Summary

Although limited associations were discovered with respect to NBS1 expression in our samples, we do report that rectal cancers express significant levels of NBS1 protein. In-keeping with a role for the DDR pathway in maintaining genome integrity in the face of oncogenesis, and that the cancer has a high mutation burden.

In addition, we are able to report marginal associations between NBS1 expression in the tumour centre and patient overall survival (as well as the expected clinicohistopathological associations reported; i.e. perineural invasion (PNI)-positivity), although additional samples need to be studied to confirm this observation; given the marginal statistical association. Patients in whom NBS1 staining was absent, perhaps due to disease or treatment stage, appear to drive the statistical association between high expression and overall survival. Sub-sets of rectal cancer patients with mutations in individual components of the DDR/MMR protein machinery would be informative for learning about disease development and pathway redundancy; such samples are likely to become increasingly available as more genomes get sequenced. Furthermore, the relative redundancy of different DDR proteins remains a controversial issue.

These results suggest that NBS1 is a less informative marker than ATM, MRE11 and RAD50 with respect to rectal cancer prognosis and disease pathophysiology, although, as noted, additional patient samples are required to convincingly demonstrate this.

Further exploration NBS1 expression utility in this context will be explored in Chapter Six, where the protein is described as forming part of a three-component biomarker panel with other MRN complex members.

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