The document analyzes the tumor transcriptomics profile of a patient with stage IV gallbladder cancer. It identifies the top 200 most significantly activated expression regulators in the patient's tumor using sub-network enrichment analysis software. Key regulators identified include histone deacetylases and DNA methyltransferases. The analysis suggests treatment with the HDAC inhibitor vorinostat and discusses how activated regulators like HDACs, PDCD1, and CTLA4 may be contributing to tumor proliferation and immune evasion. Graphical summaries show pathways enriched with active regulators in the tumor related to cancer hallmarks like histone modification and immune response evasion.
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Tumor Transcriptomics Profile
1. Analysis of tumor transcriptomics profile for the
Patient with stage IV gallbladder cancer
Contents
1. NGS data normalization..................................................................................................................................................1
2. Identification of regulators responsible for differential gene expression in patient tumor................1
3. Graphical summaries of findings from analysis tumor transcriptomics profile.......................................2
HDACs activation causes NFkB inhibition, activation of cell cycle and inhibition of apotosis................2
PDCD1 protein is activated in patient tumor .............................................................................................................2
CTLA4 protein is activated in patient tumor..............................................................................................................3
Cancer Hallmarks pathways enriched with active expression regulators in patient tumor ........................3
Deacetylases Activation in Histone Deacetylation in Cancer ...............................................................................4
Methylases in Histone Methylation Cancer.................................................................................................................5
Table 1. List of top 200 statistically significant activated expression regulators identified by sub-
network enrichment analysis (SNEA) in Pathway Studio..........................................................................................6
1. NGS data normalization
NGS RNAseq tumor transcriptomics profile was generated by Genoanalytica, Moscow Russia. RPKM
values for every gene measured in tumor sample were normalized on transcriptomics profile from
three samples of normal gallbladder from publicly available GSE132223 data from National Cancer
Institute (NCBI): M3-741_tpm, M3-760_tpm, M3-817_tpm
2. Identification of regulators responsible for differential gene
expression in patient tumor
Normalized NGS RNAseq tumor transcriptomics profile was imported into Pathway Studio software
from Elsevier to determine expression regulators upstream of the differentially expressed genes
using sub-network enrichment analysis option “What proteins regulate expression of entities
enriched in the input data?”. The list of identified top 200 significant most active regulators is shown
in Table 1. Among top most active regulators 5 were found to be histone deacetylases (HDACs).
Overexpression of histone deacetylase 2 predicts unfavorable prognosis in human gallbladder
2. carcinoma (Du, 2013), HDAC1 promoted migration and invasion binding with TCF12 by promoting
EMT progress in gallbladder cancer (He, 2016). Because it was shown that Zolinza inhibits
proliferation of galdbladder carcinoma cells (Yamaguchi, 2010) we suggest using HDAC inhibitors for
treatment. Zolinza from Merck USA is the most studied and safe HDAC inhibitor on the market.
HDAC activation enables tumor proliferation through suppression of cell cycle inhibitors CDKNs and
through evasion of immune response by down-regulation of NFkB. Other proteins found active in the
tumor is PDCD1 and CTLA4 (Table 1). Activation of these proteins provides additional mechanism
for suppression of immune response. PDCD1 is the target of immunotherapy drugs Opdivo, Keytruda.
CTLA4 is the target of immunotherapy drugs Tremelimumab and Yervoy.
3. Graphical summaries of findings from analysis tumor
transcriptomics profile.
Red proteins – activated expression regulators in tumor according to SNEA in Pathway Studio. Blue
proteins - inhibited expression regulators in tumor according to SNEA in Pathway Studio. Tumor
transcriptomics analysis has revealed profound down-regulation of inflammatory cytokines and their
receptors in the tumor, which is likely due to down-regulation of NFkB family of transcription factors.
HDACs activation causes NFkB inhibition, activation of cell cycle and inhibition of apoptosis.
Suberoylanilide hydroxamic acid is a chemical name of Zolinza.
3. PDCD1 protein is activated in patient tumor
CTLA4 protein is activated in patient tumor
Cancer Hallmarks pathways enriched with active expression
regulators in patient tumor
Collection of Cancer Hallmarks pathways is readily available in Pathway Studio. It provides
foundation for building personalized cancer mechanistic model from patient molecular profiling data.
4. Pathways below were found enriched with active expression regulators identified by sub-network
enrichment of patient tumor transcriptomics data. Red proteins – activated expression regulators in
tumor according to SNEA in Pathway Studio. Blue proteins - inhibited expression regulators in tumor
according to SNEA in Pathway Studio.
Deacetylases Activation in Histone Deacetylation in Cancer
Cancer Hallmark: Hallmarks of Cancer (9) Genome Instability
Notes: Headnote: The epigenetic changes including histone acetylation/deacetylation are thought to participate in
the onset of genomic instability and progression of cancer in numerous tumor types.
Signaling description: The acetylation status of histones H3 and H4 largely determines the status of chromatin
condensation, and, consequently, gene expression. Histone acetylation is regulated by the opposing activities
of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Histone acetylation conducted by HATs
removes the positive charge of the histone molecule, thus diminishing the interaction of the histone N termini
with the negatively charged DNA phosphate groups. This relaxes chromatin condensation allowing for a
greater level of gene transcription (highly condensed heterochromatin becomes transcriptionally active
euchromatin). The reverse process of chromatin condensation is conducted by HDACs. There exist four classes
of HDACs: class I consists of HDAC 1, 2, 3, and 8; class II consists of HDAC 4, 5, 6, 7, 9, and 10; class III consists
of sirtuins (SIRT 1-7); and class IV consists of HDAC 11, which have features of both class I and II HDACs. HDAC
2, 4, SIRT 1, 6, 7 may be mutated in cancer. HDAC 1, 2, 3, 6, 7, 8, SIRT 1 and 7 may be overexpressed in cancer,
SIRT 4 and 6 may be down-regulated.
Outcome effects: Deregulation of HDACs creates an impairment of histone acetylation and chromatin
remodeling leading to oncogenic progression. An extensive number of HDAC inhibitors are developed and
explored in clinical trials showing anti-tumor activities. The most extensively studied HDAC inhibitors target
class I and or II, and a separate set of inhibitors target class III HDACs (sirtuins).
5. Methylases in Histone Methylation Cancer
Cancer Hallmark: Hallmarks of Cancer (9) Genome Instability
Notes: Headnote: Epigenetic changes including histone methylation are now thought to participate in the onset and
progression of cancer in numerous tumor types. Methylation of specific residues in the core histones H3 and
H4 have been identified as a marker of tumor cells.
Signaling description: Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the
transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment
of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. According
to modern data, histone methylation can either repress or activate transcription. In general, methylation at
H3K4, H3K36, and H3K79 is associated with transcriptional activation, whereas H3K9, H3K27, and H3K20
methylation is associated with transcriptional repression. Monomethylations at H3K27, H3K9, H4K20, H3K79,
and H2BK5 are all linked to gene activation, whereas trimethylations at H3K27, H3K9, and H3K79 are linked to
repression. A number of HMTs can be mutated in cancer, including KMT2A/C/D, NSD1, WHSC1, WHSC1L1,
EZH2, PRDM1/2/12/16, MECOM. DOT1L may be activated by fusion proteins MLL-AF10, MLL-AF4, MLL-ELL.
Outcome effects: Deregulation of HMT leads to the impairment of chromatin remodeling and makes impact to
oncogenic progression.