenopausal women has increased due to wider use of diagnostic ultrasound and imaging quality improvements. Reliable methods to differentiate between benign and malignant tumours are required to avoid delays in treating ovarian cancer and to prevent unnecessary interventions for benign lesions. In the UK, the Royal College of Obstetricians and Gynaecologists has issued guidance for the management of adnexal cysts in postmenopausal women, which is considered standard in routine clinical practice. The protocol utilises the Risk of Malignancy Index to assess the risk of adnexal lesion being malignant. This protocol has a relatively high intervention rate in order to avoid a delay in a cancer diagnosis. The Simple Rules Protocol designed by International Ovarian Tumour Analysis Group reports a low false-positive rate in the diagnosis of ovarian cancer without a loss of sensitivity and therefore has the potential to reduce unnecessary interventions in asymptomatic postmenopausal women with benign cysts. METHODS AND ANALYSIS: 140 postmenopausal women aged 40-80, with incidentally detected adnexal tumours on ultrasound scan will be recruited to this study. They will be randomly allocated, to be assessed and managed according to either of the two protocols under investigation. In both arms of the study the tumours will be classified into three groups: high, intermediate or low risk of malignancy. Women with high risk of malignancy will be referred for management in a tertiary cancer centre, women with low-risk tumours will be managed expectantly, while those with intermediate risk findings have surgery in their local hospital units. Analysis will be on an intention-to-treat basis. ETHICS AND DISSEMINATION: Research ethical approval was granted by the North London Research Ethical Committee 2 (10/H0724/48). Trial results will be published according to the CONSORT statement. TRIAL REGISTRATION NUMBER: Registration at ISRCTN89034131.

Concepts: Cancer, Oncology, Sensitivity and specificity, Hereditary nonpolyposis colorectal cancer, Benign tumor, Ovarian cyst, BRCA2, Hysterectomy


Aurora kinase A (AURKA) localizes to centrosomes and mitotic spindles where it mediates mitotic progression and chromosomal stability. Overexpression of AURKA is common in cancer, resulting in acquisition of alternate non-mitotic functions. In the current study, we identified a novel role for AURKA in regulating ovarian cancer cell dissemination and evaluated the efficacy of an AURKA-selective small molecule inhibitor, alisertib (MLN8237), as a single agent and combined with paclitaxel using an orthotopic xenograft model of epithelial ovarian cancer (EOC). Ovarian carcinoma cell lines were used to evaluate the effects of AURKA inhibition and overexpression on migration and adhesion. Pharmacological or RNA interference-mediated inhibition of AURKA significantly reduced ovarian carcinoma cell migration and adhesion and the activation-associated phosphorylation of the cytoskeletal regulatory protein SRC at tyrosine 416 (pSRC(Y416)). Conversely, enforced expression of AURKA resulted in increased migration, adhesion and activation of SRC in cultured cells. In vivo tumor growth and dissemination were inhibited by alisertib treatment as a single agent. Moreover, combination of alisertib with paclitaxel, an agent commonly used in treatment of EOC, resulted in more potent inhibition of tumor growth and dissemination compared with either drug alone. Taken together, these findings support a role for AURKA in EOC dissemination by regulating migration and adhesion. They also point to the potential utility of combining AURKA inhibitors with taxanes as a therapeutic strategy for the treatment of EOC patients.Oncogene advance online publication, 21 January 2013; doi:10.1038/onc.2012.632.

Concepts: Gene expression, Cancer, Hereditary nonpolyposis colorectal cancer, BRCA2, Enzyme inhibitor, Mitosis, BRCA1, Aurora kinase


We assessed the measurement equivalence and feasibility of the paper-and-pencil and touch-screen modes of administration of the Taiwan Chinese version of the EORTC QLQ-PR25, a commonly used questionnaire to evaluate the health-related quality of life (HRQOL) in patients with prostate cancer in Taiwan.

Concepts: Cancer, Metastasis, Obesity, Prostate cancer, Radiation therapy, Quality, BRCA2, Screening


Germline BRCA2 mutations are associated with poorer outcome prostate cancer (PCa) compared with sporadic tumours but this association remains to be characterized. In this study, we aim to assess if there is a signature set of copy number alterations (CNA) that could aid to the identification of BRCA2 mutated tumours and would assist us to understand their aggressive clinical behaviour.

Concepts: Immune system, Cancer, Mutation, Germline mutation, DNA repair, Prostate cancer, BRCA2, Mutagen