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Title: Genotype, phenotype and outcomes in colorectal cancer
Author: Southward, Katie Hannah
ISNI:       0000 0004 6351 9328
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2016
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Stage II/III CRCs are currently treated by surgery, then stage III and stage II patients exhibiting high-risk pathological features undergo a course of 5-FUbased adjuvant chemotherapy, often with oxaliplatin added. Improved characterisation of stage 11/111 tumours is required in order to improve their treatment and to ensure that drugs are only given to patients where there is evidence of a likely response. This will reduce the unnecessary and costly overtreatment of these patients, as well as the associated unpleasant side effects. Pyrosequencing, immunohistochemistry, FISH, and next-generation sequencing were used in order to assess a number of molecular markers of high-risk stage 11 CRCs in two cohorts. Of the markers tested, only mutation in KRAS was prognostic in stage 11/11I CRC (HR = 1.4). Mutation of BRAF, NRAS, PIK3CA and overexpression/amplification of HER-2 were not prognostic or predictive of response to 5-FU chemotherapy in the QUASAR-1 trial. TOP2A was coamplified with HER-2 in 28% cases. Copy number profiles produced from this cohort showed the differences between dMMR and pMMR, and the effect of high stromal content on CNV. Cases from the QUASAR-1 fit into one of three groups regarding CNV which need further characterisation and their relationship to prognosis needs to be established. KRAS mutation is a prognostic marker in stage 11/11I disease and could be tested for routinely. Importantly none of the other markers tested predicted a worse outcome with 5-FU-based chemotherapy. TOP2A is frequently coamplified with HER-2 suggesting that a subset of these cases may respond to anthracycline therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available