Project Details
Grant Program
Social Policy Grant
Project Description
DNA MMR deficiency is the most commonly encountered abnormality in
inherited colorectal cancer syndrome. In many cases, this is the
molecular pathogenesis of Lynch Syndrome or hereditary non polyposis
colon cancer (HNPCC). Lynch syndrome (LS) is caused by a germ line
mutation in one of several genes; principally MLH1 and MSH2, but also
MSH6 and PMS2. Patients with LS have an increased risk of developing
colorectal cancer at a younger age group and cancers in other organs
including ovarian, renal, gastric, small bowel, biliary/pancreatic, skin and
brain cancers. The molecular signature of LS is microsatellite instability
(MSI) which is found in more than 95% of LS-associated colorectal
cancer (CRC). However, in some 15% of cases of CRC, MSI has been
detected with no germline mutation in any of the MMR genes. This is
referred to as sporadic CRCs and has been attributed to the epigenetic
silencing of the MLH1 gene due to hypermethylation of the promoter
region. Immunohistochemical studies for MMR protein expressions have
been shown to have comparable sensitivity and specificity to genetic
testing in detecting MSI in MMR-deficient CRCs. CRC with MSI and
negative staining for MSH2, MSH6 or MLH1 without promoter
hypermethylation is strongly suggestive of MSH2, MSH6 and MLH1
germline mutation. MSI CRCs have not been studied in great details in
Kazakhstan and quality data on the genetic profiles of colorectal cancer
is scarce. Therefore the surveillance strategy and therapeutic outcomes
in this group of patients is unclear. The main aim of our study is to
evaluate the immunohistochemical characteristics of MMR-deficient CRC
and to correlate these features with pathological and clinical parameters
such as age, sex, localization, size, multiplicity, differentiation, mucinous
differentiation, pathological tumor stage, lymphovascular and perineural
invasion, lymphocyte count in tumor microenvironment and lymph node
metastases.
inherited colorectal cancer syndrome. In many cases, this is the
molecular pathogenesis of Lynch Syndrome or hereditary non polyposis
colon cancer (HNPCC). Lynch syndrome (LS) is caused by a germ line
mutation in one of several genes; principally MLH1 and MSH2, but also
MSH6 and PMS2. Patients with LS have an increased risk of developing
colorectal cancer at a younger age group and cancers in other organs
including ovarian, renal, gastric, small bowel, biliary/pancreatic, skin and
brain cancers. The molecular signature of LS is microsatellite instability
(MSI) which is found in more than 95% of LS-associated colorectal
cancer (CRC). However, in some 15% of cases of CRC, MSI has been
detected with no germline mutation in any of the MMR genes. This is
referred to as sporadic CRCs and has been attributed to the epigenetic
silencing of the MLH1 gene due to hypermethylation of the promoter
region. Immunohistochemical studies for MMR protein expressions have
been shown to have comparable sensitivity and specificity to genetic
testing in detecting MSI in MMR-deficient CRCs. CRC with MSI and
negative staining for MSH2, MSH6 or MLH1 without promoter
hypermethylation is strongly suggestive of MSH2, MSH6 and MLH1
germline mutation. MSI CRCs have not been studied in great details in
Kazakhstan and quality data on the genetic profiles of colorectal cancer
is scarce. Therefore the surveillance strategy and therapeutic outcomes
in this group of patients is unclear. The main aim of our study is to
evaluate the immunohistochemical characteristics of MMR-deficient CRC
and to correlate these features with pathological and clinical parameters
such as age, sex, localization, size, multiplicity, differentiation, mucinous
differentiation, pathological tumor stage, lymphovascular and perineural
invasion, lymphocyte count in tumor microenvironment and lymph node
metastases.
| Status | Finished |
|---|---|
| Effective start/end date | 9/1/19 → 9/30/20 |
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.