Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer

Lacking targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically challenging subtype of breast cancer. In this study, we reveal that Death Effector Domain-containing DNA-binding protein (DEDD), which is overexpressed in > 60% of TNBCs, drives a mitogen-independent G1/S cell cycle transition through cytoplasm localization. The gain of cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock 71 kDa protein 8 (HSC70). Concurrently, DEDD interacts with Rb family proteins and promotes their proteasome-mediated degradation. DEDD overexpression renders TNBCs vulnerable to cell cycle inhibition. Patients with TNBC have been excluded from CDK 4/6 inhibitor clinical trials due to the perceived high frequency of Rb-loss in TNBCs. Interestingly, our study demonstrated that, irrespective of Rb status, TNBCs with DEDD overexpression exhibit a DEDD-dependent vulnerability to combinatorial treatment with CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo. Thus, our study provided a rationale for the clinical application of CDK4/6 inhibitor combinatorial regimens for patients with TNBC

Clinical And Imageological Features Of Lung Squamous Cell Carcinoma With EGFR Mutations.

Purpose(#br)To analyze the distribution of epidermal growth factor receptor ( EGFR ) mutations; characterize the clinical and imageological features of lung squamous cell carcinoma (LSCC) in a large population of patients; and assess correlations between clinical and imageological characteristics and clinical outcomes of LSCC patients harboring EGFR mutations.(#br)Patients and methods(#br)Three pathologists retrospectively evaluated the morphological and immunohistochemical data of 2,322 patients with LSCC resected between February 2013 and December 2017. Data on the distribution of EGFR mutations and the clinical and imageological characteristics of the patients were retrospectively collected. Correlations between the EGFR mutation status and clinical outcomes were evaluated using univariate and multivariate analyses.(#br)Results(#br) EGFR mutations were found in 3.4% of patients with LSCC and predominantly in female and non-smoking patients. Tumor lesions in patients with EGFR -positive mutations were more irregularly shaped than those in patients with EGFR -negative mutations ( P = 0.045). In non-smoking patients with LSCC, the proportion of marked spiculation was significantly higher in the EGFR -positive group than in the EGFR -negative group ( P = 0.043). No significant difference in recurrence-free survival was noted between LSCC patients harboring EGFR -positive and those harboring EGFR -negative mutations. No difference in metastases was observed between the EGFR -positive and EGFR -negative cohorts.(#br)Conclusion(#br)Female gender, non-smoking habit, irregularly shaped tumor, and marked spiculation might predict the presence of EGFR mutations in LSCC. The administration of tyrosine kinase inhibitors to patients with LSCC after screening for EGFR mutations based on their clinical and imageological features would likely result in a population with a greater sensitivity to afatinib

Family history and risk of bladder cancer:an analysis accounting for first- and second-degree relatives

Although evidence suggests that a positive family history of bladder cancer in first-degree relatives is an important risk factor for bladder cancer occurrence, results remain unclear. The influence of family history of non-bladder cancers and more distant relatives on bladder cancer risk is inconsistent. This research therefore, aims to increase the understanding of the association between family history and bladder cancer risk based on worldwide case-control studies. In total 4,327 cases and 8,948 non-cases were included. Pooled odds ratios (ORs), with corresponding 95% confidence intervals (CIs), were obtained using multilevel logistic regression models, adjusted by age, sex, ethnicity, smoking status, and smoking pack-years. The results show bladder cancer risk increased by having a first- or second-degree relative affected with bladder cancer (OR 2.72, 95%CI 1.55-4.77 and OR 1.71, 95%CI 1.22-2.40, respectively), and non-urologic cancers (OR 1.61, 95%CI 1.19-2.18). Moreover, bladder cancer risk increased by number of cancers affected first-degree relatives (for 1 and >1 first-degree relatives: OR 1.42, 95% CI 1.02-2.04; OR 2.67, 95% CI 1.84-3.86, respectively). Our findings highlight an increased bladder cancer risk for a positive bladder cancer family history in first- and second-degree relatives, and indicate a possible greater effect for an increment of numbers of affected relatives

Breast feeding, parity and breast cancer subtypes in a Spanish cohort

Background: Differences in the incidence and outcome of breast cancer among Hispanic women compared with white women are well documented and are likely explained by ethnic differences in genetic composition, lifestyle, or environmental exposures. METHODOLGY/PRINCIPAL FINDINGS: A population-based study was conducted in Galicia, Spain. A total of 510 women diagnosed with operable invasive breast cancer between 1997 and 2010 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics were collected. The different breast cancer tumor subtypes were compared on their clinico-pathological characteristics and risk factor profiles, particularly reproductive variables and breastfeeding. Among the 501 breast cancer patients (with known ER and PR receptors), 85% were ER+/PR+ and 15% were ER-&PR-. Among the 405 breast cancer with known ER, PR and HER2 status, 71% were ER+/PR+/HER2- (luminal A), 14% were ER+/PR+/HER2+ (luminal B), 10% were ER-/PR-/HER2- (triple negative breast cancer, TNBC), and 5% were ER-/PR-/HER2+ (non-luminal). A lifetime breastfeeding period equal to or longer than 7 months was less frequent in case patients with TNBC (OR = 0.25, 95% CI = 0.08-0.68) compared to luminal A breast cancers. Both a low (2 or fewer pregnancies) and a high (3-4 pregnancies) number of pregnancies combined with a long breastfeeding period were associated with reduced odds of TNBC compared with luminal A breast cancer, although the association seemed to be slightly more pronounced among women with a low number of pregnancies (OR = 0.09, 95% CI = 0.005-0.54). Conclusions/significance: In case-case analyses with the luminal A cases as the reference group, we observed a lower proportion of TNBC among women who breastfed 7 or more months. The combination of longer breastfeeding duration and lower parity seemed to further reduce the odds of having a TNBC compared to a luminal A breast cancer

Breast feeding, parity and breast cancer subtypes in a Spanish cohort

Background: Differences in the incidence and outcome of breast cancer among Hispanic women compared with white women are well documented and are likely explained by ethnic differences in genetic composition, lifestyle, or environmental exposures. METHODOLGY/PRINCIPAL FINDINGS: A population-based study was conducted in Galicia, Spain. A total of 510 women diagnosed with operable invasive breast cancer between 1997 and 2010 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics were collected. The different breast cancer tumor subtypes were compared on their clinico-pathological characteristics and risk factor profiles, particularly reproductive variables and breastfeeding. Among the 501 breast cancer patients (with known ER and PR receptors), 85% were ER+/PR+ and 15% were ER-&PR-. Among the 405 breast cancer with known ER, PR and HER2 status, 71% were ER+/PR+/HER2- (luminal A), 14% were ER+/PR+/HER2+ (luminal B), 10% were ER-/PR-/HER2- (triple negative breast cancer, TNBC), and 5% were ER-/PR-/HER2+ (non-luminal). A lifetime breastfeeding period equal to or longer than 7 months was less frequent in case patients with TNBC (OR = 0.25, 95% CI = 0.08-0.68) compared to luminal A breast cancers. Both a low (2 or fewer pregnancies) and a high (3-4 pregnancies) number of pregnancies combined with a long breastfeeding period were associated with reduced odds of TNBC compared with luminal A breast cancer, although the association seemed to be slightly more pronounced among women with a low number of pregnancies (OR = 0.09, 95% CI = 0.005-0.54). Conclusions/significance: In case-case analyses with the luminal A cases as the reference group, we observed a lower proportion of TNBC among women who breastfed 7 or more months. The combination of longer breastfeeding duration and lower parity seemed to further reduce the odds of having a TNBC compared to a luminal A breast cancer

The association between coffee consumption and bladder cancer in the bladder cancer epidemiology and nutritional determinants (BLEND) international pooled study

Background: Inconsistent results for coffee consumption and bladder cancer (BC) risk have been shown in epidemiological studies. This research aims to increase the understanding of the association between coffee consumption and BC risk by bringing together worldwide case-control studies on this topic. Methods: Data were collected from 13 case-control comprising of 5,911 cases and 16,172 controls. Pooled multivariate odds ratios (ORs), with corresponding 95% confidence intervals (CIs), were obtained using multilevel logistic regression models. Furthermore, linear dose-response relationships were examined using fractional polynomial models. Results: No association of BC risk was observed with coffee consumption among smokers. However, after adjustment for age, gender, and smoking, the risk was significantly increased for never smokers (ever vs. never coffee consumers: ORmodel2 1.30, 95% CI 1.06-1.59; heavy (> 4 cups/day) coffee consumers vs. never coffee consumers: ORmodel2 1.52, 95% CI 1.18-1.97, p trend = 0.23). In addition, dose-response analyses, in both the overall population and among never smokers, also showed a significant increased BC risk for coffee consumption of more than four cups per day. Among smokers, a significant increased BC risk was shown only after consumption of more than six cups per day. Conclusion: This research suggests that positive associations between coffee consumption and BC among never smokers but not smokers

A data mining approach to investigate food groups related to incidence of bladder cancer in the BLadder cancer Epidemiology and Nutritional Determinants International Study

At present, analysis of diet and bladder cancer (BC) is mostly based on the intake of individual foods. The examination of food combinations provides a scope to deal with the complexity and unpredictability of the diet and aims to overcome the limitations of the study of nutrients and foods in isolation. This article aims to demonstrate the usability of supervised data mining methods to extract the food groups related to BC. In order to derive key food groups associated with BC risk, we applied the data mining technique C5.0 with 10-fold cross-validation in the BLadder cancer Epidemiology and Nutritional Determinants study, including data from eighteen case-control and one nested case-cohort study, compromising 8320 BC cases out of 31 551 participants. Dietary data, on the eleven main food groups of the Eurocode 2 Core classification codebook, and relevant non-diet data (i.e. sex, age and smoking status) were available. Primarily, five key food groups were extracted; in order of importance, beverages (non-milk); grains and grain products; vegetables and vegetable products; fats, oils and their products; meats and meat products were associated with BC risk. Since these food groups are corresponded with previously proposed BC-related dietary factors, data mining seems to be a promising technique in the field of nutritional epidemiology and deserves further examination

International pooled study on diet and bladder cancer: The bladder cancer, epidemiology and nutritional determinants (BLEND) study: Design and baseline characteristics

In 2012, more than 400,000 urinary bladder cancer cases occurred worldwide, making it the 7th most common type of cancer. Although many previous studies focused on the relationship between diet and bladder cancer, the evidence related to specific food items or nutrients that could be involved in the development of bladder cancer remains inconclusive. Dietary components can either be, or be activated into, potential carcinogens through metabolism, or act to prevent carcinogen damage

Family History and Breast Cancer Hormone Receptor Status in a Spanish Cohort

Breast cancer is a heterogenous disease that impacts racial/ethnic groups differently. Differences in genetic composition, lifestyles, reproductive factors, or environmental exposures may contribute to the differential presentation of breast cancer among Hispanic women.A population-based study was conducted in the city of Santiago de Compostela, Spain. A total of 645 women diagnosed with operable invasive breast cancer between 1992 and 2005 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics of the tumors were collected. Hormone receptor negative tumors were compared with hormone receptor postive tumors on their clinico-pathological characteristics as well as risk factor profiles.Among the 645 breast cancer patients, 78% were estrogen receptor-positive (ER+) or progesterone receptor-positive (PR+), and 22% were ER−&PR−. Women with a family history of breast cancer were more likely to have ER−&PR− tumors than women without a family history (Odds ratio, 1.43; 95% confidence interval, 0.91–2.26). This association was limited to cancers diagnosed before age 50 (Odds ratio, 2.79; 95% confidence interval, 1.34–5.81).An increased proportion of ER−&PR− breast cancer was observed among younger Spanish women with a family history of the disease

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways