My note on paper: Exome sequencing of liver fluke-associated cholangiocarcinoma

Paper: Exome sequencing of liver fluke-associated cholangiocarcinoma
(doi: 10.1038/ng.2273)

Point out only the points that I have been interested.

Whole exome sequencing: Expected result;
-provide insight into mutational landscape contributing to OV-CCA

-8 OV-related tumors and matched normal tissue
*206 somatic mutations in 187 genes
-validate bySangerr sequencing in another 46 cases (prevalent set) to detect recurrently mutated genes (15 genes)


Known cancer-related genes:
*TP53 -- 44.4%
*KRAS -- 16.7%
SMAD4 -- 16.7%

Somatic mutation in newly identified genes;
inactivation mutations
*MLL3 -- 14.85%
*ROBO2 -- 9.3%
*RNF43 -- 9.3%
*PEG3 -- 5.65%

activating mutation
GNAS -- 9.3%

These group of gene mutations can be divided;
1. deactivation of histone modifiers
2. activation of G protein signaling
3. loss of genome stability

Intro:
CCA -
*account for 10-25% of all primary liver cancers
*western -- 1.5/100,000 in western countries (age-standardized incidence rates - ASRs)
*dominant of liver cancer - northeastern Thailand and neighboring Loas and Cambodia (ASR -- 94.8-39.4/100,000)

Database
1. Genome MUtation Significance In Cancer (MUSiC)
2. Catalogue of Somatic Mutation in Caner (COSMIC)


PDAC = pancreatic ductal adenocarcinoma

TP53 = p53
*role in maintaining genomic stability
*RNF43 and PEG3 regulates p53
*functional disruption of p53, RNF43, PEG3 affect on genomic stability.
---
*SNP in RNF43 (rs2257205) -- associated with increased risk of pancreatic cancer in Japanese population
*In CCA exome sequencing; RNF43 somatic mutation - 2/5 nonsense, 3/5 missense (predicted by Polyphen)

RNF43 mutation showed poorer survival, might serve an independent predictive factor for survival

PEG3 - maternal imprinted gene, induce apoptosis through interaction with Siah1a (E3-Ub)

CCA shares common similarity in chromosonal aberration patterns with PDAC (pancreatic ductal adenocarcinoma) than HCC

Molecular level,
CCA and PDAC -- mutation spectra have more in common, suggested common pathway to tumorigenesis

Genetic alterations of GNAS, RNF43, ROBO2, PEG3 and XIRP2 - unique to CCA

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