This study aims to investigate the role of RNF43 in the development of SPS.
- One Master of Biomedical Science
- One Honours
Serrated polyposis syndrome (SPS) is a condition characterised by the development of 10s-100s of premalignant lesions known as polyps throughout the colon and rectum (large bowel) and, therefore, a high risk of developing colorectal cancer (CRC). The polyps that develop in people with SPS have a distinct morphology and unique molecular features, namely serrated architecture and high levels of genome-wide DNA methylation at gene promoters (CpG Island Methylator Phenotype or CIMP), respectively. The cause for the vast majority of SPS is unknown (idiopathic) although in a small proportion of cases, germline pathogenic variants in the RNF43 gene have been recently described as a cause of SPS. Currently, we have limited knowledge on the mechanism by which defects in RNF43 cause SPS, limiting the clinical actionability of testing for RNF43-casused SPS.
Our lab has recently identified several families with SPS who carry rare germline variants in RNF43 including pathogenic variants and variants that have uncertain clinical significance, where the functional importance of these variants is not fully understood.
This project aims to investigate the role of RNF43 in the development of SPS.
Aim 1 – investigate the expression of RNF43 in colonic mucosa and serrated polyps/CRC of people with SPS using RNA in situ hybridization (RNA-scope) and immunohistochemistry for RNF43 protein expression.
Aim 2 – detail the transcriptome and tumour microenvironment of serrated lesions from RNF43 pathogenic variant carriers using RNA-seq and Nanostring digital spatial profiling, respectively.
Aim 3 - exploit the CRISPR gene-editing technologies on human intestinal epithelial organoids derived from SPS patients to validate the functional and clinical significances of RNF43 mutations.
The outcomes from this project will inform the role of RNF43 in SPS tumourigenesis that may further aid in characterizing the functional consequences of rare germline variants in RNF43, which would have a direct and important clinical impact on families with inherited RNF43 variants of unknown clinical significances and the prevention of CRC development. The student will develop skills in molecular genetics, data analysis, cell culture and clinical histology. A stipend is available to the selected student.
Contact and more information
Associate Professor Daniel Buchanan