My note on paper: Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas
Paper: Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas
(doi:10.1053/j.gastro.2013.10.045)
colon polyps (sessile or traditional serrated adenomas)
------------------------
Research gap:
genetic factor that facilitating the colon polyps.
Evident:
SSA
- contain BRAF or KRAS mutation early in development
- mutation causes oncogene-induced senescence (OIS) of the intestinal crypt cell
- escape from OIS facilitates the development of serrated neoplasia by inactivating of tumor suppressor
Aim:
Investigate subject having SSA contains germline loss of function mutation (nonsense and splice site) in gene regulate the OIS (p16-Rb and ATM-ATR) -- cause the transition from OIS to SSA
Method:
1.Bioinformatics reveal set of gene function in the main node of p16-Rb and ATM-ATR dna damage response pw
2.Whole-exosome sequencing on multiple SSA (compare SSA (20 cases) vs control group with same ethnicity)
3.Integrative genomics to identify additional genes involves in senescence
Results:
1.Identify gene mutation of genes that regulate the senescence; ATM, PIF1, TEL02, XAF1, and RBL1 - 5/20 (SSA cases) - associated but not significant
2.Nonsense mutation on RNF43; 2/20 (SSA cases) - associate and significant
3.Knockdown experiments on RNF43 in pancreatic duct cell exposed to the UV - indicate RNF43 regulates ATM-ATR damage response
Conclusion:
1.Germ-line LOF in gene -- regulate senescence -- SSA
2.RNF43 regulate the DNA damage response
3.Mutation of RNF43 is high risk to develop SSA
------------------------
Intro:
1. SSA is prerequisite symptom for colon cancer
2. SSA -- give rise to sporadic microsatellite-high colon cancer and BRAF-mutated microsatellite stable colon cancer
3. SSA -- 20-35% of colon cancer
4. SSA -- not dependence on APC/b-catenin, but relate to BRAF (more) and KRAS (less)
5. Model of SSA is not clear whether it is involved in monogenic or Mendelian through linkage analysis
5. SSA - variable clinical presentation which refer to genetic complexity involved
6. Hypothesized that high-risk variants rely on the specific pw rather than single gene
7. evident shows APC mutation causes tubular adenomas
8. either BRAF or KRAS mutations not solely factors contribute to cause tumorigenesis
9. The fact, after short period of hyperproliferation, crypt cells will be in growth arrest due to metabolic and replicative stress (OIS) - oncogene induced senescence (too tired to proliferate)
10. more mutations causes neoplasia progression
11. evident shows bypass OIS causes serrated neoplasia phenotype
--
Gap:
unknown genetic susceptibility of SSA (pick the subjects with multiple SSA - hallmarks for serrated polyposis syndrome)
--
Gap:
Bypasss of OIS to SSA - fundamental process; and the genetic factors are not indicated yet.
Objective:
Find out the genes in the whole pw from the patients with multiples SSAs whether they have germline, strong LOF mutation in p16-RB and ATM-ATR-mediated DNA damage response
--
RNF43-R113X (germline mutation)
--
1.higher expression can be found in tubular adenomas and conventional adenocarcinomas
2.RNF43 show homeostatic role and tumor suppressive role by inducing endocytosis of Wnt receptor
3.Lower expression of RNF43 in serrated pw relates to colon carcinogenesis
--
Evident based observation:
RNF43 is linked to UV-induced apoptosis
Therefore:
1.Investigating more on RNF43 in DNA damage response - in prcancerous lesion
2.Using pancreatic duct cells with KRAS(G12D-activated); having intact OIS checkpoint genes to study the genetic interaction between KRAS + RNF43 mutations (lesion observe in sunset of pancreatic cystic tumors)
3.Irradiate with UV in RNF43 depleted cell - reduce gH2Ax and Chk1-P accumulation
4. Growth rate of RNF43(KD) and WT -the same - indicating that the reduction of gH2Ax and Chk1 not affect from cycle arrest, rather dampening DDR pw
--
1.ATM mutations developing of hereditary breast and pancreatic cancer
2.RNF43 most frequently mutated gene in cystic neoplasms of pancreas
3.OIS is relevant to SSA as well as development of most neoplasia
(doi:10.1053/j.gastro.2013.10.045)
colon polyps (sessile or traditional serrated adenomas)
------------------------
Research gap:
genetic factor that facilitating the colon polyps.
Evident:
SSA
- contain BRAF or KRAS mutation early in development
- mutation causes oncogene-induced senescence (OIS) of the intestinal crypt cell
- escape from OIS facilitates the development of serrated neoplasia by inactivating of tumor suppressor
Aim:
Investigate subject having SSA contains germline loss of function mutation (nonsense and splice site) in gene regulate the OIS (p16-Rb and ATM-ATR) -- cause the transition from OIS to SSA
Method:
1.Bioinformatics reveal set of gene function in the main node of p16-Rb and ATM-ATR dna damage response pw
2.Whole-exosome sequencing on multiple SSA (compare SSA (20 cases) vs control group with same ethnicity)
3.Integrative genomics to identify additional genes involves in senescence
Results:
1.Identify gene mutation of genes that regulate the senescence; ATM, PIF1, TEL02, XAF1, and RBL1 - 5/20 (SSA cases) - associated but not significant
2.Nonsense mutation on RNF43; 2/20 (SSA cases) - associate and significant
3.Knockdown experiments on RNF43 in pancreatic duct cell exposed to the UV - indicate RNF43 regulates ATM-ATR damage response
Conclusion:
1.Germ-line LOF in gene -- regulate senescence -- SSA
2.RNF43 regulate the DNA damage response
3.Mutation of RNF43 is high risk to develop SSA
------------------------
Intro:
1. SSA is prerequisite symptom for colon cancer
2. SSA -- give rise to sporadic microsatellite-high colon cancer and BRAF-mutated microsatellite stable colon cancer
3. SSA -- 20-35% of colon cancer
4. SSA -- not dependence on APC/b-catenin, but relate to BRAF (more) and KRAS (less)
5. Model of SSA is not clear whether it is involved in monogenic or Mendelian through linkage analysis
5. SSA - variable clinical presentation which refer to genetic complexity involved
6. Hypothesized that high-risk variants rely on the specific pw rather than single gene
7. evident shows APC mutation causes tubular adenomas
8. either BRAF or KRAS mutations not solely factors contribute to cause tumorigenesis
9. The fact, after short period of hyperproliferation, crypt cells will be in growth arrest due to metabolic and replicative stress (OIS) - oncogene induced senescence (too tired to proliferate)
10. more mutations causes neoplasia progression
11. evident shows bypass OIS causes serrated neoplasia phenotype
--
Gap:
unknown genetic susceptibility of SSA (pick the subjects with multiple SSA - hallmarks for serrated polyposis syndrome)
--
Gap:
Bypasss of OIS to SSA - fundamental process; and the genetic factors are not indicated yet.
Objective:
Find out the genes in the whole pw from the patients with multiples SSAs whether they have germline, strong LOF mutation in p16-RB and ATM-ATR-mediated DNA damage response
--
RNF43-R113X (germline mutation)
--
1.higher expression can be found in tubular adenomas and conventional adenocarcinomas
2.RNF43 show homeostatic role and tumor suppressive role by inducing endocytosis of Wnt receptor
3.Lower expression of RNF43 in serrated pw relates to colon carcinogenesis
--
Evident based observation:
RNF43 is linked to UV-induced apoptosis
Therefore:
1.Investigating more on RNF43 in DNA damage response - in prcancerous lesion
2.Using pancreatic duct cells with KRAS(G12D-activated); having intact OIS checkpoint genes to study the genetic interaction between KRAS + RNF43 mutations (lesion observe in sunset of pancreatic cystic tumors)
3.Irradiate with UV in RNF43 depleted cell - reduce gH2Ax and Chk1-P accumulation
4. Growth rate of RNF43(KD) and WT -the same - indicating that the reduction of gH2Ax and Chk1 not affect from cycle arrest, rather dampening DDR pw
--
1.ATM mutations developing of hereditary breast and pancreatic cancer
2.RNF43 most frequently mutated gene in cystic neoplasms of pancreas
3.OIS is relevant to SSA as well as development of most neoplasia
--
Cell line used for knockdown experiment:
Pancreatic ductal cells (KRAS-G12D-activated KRAS)
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