Kjong Lehmann, PhD. Computational Biology

Post Doc

E-Mail
kjong.lehmann@get-your-addresses-elsewhere.inf.ethz.ch
Phone
+41 43 254 0225
Address
Biomedical Informatics Group
Schmelzbergstrasse 26
SHM 26 B 5
8006 Zürich
Room
SHM 26 B 5

I received my PhD in Computational Biology from the University of Southern California, after which I joined the Rätsch group at Memorial Sloan Kettering Cancer Center in New York. My main interests are trying to understand genetic architecture underlying complex phenotypes using and developing state of the art approaches, including variant effect predictions and linear mixed models. I am also deeply involved in large-scale cancer genomics efforts such as TCGA PanCanAtlas and ICGC Pan-Cancer Analysis Group.

Abstract Cancer is characterised by somatic genetic variation, but the effect of the majority of non-coding somatic variants and the interface with the germline genome are still unknown. We analysed the whole genome and RNA-seq data from 1,188 human cancer patients as provided by the Pan-cancer Analysis of Whole Genomes (PCAWG) project to map cis expression quantitative trait loci of somatic and germline variation and to uncover the causes of allele-specific expression patterns in human cancers. The availability of the first large-scale dataset with both whole genome and gene expression data enabled us to uncover the effects of the non-coding variation on cancer. In addition to confirming known regulatory effects, we identified novel associations between somatic variation and expression dysregulation, in particular in distal regulatory elements. Finally, we uncovered links between somatic mutational signatures and gene expression changes, including TERT and LMO2, and we explained the inherited risk factors in APOBEC-related mutational processes. This work represents the first large-scale assessment of the effects of both germline and somatic genetic variation on gene expression in cancer and creates a valuable resource cataloguing these effects.

Authors Claudia Calabrese, Kjong-Van Lehmann, Lara Urban, Fenglin Liu, Serap Erkek, Nuno Fonseca, Andre Kahles, Leena Helena Kilpinen-Barrett, Julia Markowski, PCAWG-3, Sebastian Waszak, Jan Korbel, Zemin Zhang, Alvis Brazma, Gunnar Raetsch, Roland Schwarz, Oliver Stegle

Submitted bioRxiv

Link DOI

Abstract Most human protein-coding genes are regulated by multiple, distinct promoters, suggesting that the choice of promoter is as important as its level of transcriptional activity. While the role of promoters as driver elements in cancer has been recognized, the contribution of alternative promoters to regulation of the cancer transcriptome remains largely unexplored. Here we show that active promoters can be identified using RNA-Seq data, enabling the analysis of promoter activity in more than 1,000 cancer samples with matched whole genome sequencing data. We find that alternative promoters are a major contributor to tissue-specific regulation of isoform expression and that alternative promoters are frequently deregulated in cancer, affecting known cancer-genes and novel candidates. Noncoding passenger mutations are enriched at promoters of genes with lower regulatory complexity, whereas noncoding driver mutations occur at genes with multiple promoters, often affecting the promoter that shows the highest level of activity. Together our study demonstrates that the landscape of active promoters shapes the cancer transcriptome, opening many opportunities to further explore the interplay of regulatory mechanism and noncoding somatic mutations with transcriptional aberrations in cancer.

Authors Deniz Demircioğlu, Martin Kindermans, Tannistha Nandi, Engin Cukuroglu, Claudia Calabrese, Nuno A. Fonseca, Andre Kahles, Kjong Lehmann, Oliver Stegle, PCAWG-3, PCAWG-Network, Alvis Brazma, Angela Brooks, Gunnar Rätsch, Patrick Tan, Jonathan Göke

Submitted bioRxiv

Link DOI

Authors Natalie R. Davidson, ; PanCancer Analysis of Whole Genomes 3 (PCAWG-3) for ICGC, Alvis Brazma, Angela N. Brooks, Claudia Calabrese, Nuno A. Fonseca, Jonathan Goke, Yao He, Xueda Hu, Andre Kahles, Kjong-Van Lehmann, Fenglin Liu, Gunnar Rätsch, Siliang Li, Roland F. Schwarz, Mingyu Yang, Zemin Zhang, Fan Zhang and Liangtao Zheng

Submitted Proceedings of the American Association for Cancer Research Annual Meeting 2017

Link DOI

Abstract We present a genome-wide analysis of splicing patterns of 282 kidney renal clear cell carcinoma patients in which we integrate data from whole-exome sequencing of tumor and normal samples, RNA-seq and copy number variation. We proposed a scoring mechanism to compare splicing patterns in tumor samples to normal samples in order to rank and detect tumor-specific isoforms that have a potential for new biomarkers. We identified a subset of genes that show introns only observable in tumor but not in normal samples, ENCODE and GEUVADIS samples. In order to improve our understanding of the underlying genetic mechanisms of splicing variation we performed a large-scale association analysis to find links between somatic or germline variants with alternative splicing events. We identified 915 cis- and trans-splicing quantitative trait loci (sQTL) associated with changes in splicing patterns. Some of these sQTL have previously been associated with being susceptibility loci for cancer and other diseases. Our analysis also allowed us to identify the function of several COSMIC variants showing significant association with changes in alternative splicing. This demonstrates the potential significance of variants affecting alternative splicing events and yields insights into the mechanisms related to an array of disease phenotypes.

Authors Kjong Van Lehmann, Andre Kahles, Cyriac Kandoth, William Lee, Nikolaus Schultz, Oliver Stegle, Gunnar Rätsch

Submitted Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing

Link Pubmed