Genomic copy number alterations in poorly differentiated breast cancer

Abstract

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.