This project was designed to assess clinical and biological parameters of prognosis
in high grade breast cancer (BC). The first approach aimed to define Clinicoepidemiological
parameters associated with poor survival in a retrospective BC
cohort of 1339 non-metastatic patients presenting at Singleton Hospital, South
Wales, UK. Median follow-up was 5.4 years (range 0.09-10.14 years). Results of this
analysis supported the role of histological grade (HG) as a prognostic factor and a
tumour classifier. HG stood as one of the main variables associated with OS, DDFS
and DFS with only N3 disease conferring worse prognosis. This analysis contributed
with clinical information and survival data required for sample selection for
subsequent comparative genomic hybridisation (CGH) studies.
Array Comparative genomic hybridisation (aCGH) was performed in 78 cases (67
HG3 and 11 HG2) cases aiming to identify copy number alterations (CNA)
associated with poor survival. aCGH protocol optimisation was required to obtain
reproducible results and a new simplified aCGH protocol was described. A region of
chromosomal gain in Chromosome 5 (5q35.1 to 5q35.2) was significantly associated
with Cancer-specific survival (CSS; FDR<0.2). DUSP-1 and MSX2 genes were
among those candidate genes validated In-silico for poorer prognosis in BC.
FINALLY, THE ISSUE OF TAMOXIFEN RESISTANCE WAS ADDRESSED BY
ATTEMPTING TO IDENTIFY CNA IN OESTROGEN RECEPTOR (ER)
POSITIVE/TAMOXIFEN TREATED PATIENTS ASSOCIATED WITH EARLY
RELAPSE/DEATH ≤5 YEARS (TAMRG) COMPARED WITH A SUB-GROUP OF
PATIENTS ALIVE AND WELL AFTER 5 YEARS ON FOLLOW-UP (TAMCG). A
REGION OF GAIN ON CHROMOSOME 7 (188219-6234052) WAS ASSOCIATED
WITH TMACG (P:0.05) WHICH WAS ALSO ASSOCIATED WITH SIGNIFICANT
OVER-EXPRESSION OF SNX8 USING IN-SILICO VALIDATION IN LOI ET AL
DATASET. RESULTS FROM THIS STUDY CONTRIBUTE TOWARDS THE
IDENTIFICATION OF CANDIDATE PROGNOSTIC GENES IN BC. BIOLOGICAL
VALIDATION OF THESE RESULTS IS RECOMMENDED. FURTHER RESEARCH IS NEEDED TO ASSESS THE FUNCTIONAL RELEVANCE OF THESE
CANDIDATE GENES
