Development of epigenetic-based prognostic biomarkers to stratify risk of recurrence in early rectal cancer

Leong, Kai Juen (2013). Development of epigenetic-based prognostic biomarkers to stratify risk of recurrence in early rectal cancer. University of Birmingham. Ph.D.

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Abstract

Organ-preservation surgery for early rectal cancer is an alternative treatment to conventional radical surgery that offers comparable oncological outcome but has lower morbidity and mortality. The efficacy of this strategy relies on accurate preoperative staging of mesorectal nodal metastasis which current staging modalities are unable to deliver. DNA methylation has a prognostic role in colorectal carcinogenesis and may select for tumours suitable for local excision, although this has not been explored in rectal cancer.

A panel of staged rectal cancers was analysed for differential DNA methylation patterns. This identified a unique signature consisting of concomitant hypermethylation of three or more of APC, RARB, GSTP1, TIMP3, CASP8, DAPK1 and CXCL12 that was associated with histopathologically localised disease. Correlation of protein expression with clinicopathological features found UNC5C expression to be associated with nodal status. Genome-wide screening found >7000 differentially methylated genes between node-negative and node-positive rectal cancer. Validation was performed on a subset of these genes and this confirmed hypermethylation of SNAP25, SOX7 and TIAM1 to be associated with favourable histological indices.

This study has provided insight into the methylation patterns of rectal cancer and has identified novel prognostic biomarkers. Further work will determine their clinical usefulness in rectal cancer risk stratification.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):