Molecular analysis of urothelial cancer cell lines for modeling tumor biology and drug response.
The utility of tumor-derived cell lines is dependent on their ability to recapitulate underlying genomic aberrations and primary tumor biology. Here, we sequenced the exomes of 25 bladder cancer (BCa) cell lines and compared mutations, copy number alterations (CNAs), gene expression and drug response to BCa patient profiles in The Cancer Genome Atlas (TCGA). We observed a mutation pattern associated with altered CpGs and APOBEC-family cytosine deaminases similar to mutation signatures derived from somatic alterations in muscle-invasive (MI) primary tumors, highlighting a major mechanism(s) contributing to cancer-associated alterations in the BCa cell line exomes. Non-silent sequence alterations were confirmed in 76 cancer-associated genes, including mutations that likely activate oncogenes TERT and PIK3CA, and alter chromatin-associated proteins (MLL3, ARID1A, CHD6 and KDM6A) and established BCa genes (TP53, RB1, CDKN2A and TSC1). We identified alterations in signaling pathways and proteins with related functions, including the PI3K/mTOR pathway, altered in 60% of lines; BRCA DNA repair, 44%; and SYNE1-SYNE2, 60%. Homozygous deletions of chromosome 9p21 are known to target the cell cycle regulators CDKN2A and CDKN2B. This loci was commonly lost in BCa cell lines and we show the deletions extended to the polyamine enzyme methylthioadenosine (MTA) phosphorylase (MTAP) in 36% of lines, transcription factor DMRTA1 (27%) and antiviral interferon epsilon (IFNE, 19%). Overall, the BCa cell line genomic aberrations were concordant with those found in BCa patient tumors. We used gene expression and copy number data to infer pathway activities for cell lines, then used the inferred pathway activities to build a predictive model of cisplatin response. When applied to platinum-treated patients gathered from TCGA, the model predicted treatment-specific response. Together, these data and analysis represent a valuable community resource to model basic tumor biology and to study the pharmacogenomics of BCa.
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
M L
ML
Nickerson
Computational Bioscience Program, University of Colorado, Aurora, CO, USA.
N
N
Witte
Data Science for Genomics, LLC, Ellicott City, MD, USA.
K M
KM
Im
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
S
S
Turan
Department of Surgery (Urology), University of Colorado, Aurora, CO, USA.
C
C
Owens
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
K
K
Misner
BGI-Shenzhen, Shenzhen, China.
S X
SX
Tsang
Shenzhen Second People's Hospital, Shenzhen, China.
Z
Z
Cai
Shenzhen Second People's Hospital, Shenzhen, China.
S
S
Wu
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
M
M
Dean
Computational Bioscience Program, University of Colorado, Aurora, CO, USA.|Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.|University of Colorado Comprehensive Cancer Center, Aurora, CO, USA.
J C
JC
Costello
Department of Surgery (Urology), University of Colorado, Aurora, CO, USA.|Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.|University of Colorado Comprehensive Cancer Center, Aurora, CO, USA.
D
D
Theodorescu
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D059472:Exome; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome; D014571:Urologic Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
D000970:Antineoplastic Agents; D015415:Biomarkers; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases