My note on paper: Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer
Paper: Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer
(doi: 10.1038/ng.2983)
Abstract:
Gastric cancer-
diverse histological subtypes
diverse molecular subtypes
Method-
Whole genome sequencing on
**100 tumor-normal
** DNA copy number profile
**gene expression profile
**methylation profile
Results-
Tumor subtype relates to
**genetic perturbation
**epigenetic perturbation
**unique mutational signatures
Found driver genes:
TP53, ARID1A, CDH1 (previously known)
MUC6, CTNNA2, GLI3, RNF43 and others (newly found)
Found RHOA (Ras Homolog Family Member A, member of the Rho family of small GTPases) mutation mostly in diffuse-type tumors (14.3%) not in intestinal-type tumors
In recurrent hotspots;
*clustered mutation in functional domains that affect RHOA signaling, promoting escape from anoikis (a programmed cell death induced upon cell detachment from extracellular matrix) in organoid cultures
Top perturbed pw in gastric CA:
*adherens junction
*focal adhesion
RHOA and other mutated - play the key roles
Benefit of this;
to know the molecular evolution each step helps us on designing the personalized medicine
-----
Intro:
Gastric cancer;
1. heterogeneity in
*phenotypes
*molecular subtypes (microsatellite instability - MSI) and Epstein-Barr virus (EBV)
*histological subtypes (gland forming adenocarcinoma (intestinal type) -- highly infiltrating isolated cells (diffuse type))
Gap;
1.Exome sequencing of small cohort; get some data but not enough to cover all the diversity of gastric cancer
2.require global molecular portrait of gastric cancer
Objective:
1.whole-genome sequencing of 100 paired tumor and non-tumor
2. uncover diverse phenotypic and molecular subtypes
3. uncover the complex interplay of genetic and epigenetic that unique to each subtype of gastric cancer
---------
the pattern of base changed reflects the mutagen challenge
The distance between the mutation and transcription start site also reflects the information on transcription coupled-repair
RNF43 was truncated mutation;
MSS - 4.8%
MSI - 54.6% (62.5% is truncated)
The expression level is induced by WNT as the feedback loop.
Inactivation of RNF43 caused WNT-signaling dysfunction
The molecular subtypes of gastric cancer:
MSI
EBV
Diffuse
Mixed
Intestinal
Cancer Gene Census (CGC)
-the database collecting the gene mutation which contributes to cancer
True driver evident;
hot spot mutations in a particular gene, like in this paper, RHOA - the hotspot encoding Y42C, L57V which function as GTP binding
Finding the hotspot (forward genetic study) - prove by functional study (reverse genetic study)
Mapping the mutated genes to the KEGG pathway to retrieve the overall picture of pw contributing the complexity of gastric cancer
Molecular subtype signature (specific mutational mechanism);
MSI tumor - RNF43 and CDH1 in activated by indel and affecting mononucleotide repeat
MSS tumor - missense and nonsense indel mutation in non-repeat region
(doi: 10.1038/ng.2983)
Abstract:
Gastric cancer-
diverse histological subtypes
diverse molecular subtypes
Method-
Whole genome sequencing on
**100 tumor-normal
** DNA copy number profile
**gene expression profile
**methylation profile
Results-
Tumor subtype relates to
**genetic perturbation
**epigenetic perturbation
**unique mutational signatures
Found driver genes:
TP53, ARID1A, CDH1 (previously known)
MUC6, CTNNA2, GLI3, RNF43 and others (newly found)
Found RHOA (Ras Homolog Family Member A, member of the Rho family of small GTPases) mutation mostly in diffuse-type tumors (14.3%) not in intestinal-type tumors
In recurrent hotspots;
*clustered mutation in functional domains that affect RHOA signaling, promoting escape from anoikis (a programmed cell death induced upon cell detachment from extracellular matrix) in organoid cultures
Top perturbed pw in gastric CA:
*adherens junction
*focal adhesion
RHOA and other mutated - play the key roles
Benefit of this;
to know the molecular evolution each step helps us on designing the personalized medicine
-----
Intro:
Gastric cancer;
1. heterogeneity in
*phenotypes
*molecular subtypes (microsatellite instability - MSI) and Epstein-Barr virus (EBV)
*histological subtypes (gland forming adenocarcinoma (intestinal type) -- highly infiltrating isolated cells (diffuse type))
Gap;
1.Exome sequencing of small cohort; get some data but not enough to cover all the diversity of gastric cancer
2.require global molecular portrait of gastric cancer
Objective:
1.whole-genome sequencing of 100 paired tumor and non-tumor
2. uncover diverse phenotypic and molecular subtypes
3. uncover the complex interplay of genetic and epigenetic that unique to each subtype of gastric cancer
---------
the pattern of base changed reflects the mutagen challenge
The distance between the mutation and transcription start site also reflects the information on transcription coupled-repair
RNF43 was truncated mutation;
MSS - 4.8%
MSI - 54.6% (62.5% is truncated)
The expression level is induced by WNT as the feedback loop.
Inactivation of RNF43 caused WNT-signaling dysfunction
The molecular subtypes of gastric cancer:
MSI
EBV
Diffuse
Mixed
Intestinal
Cancer Gene Census (CGC)
-the database collecting the gene mutation which contributes to cancer
True driver evident;
hot spot mutations in a particular gene, like in this paper, RHOA - the hotspot encoding Y42C, L57V which function as GTP binding
Finding the hotspot (forward genetic study) - prove by functional study (reverse genetic study)
Mapping the mutated genes to the KEGG pathway to retrieve the overall picture of pw contributing the complexity of gastric cancer
Molecular subtype signature (specific mutational mechanism);
MSI tumor - RNF43 and CDH1 in activated by indel and affecting mononucleotide repeat
MSS tumor - missense and nonsense indel mutation in non-repeat region
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