Identification of cis-HOX-HOXC10 axis as a therapeutic target for colorectal tumor-initiating cells without APC mutations.

Colorectal cancer (CRC) is one of the most common cancers worldwide, in which adenomatous polyposis coli (APC) mutations are frequently and uniquely observed. Here we find that cis-HOX (circular RNA stabilizing HOXC10) is robustly expressed in colorectal tumor-initiating cells (TICs). cis-HOX knockout decreases colorectal TIC numbers and impairs the self-renewal, tumorigenesis, and metastatic capacities of TICs, whereas cis-HOX overexpression drives colorectal TIC self-renewal and metastasis. Mechanistically, cis-HOX binds to HOXC10 mRNA to attenuate its decay through blocking the K-homology splicing regulatory protein (KSRP)-binding sequence of HOXC10 3' UTR. HOXC10 is highly expressed in colorectal tumors and TICs and triggers Wnt/ß-catenin activation by activating FZD3 expression. HOXC10 inhibitor salinomycin exerts efficient therapeutic effects in APC-wild-type colorectal tumors, but not in tumors with APC nonsense mutations. Therefore, the cis-HOX-HOXC10 pathway drives colorectal tumorigenesis, stemness, and metastasis and serves as a potential therapeutic target for APC-wild-type colorectal tumors.

Genome-wide mutational signatures revealed distinct developmental paths for human B cell lymphomas.

Both somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by activation-induced cytidine deaminase (AID). Dysregulation of these processes has been linked to B cell lymphomagenesis. Here we performed an in-depth analysis of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) genomes. We characterized seven genomic mutational signatures, including two B cell tumor-specific signatures, one of which is novel and associated with aberrant SHM. We further identified two major mutational signatures (K1 and K2) of clustered mutations (kataegis) resulting from the activities of AID or error-prone DNA polymerase η, respectively. K1 was associated with the immunoglobulin (Ig) switch region mutations/translocations and the ABC subtype of DLBCL, whereas K2 was related to the Ig variable region mutations and the GCB subtype of DLBCL and FL. Similar patterns were also observed in chronic lymphocytic leukemia subtypes. Thus, alterations associated with aberrant CSR and SHM activities can be linked to distinct developmental paths for different subtypes of B cell lymphomas.

Driver mutations of the adenoma-carcinoma sequence govern the intestinal epithelial global translational capacity.

Deregulated global mRNA translation is an emerging feature of cancer cells. Oncogenic transformation in colorectal cancer (CRC) is driven by mutations in APC, KRAS, SMAD4, and TP53, known as the adenoma-carcinoma sequence (ACS). Here we introduce each of these driver mutations into intestinal organoids to show that they are modulators of global translational capacity in intestinal epithelial cells. Increased global translation resulting from loss of Apc expression was potentiated by the presence of oncogenic KrasG12D Knockdown of Smad4 further enhanced global translation efficiency and was associated with a lower 4E-BP1-to-eIF4E ratio. Quadruple mutant cells with additional P53 loss displayed the highest global translational capacity, paralleled by high proliferation and growth rates, indicating that the proteome is heavily geared toward cell division. Transcriptional reprogramming facilitating global translation included elevated ribogenesis and activation of mTORC1 signaling. Accordingly, interfering with the mTORC1/4E-BP/eIF4E axis inhibited the growth potential endowed by accumulation of multiple drivers. In conclusion, the ACS is characterized by a strongly altered global translational landscape in epithelial cells, exposing a therapeutic potential for direct targeting of the translational apparatus.

Retalho toracoabdominal para reconstrução de tumor de mama localmente avançado, em paciente com mutação de BRCA1 / Thoracoabdominal flap for locally advanced breast tumor reconstruction in a patient with BRCA1 mutation

O presente estudo objetiva relatar a técnica do retalho toracoabdominal pós-mastectomia por tumor localmente avançado em paciente com mutação de BRCA1. Foi realizada a mastectomia com ressecção de quase todo o músculo peitoral maior à esquerda, com linfonodectomia axilar homolateral e reconstrução do grande defeito da parede torácica com retalho toracoabdominal fasciocutâneo, baseado nas artérias intercostais posteriores.

This case report describes the application of the thoracoabdominal flap technique after locally advanced tumor mastectomy in a patient with breast cancer 1 (BRCA1) mutation. The mastectomy included resection of nearly the entire left pectoralis major muscle, with homolateral axillary lymphadenectomy and reconstruction of the large chest wall defect with a fasciocutaneous thoracoabdominal flap based on the posterior intercostal arteries.

A dynamic sandwich assay on magnetic beads for selective detection of single-nucleotide mutations at room temperature.

Single-nucleotide mutation (SNM) has proven to be associated with a variety of human diseases. Development of reliable methods for the detection of SNM is crucial for molecular diagnosis and personalized medicine. The sandwich assays are widely used tools for detecting nucleic acid biomarkers due to their low cost and rapid signaling. However, the poor hybridization specificity of signal probe at room temperature hampers the discrimination of mutant and wild type. Here, we demonstrate a dynamic sandwich assay on magnetic beads for SNM detection based on the transient binding between signal probe and target. By taking the advantage of mismatch sensitive thermodynamics of transient DNA binding, the dynamic sandwich assay exhibits high discrimination factor for mutant with a broad range of salt concentration at room temperature. The beads used in this assay serve as a tool for separation, and might be helpful to enhance SNM selectivity. Flexible design of signal probe and facile magnetic separation allow multiple-mode downstream analysis including colorimetric detection and isothermal amplification. With this method, BRAF mutations in the genomic DNA extracted from cancer cell lines were tested, allowing sensitive detection of SNM at very low abundances (0.1-0.5% mutant/wild type).

How to catch all those mutations--the report of the third Human Variome Project Meeting, UNESCO Paris, May 2010.

The third Human Variome Project (HVP) Meeting "Integration and Implementation" was held under UNESCO Patronage in Paris, France, at the UNESCO Headquarters May 10-14, 2010. The major aims of the HVP are the collection, curation, and distribution of all human genetic variation affecting health. The HVP has drawn together disparate groups, by country, gene of interest, and expertise, who are working for the common good with the shared goal of pushing the boundaries of the human variome and collaborating to avoid unnecessary duplication. The meeting addressed the 12 key areas that form the current framework of HVP activities: Ethics; Nomenclature and Standards; Publication, Credit and Incentives; Data Collection from Clinics; Overall Data Integration and Access-Peripheral Systems/Software; Data Collection from Laboratories; Assessment of Pathogenicity; Country Specific Collection; Translation to Healthcare and Personalized Medicine; Data Transfer, Databasing, and Curation; Overall Data Integration and Access-Central Systems; and Funding Mechanisms and Sustainability. In addition, three societies that support the goals and the mission of HVP also held their own Workshops with the view to advance disease-specific variation data collection and utilization: the International Society for Gastrointestinal Hereditary Tumours, the Micronutrient Genomics Project, and the Neurogenetics Consortium.

Polymorphism and drug selected mutations of reverse transcriptase gene in 102 HIV-1 infected patients living in China.

Few data are available for genotypic patterns within human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT) in drug-naive patients and RT inhibitor (RTI) treated patients in China. This study aimed at characterizing the polymorphism of RT HIV-1 in the absence of drug treatment and to identify known and unknown mutations emerging under RTI selective pressure. The HIV-1 RT gene from 21 drug-naive patients and 81 RTI treated patients from three provinces in China was analyzed. Most patients (>80%) received a triple regimen including stavudine (d4T) plus didanosine (ddI) and nevirapine (NVP), or d4T plus lamivudine (3TC) and efavirenz (EFV), or zidovudine (AZT) +ddI + NVP. In untreated patients, four highly polymorphic positions were found (122, 200, 207, and 211). In treated patients, two patterns of resistance associated mutations (RAMs) were observed: (1) K65R (9.8%), L74V (7.4%), M184V (7.4%), Q151M (5%), and thymidine analogue mutations (TAMs) (9.3%) including T215Y (5.5%), in patients who underwent ddI + d4T + NVP. (2) T215Y (23%), M184V (20%), and TAMs (15.4%) in patients receiving d4T + 3TC + EFV. In all cases, a high prevalence of non-nucleoside RTIs (NNRTI) RAMs (41.9%) was found. Four RTI suspected new RAMs were described at position 142, 221, 224, and 228. An association between H221Y and L228H/R with Y181C was noted. These data highlight the predominant spread of NNRTI RAM in China, depict the specific genotypic pattern of RTI selected mutations in China, and suggest the association of newly described mutations with RTI therapy.

Locus-specific databases: from ethical principles to practice.

Locus-specific databases (LSDBs) play an essential role in clinical care and research. They differ from traditional genetic databases in that they propose to place the mutations of "anonymized" patients directly on the World Wide Web. The proliferation of ethical guidelines and legal requirements affects the rapid and free transmission of clinical data, which is vital for both the daily management of patients and research into better diagnostics and treatment. This paper proposes a review of ethical principles endorsed by international instruments that are of particular relevance to LSDBs. It aims to translate them into 12 proposed practical guidelines that LSDB curators can use in collecting data for clinical research. Perhaps these guideposts will serve as a first step toward translating principles into practice.