No abstract
Single-cell RNA-seq (scRNA-seq) is an emerging platform for high-throughput profiling of individual cells in a sample and is routinely employed to investigate the transcriptional landscapes of the cellular constituents of tumors. To this end, many scRNA-seq specific clustering algorithms have emerged to analytically partition cells into modules of comparatively similar profiles. To facilitate data driven molecular subtyping of such scRNA-seq clustering results and other large-scale-omics studies, we have developed K2 Taxonomer. K2 Taxonomer is an R package built around a novel top-down hierarchical clustering algorithm, utilizing repeated perturbations of the data to generate robust taxonomical partitions of observations. The software runs additional analyses to define gene co-expression signatures of these modules, as well as to integrate user-input annotations of genes and/or observations. An interactive web portal has been generated to assist in the interrogation of the full compendium of results. We applied K2 Taxonomer to publicly available HNSCC scRNA-seq data, identifying pertinent tumor cell subtypes, distinguished by cell cycle and epithelial-to-mesenchymal transition, and with analytical projection of this signature onto TCGA-HNSCC bulk RNA-seq data exhibiting association with worse survival in TCGA-HNSCC patients. A transcriptional signature corresponding to suppression of Mtorc1 and Wnt/β-catenin signaling was also identified in a sub-population of HNSCCs, and shown to be associated with improved patient survival. Of notice, highly ranked markers of this signature are significantly associated with gene expression changes altered by E7386 - a novel β-catenin/CBP modulator with an activity profile that closely overlaps with that of ICG-001, but exhibits ~50-100-fold lower EC50 values - suggesting a role for this signaling axis in subsets of HNSCC. In conclusion, taxonomical subtyping with K2 Taxonomer provides a novel framework to expand the scope of applicability of scRNA-seq clustering results, and has revealed potentially novel HNSCC subtypes that offer directions for future studies. Citation Format: Eric Reed, Takashi Owa, Kenichi Nomoto, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti. Subtyping of HNSCC single-cell RNA-seq identifies transcriptional programs characterized by suppression of Mtorc1 and Wnt signaling pathways and better patient prognosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4419.
10514 Background: Alterations in the DNA double-strand break repair (DSBR) pathway are associated with cancer risk. Mutations in the genes BRCA1/2 disrupt DNA DSBR. Variations in breast cancer penetrance among BRCA1/2 mutation carriers, and familial patterns among women without known BRCA1/2 mutations may be related to polymorphisms of genes in the DNA-DSBR pathway. Methods: Using a case-control study design with individuals in the UCLA Family Cancer Registry (FCR), we examined the independent effects of 100 SNPs in 19 DNA-DSBR genes. SNPs were assayed using the Applied Biosystems SNPlex™ assay. Results: 630 consecutive females from 508 families in the UCLA FCR selected for familial risk of breast cancer were included in the study. Table 1 describes select subject characteristics. Preliminary association analysis of the Caucasian subset using a nonparametric permutation method, which controls for Ashkenazi Jewish heritage and dependencies among relatives, suggests that polymorphisms within RAD21 (p=0.0044, p=0.0005), XRCC2 (p = 0.0069), XRCC4 (p =0.0511), and BRIP1 (p =0.0107) may be associated with a change in risk of breast cancer. Using only unrelated Caucasian subjects in a logistic regression analysis with covariates such as age, BMI, and Ashkenazi Jewish heritage, the effects of these polymorphisms remain significant, with 32% to 74% change in the odds of breast cancer. Conclusions: We have identified five potential SNPs in genes in the DNA-DSBR pathway that appear to be associated with a change in risk of breast cancer. This hypothesis generating study lends support to a role for polymorphisms of the DNA-repair pathway in breast carcinogenesis. Assessment of gene-environment and gene-gene interactions will help to elucidate carcinogenic mechanisms. Further validation in similar populations is warranted. (Funded by the Breast Cancer Research Foundation and NIH/NCI CA87949 R25 Career Development Program.) [Table: see text] No significant financial relationships to disclose.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.