5 research outputs found
Prognostic microRNA signatures derived from The Cancer Genome Atlas for head and neck squamous cell carcinomas
Identification of novel prognostic biomarkers typically requires a large dataset which provides sufficient statistical power for discovery research. To this end, we took advantage of the highâthroughput data from The Cancer Genome Atlas (TCGA) to identify a set of prognostic biomarkers in head and neck squamous cell carcinomas (HNSCC) including oropharyngeal squamous cell carcinoma (OPSCC) and other subtypes. In this study, we analyzed miRNAâseq data obtained from TCGA patients to identify prognostic biomarkers for OPSCC. The identified miRNAs were further tested with an independent cohort. miRNAâseq data from TCGA was also analyzed to identify prognostic miRNAs in oral cavity squamous cell carcinoma (OSCC) and laryngeal squamous cell carcinoma (LSCC). Our study identified that miRâ193bâ3p and miRâ455â5p were positively associated with survival, and miRâ92aâ3p and miRâ497â5p were negatively associated with survival in OPSCC. A combined expression signature of these four miRNAs was prognostic of overall survival in OPSCC, and more importantly, this signature was validated in an independent OPSCC cohort. Furthermore, we identified four miRNAs each in OSCC and LSCC that were prognostic of survival, and combined signatures were specific for subtypes of HNSCC. A robust 4âmiRNA prognostic signature in OPSCC, as well as prognostic signatures in other subtypes of HNSCC, was developed using sequencing data from TCGA as the primary source. This demonstrates the power of using TCGA as a potential resource to develop prognostic tools for improving individualized patient care
Lymphovascular space invasion and lack of downstaging after neoadjuvant chemotherapy are strong predictors of adverse outcome in young women with locally advanced breast cancer
Younger age diagnosis of breast cancer is a predictor of adverse outcome. Here, we evaluate prognostic factors in young women with locally advanced breast cancer (LABC). We present a retrospective review of 104 patients younger than 40Â years with LABC treated with surgery, radiotherapy (RT), and chemotherapy from 2003 to 2014. Patientâ, tumorâ, and treatmentârelated factors important for overall survival (OS), local/regional recurrence (LRR), distant metastasis (DM), and recurrenceâfree survival (RFS) were evaluated. Mean age at diagnosis was 34Â years (23â39Â years) with a median followâup of 47Â months (8â138Â months). Breastâconserving surgery was performed in 27%. Axillary lymph node dissection was performed in 85%. Sixty percent of patients received neoadjuvant chemotherapy with 19% achieving pathologic complete response (pCR), and 61% downstaged. Lymph node positivity was present in 91% and lymphovascular space invasion (LVSI) in 35%. Thirtyâtwo percent of patients had triple negative tumors (TN, ERâ/PRâ/HER2 nonamplified). Fourâyear OS and RFS was 84% and 71%, respectively. Factors associated with worse OS on multivariate analysis include TN status, LVSI, and number of positive lymph nodes. LVSI was also associated with DM and LRR, as well as worse RFS. Downstaging was associated with improved 4Â year RFS in patients receiving neoadjuvant chemotherapy (74% vs. 38%, PÂ =Â 0.002). With high risks of recurrence and inferior OS compared to older women, breast cancer in young women can be difficult to treat. Among additional factors, presence of LVSI and lack of downstaging portends a particularly worse prognosis
HIV-1 Revâbinding protein accelerates cellular uptake of iron to drive Notch-induced T cell leukemogenesis in mice
Somatic activating mutations in Notch1 contribute to the pathogenesis of T cell acute lymphoblastic lymphoma (T-ALL), but how activated Notch1 signaling exerts this oncogenic effect is not completely understood. Here we identify HIV-1 Revâbinding protein (Hrb), a component of the clathrin-mediated endocytosis machinery, as a critical mediator of Notch-induced T-ALL development in mice. Hrb was found to be a direct transcriptional target of Notch1, and Hrb loss reduced the incidence or delayed the onset of T-ALL in mouse models in which activated Notch1 signaling either contributes to or drives leukemogenesis. Consistent with this observation, Hrb supported survival and proliferation of hematopoietic and T cell precursor cells in vitro. We demonstrated that Hrb accelerated the uptake of transferrin, which was required for upregulation of the T cell protooncogene p21. Indeed, iron-deficient mice developed Notch1-induced T-ALL substantially more slowly than control mice, further supporting a critical role for iron uptake during leukemogenesis. Taken together, these results reveal that Hrb is a critical Notch target gene that mediates lymphoblast transformation and disease progression via its ability to satisfy the enhanced demands of transformed lymphoblasts for iron. Further, our data suggest that Hrb may be targeted to improve current treatment or design novel therapies for human T-ALL patients