Natalie Davidson, MSc. UCLA Computer Science
- natalie.davidson@ inf.ethz.ch
- +41 43 254 0224
Biomedical Informatics Group
- SHM 26 B 3
I am interested in extending statistical models to gain deeper understanding of transcriptional dysregulation in cancer.
I am interested in understanding the role transcriptional dysregulation plays in cancer. Through my collaborations during my Ph.D., I have been able to conduct single cancer and pan-cancer analyses using RNA-Seq and Ribosome Profiling data. I typically use generalized linear models and generalized linear mixed models, but I am interested in extending to other models as the numbers of samples in cancer analyses grow. I am currently a part of the International Cancer Genome Consortium, where I integrate multiple transcriptional aberrations such as splicing, fusions, over/under expression, allele specific expression, and others in over 1,000 samples to identify cancer relevant genes and alteration patterns. I received my B.Sc. in computer science and minor in mathematics from University of California, Santa Barbara. I received my M.Sc. in computer science from University of California, Los Angeles under the advisement of Dr. Jason Ernst. I am currently obtaining my Ph.D from Tri-Institutional Program for Computational Biology and Medicine in New York, while conducting research at ETH Zürich.
Abstract Translation initiation is orchestrated by the cap binding and 43S pre-initiation complexes (PIC). Eukaryotic initiation factor 1A (EIF1A) is essential for recruitment of the ternary complex and for assembling the 43S PIC. Recurrent EIF1AX mutations in papillary thyroid cancers are mutually exclusive with other drivers, including RAS. EIF1AX is enriched in advanced thyroid cancers, where it displays a striking co-occurrence with RAS, which cooperates to induce tumorigenesis in mice and isogenic cell lines. The C-terminal EIF1AX-A113splice mutation is the most prevalent in advanced thyroid cancer. EIF1AX-A113spl variants stabilize the PIC and induce ATF4, a sensor of cellular stress, which is co-opted to suppress EIF2α phosphorylation, enabling a general increase in protein synthesis. RAS stabilizes c-MYC, an effect augmented by EIF1AX-A113spl. ATF4 and c-MYC induce expression of aminoacid transporters and enhance sensitivity of mTOR to aminoacid supply. These mutually reinforcing events generate therapeutic vulnerabilities to MEK, BRD4 and mTOR kinase inhibitors.
Authors Gnana P. Krishnamoorthy, Natalie R Davidson, Steven D Leach, Zhen Zhao, Scott W. Lowe, Gina Lee, Iñigo Landa, James Nagarajah, Mahesh Saqcena, Kamini Singh, Hans-Guido Wendel, Snjezana Dogan, Prasanna P. Tamarapu, John Blenis, Ronald Ghossein, Jeffrey A. Knauf, Gunnar Rätsch and James A. Fagin
Submitted Cancer Discovery
Abstract We present the most comprehensive catalogue of cancer-associated gene alterations through characterization of tumor transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes project. Using matched whole-genome sequencing data, we attributed RNA alterations to germline and somatic DNA alterations, revealing likely genetic mechanisms. We identified 444 associations of gene expression with somatic non-coding single-nucleotide variants. We found 1,872 splicing alterations associated with somatic mutation in intronic regions, including novel exonization events associated with Alu elements. Somatic copy number alterations were the major driver of total gene and allele-specific expression (ASE) variation. Additionally, 82% of gene fusions had structural variant support, including 75 of a novel class called "bridged" fusions, in which a third genomic location bridged two different genes. Globally, we observe transcriptomic alteration signatures that differ between cancer types and have associations with DNA mutational signatures. Given this unique dataset of RNA alterations, we also identified 1,012 genes significantly altered through both DNA and RNA mechanisms. Our study represents an extensive catalog of RNA alterations and reveals new insights into the heterogeneous molecular mechanisms of cancer gene alterations.
Authors Claudia Calabrese, Natalie R Davidson, Nuno A Fonseca, Yao He, André Kahles, Kjong-Van Lehmann, Fenglin Liu, Yuichi Shiraishi, Cameron M Soulette, Lara Urban, Deniz Demircioğlu, Liliana Greger, Siliang Li, Dongbing Liu, Marc D Perry, Linda Xiang, Fan Zhang, Junjun Zhang, Peter Bailey, Serap Erkek, Katherine A Hoadley, Yong Hou, Helena Kilpinen, Jan O Korbel, Maximillian G Marin, Julia Markowski, Tannistha Nandi, Qiang Pan-Hammarström, Chandra S Pedamallu, Reiner Siebert, Stefan G Stark, Hong Su, Patrick Tan, Sebastian M Waszak, Christina Yung, Shida Zhu, Philip Awadalla, Chad J Creighton, Matthew Meyerson, B Francis F Ouellette, Kui Wu, Huanming Yang, Alvis Brazma, Angela N Brooks, Jonathan Göke, Gunnar Rätsch, Roland F Schwarz, Oliver Stegle, Zemin Zhang
Authors N Davidson, Kjong Van Lehmann, Andre Kahles, A Perez, Gunnar Rätsch