Interseismic coupling and seismic potential along the Central Andes subduction zone

We use about two decades of geodetic measurements to characterize interseismic strain build up along the Central Andes subduction zone from Lima, Peru, to Antofagasta, Chile. These measurements are modeled assuming a 3-plate model (Nazca, Andean sliver and South America Craton) and spatially varying interseismic coupling (ISC) on the Nazca megathrust interface. We also determine slip models of the 1996 M_w = 7.7 Nazca, the 2001 M_w = 8.4 Arequipa, the 2007 M_w = 8.0 Pisco and the M_w = 7.7 Tocopilla earthquakes. We find that the data require a highly heterogeneous ISC pattern and that, overall, areas with large seismic slip coincide with areas which remain locked in the interseismic period (with high ISC). Offshore Lima where the ISC is high, a M_w∼8.6–8.8 earthquake occurred in 1746. This area ruptured again in a sequence of four M_w∼8.0 earthquakes in 1940, 1966, 1974 and 2007 but these events released only a small fraction of the elastic strain which has built up since 1746 so that enough elastic strain might be available there to generate a M_w > 8.5 earthquake. The region where the Nazca ridge subducts appears to be mostly creeping aseismically in the interseismic period (low ISC) and seems to act as a permanent barrier as no large earthquake ruptured through it in the last 500 years. In southern Peru, ISC is relatively high and the deficit of moment accumulated since the M_w∼8.8 earthquake of 1868 is equivalent to a magnitude M_w∼8.4 earthquake. Two asperities separated by a subtle aseismic creeping patch are revealed there. This aseismic patch may arrest some rupture as happened during the 2001 Arequipa earthquake, but the larger earthquakes of 1604 and 1868 were able to rupture through it. In northern Chile, ISC is very high and the rupture of the 2007 Tocopilla earthquake has released only 4% of the elastic strain that has accumulated since 1877. The deficit of moment which has accumulated there is equivalent to a magnitude M_w∼8.7 earthquake. This study thus provides elements to assess the location, size and magnitude of future large megathurst earthquakes in the Central Andes subduction zone. Caveats of this study are that interseismic strain of the forearc is assumed time invariant and entirely elastic. Also a major source of uncertainty is due to fact that the available data place very little constraints on interseismic coupling at shallow depth near the trench, except offshore Lima where sea bottom geodetic measurements have been collected suggesting strong coupling

Pooled Analysis of Prognostic Impact of Urokinase-Type Plasminogen Activator and Its Inhibitor PAI-1 in 8377 Breast Cancer Patients

Background: Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer-Receptor and Biomarker Group (EORTC-RBG). Methods: The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided. Results: Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph node-negative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P<.001). Conclusions: This pooled analysis of the EORTC-RBG datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. For patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especially useful for designing individualized treatment strategie

Exploring the link between MORF4L1 and risk of breast cancer.

INTRODUCTION: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. METHODS: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. RESULTS: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. CONCLUSIONS: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

Détection de l'envahissement ganglionnaire dans les cancers du col utérin

Le cancer du col de l'utérus occupe le second rang des cancers de la femme dans le monde. En France, son incidence se situe autour de 3500 nouveaux cas par an. Le principal facteur pronostic est l'atteinte ganglionnaire. Dix à 15% des patientes présentent une récidive alors que leurs ganglions étaient histologiquement indemnes. La détection de micrométastases ou de cellules tumorales isolées non diagnostiquée par l'examen anatomopathologique pourrait améliorer la connaissance de l'évolution tumorale. Les techniques de biologie moléculaire (RT-PCR) se sont révélées très sensibles pour mettre en évidence un envahissement ganglionnaire par des cellules tumorales, mais peu spécifiques. Nous avons testé différents marqueurs biologiques caractéristiques des cellules épithéliales (CK19, MUC1, HER 1-4), des cellules cancéreuses du col utérin (HVP16-E6) ou impliqués dans le cycle cellulaire (Cycline D1, p16, p21, p27), l'angiogénèse (VEGF et VEGF-C) et l'invasion (uPA et MMP9). Nous avons caractérisé l'expression de ces marqueurs sur des échantillons humains de cols sains, de tumeurs de col de l'utérus et de ganglions lombo-aortiques et scaléniques. CK19, HPV16-E6 et MUC1 ont des niveaux d'expression significativement plus élevés dans les ganglions histologiquement envahis par des cellules tumorales que dans les ganglions indemnes. L'étude concomitante de CK19 et HPV16-E6 permet de détecter la totalité des ganglions histologiquement atteint. D'autre part, ces biomarqueurs étaient exprimés dans 6% des ganglions histologiquement indemnes d'envahissement tumoral et pour lesquels une étude rétrospective en immunohistochimie a révélé la présence de cellules tumorales. L'utilisation de CK19 et HPV16-E6 en RT-PCR est fiable et plus sensible que les techniques histologiques classiques. Notre étude conduit à proposer l'utilisation de la RT-PCR pour diagnostiquer l'envahissement ganglionnaire dans le cancer du col de l'utérus.LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Comparison of the Screening Practices of Unaffected Noncarriers under 40 and between 40 and 49 in BRCA1/2 Families

International audienceThis study aimed to 1) compare the cancer screening practices of unaffected noncarrier women under 40 and those aged 40 to 49, following the age-based medical screening guidelines, and 2) consider the way the patients justified their practices of screening or over-screening. For this study, 131 unaffected noncarriers—77 women under age 40 and 54 between 40 and 49, all belonging to a BRCA1/2 family—responded to a questionnaire on breast or ovarian cancer screenings they had undergone since receiving their negative genetic test results, their motives for seeking these screenings, and their intentions to pursue these screenings in the future. Unaffected noncarriers under age 40 admitted practices that could be qualified as over-screening. Apart from mammogram and breast ultrasounds, which the women under 40 reported seeking less often, these women’s screening practices were comparable to those of women between 40 and 49. Cancer prevention and a family history of cancer were the two most frequently cited justifications for pursuing these screenings. We suggest that health care professionals discuss with women under 50 the ineffectiveness of breast and ovarian cancer screenings so that they will adapt their practices to conform to medical guidelines and limit their exposure to the potentially negative impacts of early cancer screening

Expression of the putative tumor suppressor gene PTPN13/PTPL1 is an independent prognostic marker for overall survival in breast cancer.

We are particularly grateful to Françoise Vignon who played an essential role in the initiation of this work.International audienceAlthough it is well established that some protein tyrosine kinases have a prognostic value in breast cancer, the involvement of protein tyrosine phosphatases (PTPs) is poorly substantiated for breast tumors. Three of these enzymes (PTP-gamma, LAR, and PTPL1) are already known to be regulated by estrogens or their antagonists in human breast cancer cells. We used a real-time reverse transcriptase polymerase chain reaction method to test the expression levels of PTP-gamma, LAR and its neuronal isoform, and PTPL1 in a training set of RNA from 59 breast tumors. We sought correlations between levels of these molecular markers, current tumor markers, and survival. We then quantified the expression level of the selected phosphatase in 232 additional samples, resulting in a testing set of 291 breast tumor RNAs from patients with a median follow-up of 6.4 years. The Spearman nonparametric test revealed correlations between PTPL1 expression and differentiation markers. Cox univariate analysis of the overall survival studies demonstrated that PTPL1 is a prognostic factor [risk ratio (RR) = 0.45], together with the progesterone receptor (PR) (RR = 0.52) and node involvement (RR = 1.58). In multivariate analyses, PTPL1 and PR retained their prognostic value (RRs of 0.48 and 0.55, respectively). This study demonstrates for the first time that PTPL1 expression level is an independent prognostic indicator of favorable outcome for patients with breast cancer. In conjunction with our mechanistic studies, this finding identifies PTPL1 as an important regulatory element of human breast tumor aggressiveness and sensitivity to treatments such as antiestrogens and antiaromatase. (c) 2008 Wiley-Liss, Inc