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FACULTY RESEARCH DAY

DEPARTMENT OF SURGERYwww.medicine.usask.ca/surgery. RESIDENT RESEARCH OPPORTUNITIES IN MOLECULAR ONCOLOGY . New translational research programResearch experienceGraduate studies (MSc PhD)Clinical Investigator program (RCPSC)Genomic Medicine

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FACULTY RESEARCH DAY

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    1. Molecular Oncology of Gastrointestinal Malignancy Ronghua Zhao MD PhD Alan Casson FRCSC FACULTY RESEARCH DAY

    2. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery RESIDENT RESEARCH OPPORTUNITIES IN MOLECULAR ONCOLOGY New translational research program Research experience Graduate studies (MSc PhD) Clinical Investigator program (RCPSC) Genomic Medicine & Pathobiology Group (Cancer Research Unit, Lab 4: Drs. Geyer, DeCoteau, Zhao, Casson) Focus on upper gastrointestinal malignancy Insulin Growth Factor (IGF) expression Riz-1 expression in leukemia (Geyer, DeCoteau) IGF2 imprinting in colorectal cancer (Zhao) IGF1R in Barrett adenocarcinoma (Casson) Inflammation-carcinogenesis progression Small animal model of bile reflux Collaboration with the Canadian Light Source (Drs. L Quaroni, D. Chapman) Stem cell initiative

    3. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery Why look at upper gastrointestinal (esophago-gastric) malignancy? Worldwide problem Changing epidemiology in N. America Well defined premalignant lesion- most tumors are thought to arise from a columnar epithelium-lined (Barrett) esophagus, which is predisposed by gastroesophageal reflux disease (GERD) Clinically challenging disease, with a generally poor prognosis Interesting biology

    4. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery

    5. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery ESOPHAGEAL ADENOCARCINOMA: LIFESTYLE RISK FACTORS & OBESITY (multivariate analysis)

    6. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery ESOPHAGEAL ADENOCARCINOMA: OBESITY & RISK MODIFICATION BY GENETIC POLYMORPHISMS OF IGF1R

    7. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery Epigenetic modification of gene/chromosome Present in the zygote or gamete Leads to differential expression of parental alleles, in particular monoallelic expression in somatic cells of offspring What is the genomic imprinting? As mentioned above, it is an epigenetic modification, presents in the zygote or gamete that leads to differential expression of parental alleles in the somatic cells of an offspring. Genomic imprinting results in monoallelic expression. What is the genomic imprinting? As mentioned above, it is an epigenetic modification, presents in the zygote or gamete that leads to differential expression of parental alleles in the somatic cells of an offspring. Genomic imprinting results in monoallelic expression.

    8. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery Genomic imprinting So, for the normally non-imprinted genes, both alleles from father and mother can be actively transcript to RNA. In contrast, for the normally imprinted genes, only one allele either from father or mother is actively transcripted to RNA while the other is silent. So, for the normally non-imprinted genes, both alleles from father and mother can be actively transcript to RNA. In contrast, for the normally imprinted genes, only one allele either from father or mother is actively transcripted to RNA while the other is silent.

    9. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery Located on chromosome 11p15 Normally imprinted: ----Paternally expressed, maternally silenced LOI of IGF2 was first described on Wilms’ tumor; later in adult tumors including ovarian, lung, breast, and colorectal cancer To date, there have been no reports of LOI in esophageal adenocarcinoma IGF2 gene IGF-2 gene is normally imprinted, located in chromosome 11p15. It is paternally expressed and maternally silenced. LOI of IGF-2 was firstly described on Wilms tumor and later it was found in various adult tumors, including colorectal cancer. IGF-2 gene is normally imprinted, located in chromosome 11p15. It is paternally expressed and maternally silenced. LOI of IGF-2 was firstly described on Wilms tumor and later it was found in various adult tumors, including colorectal cancer.

    10. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery Normal Regulation IGF2 Gene The IGF2 gene is regulated Via a competiting enhancing mechanism between the IGF2 and H19 genes, the Imprinting control region and the differentially methylated regions. In the paternal allele, the ICR is methylated which prevents CTCF to bind the site and allows enhancers distal to H19 to estimulate the IGF2 promoter region. In the maternal allele, the ICR is unmethylated, which allows CTCF to bind, subsequent chromatin barrier formation at the DMR, resulting in prevention of enhancers from stimulating IGF2 promoter. The IGF2 gene is regulated Via a competiting enhancing mechanism between the IGF2 and H19 genes, the Imprinting control region and the differentially methylated regions. In the paternal allele, the ICR is methylated which prevents CTCF to bind the site and allows enhancers distal to H19 to estimulate the IGF2 promoter region. In the maternal allele, the ICR is unmethylated, which allows CTCF to bind, subsequent chromatin barrier formation at the DMR, resulting in prevention of enhancers from stimulating IGF2 promoter.

    11. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery Via a competitive enhancing mechanism between the H19 and IGF2 geneVia a competitive enhancing mechanism between the H19 and IGF2 gene

    12. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery Apa I Restriction Fragment Length Polymorphism (RFLP)

    13. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery Similarly, LOI of IGF-2 was found to be associated with both personal and family history of colorectal cancer. Similarly, LOI of IGF-2 was found to be associated with both personal and family history of colorectal cancer.

    14. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery Clinical associations of IGF2 LOI in colorectal cancer In this table we present baseline clinical characteristics of our cohort according to LOI status. There was no statistically significant difference among LOI-positive and LOI-negative patients in regards to age and gender. However, LOI-positive individuals had significantly more HPP, adenomas and CRC compared to LOI-negative individuals.In this table we present baseline clinical characteristics of our cohort according to LOI status. There was no statistically significant difference among LOI-positive and LOI-negative patients in regards to age and gender. However, LOI-positive individuals had significantly more HPP, adenomas and CRC compared to LOI-negative individuals.

    15. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery IGF2 LOI and response of rectal cancer to chemo-radiation therapy

    16. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery What is the genomic imprinting? As mentioned above, it is an epigenetic modification, presents in the zygote or gamete that leads to differential expression of parental alleles in the somatic cells of an offspring. Genomic imprinting results in monoallelic expression. What is the genomic imprinting? As mentioned above, it is an epigenetic modification, presents in the zygote or gamete that leads to differential expression of parental alleles in the somatic cells of an offspring. Genomic imprinting results in monoallelic expression.

    17. DEPARTMENT OF SURGERY www.medicine.usask.ca/surgery SUMMARY: RESIDENT RESEARCH OPPORTUNITIES IN MOLECULAR ONCOLOGY New translational research program: Research experience Graduate studies (MSc PhD) Clinical Investigator program (RCPSC) Genomic Medicine & Pathobiology Group: Selected molecular markers in gastrointestinal malignancy Insulin Growth Factor (IGF) expression Inflammation-carcinogenesis progression Small animal model of bile reflux Stem cell initiative

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