Breast cancer is the most common and the leading cause of female mortality among South African (SA) women. Several non-biological and biological risk factors may be attributed to their observed high mortality rate; however, the molecular profiles associated with their breast tumors are poorly characterized. The present study examined the patterns of genome-wide copy number alterations (CNAs) and their potential impact on functional cellular pathways targeted by cancer driver genes in patients with breast cancer from the Western Cape region of SA. Array-comparative genomic hybridization analysis, performed in 28 cases of invasive breast cancer, revealed a mean number of 8.68±6.18 CNAs per case, affecting primarily the Xp22.3 and 6p21-p25 cytobands (57.14% of the cases), followed by 19p13.3-p13.11 (35.7%), 2p25.3-p24.3, 4p16.3-p15.3, 8q11.1-q24.3 and 16 p13.3-p11.2 (32.14%). Functional enrichment analysis of genes and microRNA targets mapped in these affected cytobands revealed critical cancer-associated pathways, including fatty acid biosynthesis and metabolism, extracellular matrix-receptor interaction, hippo and tumor protein p53 signaling pathways, which are regulated by known cancer genes, including CCND1, CDKN1A, MAPK1, MDM2, TP53 and SMAD2. An inverse correlation was observed among the number of CNAs and tumor size and grade; CNAs on the 4p and 6p cytobands were also inversely correlated with tumor grade. No association was observed in the number of CNAs and/or the affected cytobands and the different ethnic groups of the SA patients, indicating that their tumor genome is affected by CNAs, irrespectively of their genetic descent. Additional genomic tumor profiling in SA and other Sub-Saharan African patients with breast cancer is required to determine the associations of the CNAs observed with prognosis and clinical outcome.

Breast cancer is one of the main causes of cancer death among South African women. Although several risk factors can be attributed to the observed high mortality rate, the biology of the tumors is not extensively investigated. Copy number gain of the DLX4 homeobox gene has been observed in breast cancer in association with poor prognosis and specific racial groups. Therefore, we aimed to assess the copy number and prognostic role of DLX4 in breast cancer from South African patients. Due to the co-location of ERBB2 and DLX4 in the 17q21 region, its copy number was also evaluated. Our results in the analysis of 66 cases demonstrated copy number gains of DLX4 and ERBB2 in 24.1 and 29.7% of the cases, respectively. Linear regression analysis showed no dependency between the copy number alterations in these genes. Although not significant, patients with DLX4 and ERBB2 gains presented a higher frequency of advanced-grade tumors. In addition, copy number alterations of these genes were not significantly differently observed in the 3 main racial groups of the Western Cape population: Colored, White, and Black. These findings indicate that gains of DLX4 and ERBB2 occur in South African breast cancer patients irrespectively of their race and factors known to influence prognosis.

Introduction: Breast cancer is the most common cancer among South African women, where as in many other Sub-Saharan countries, is the leading cause of female death. Although several risk factors can be attributed to their observed high mortality rate, the biology of their tumors are not extensively investigated; consequently the molecular profiles associated with their disease is poorly characterized. Main goal: In this study our main goal was to characterize the wide-genomic copy number profile of a group of patients with breast cancer diagnosed at the Groote Schuur Hospital, Cape Town, South Africa and associate with their corresponding clinical-pathological data. Material and Methods: Twenty-eight specimens of formalin fixed paraffin embedded (FFPE) material from twenty-eight patients with invasive breast cancer were acquired prior to any treatment and with complete clinical annotation from the archives of the Division of Anatomical Pathology, National Health Laboratory Service-Groote Schuur Hospital. The mean age and tumor size of the patients at diagnosis was 48.2±12.9 years and 38.2±14.0 mm, respectively. Most of the tumors were of grade 2 and 3 (39.2% and 37.7%, respectively) and stage III (67.8%). ER and ERBB2 positivity was observed in 57.1% and 53.8% of the patients, respectively. PR status was available for only 21.4% of the patients, out of which 33% (2/6) were positive. Three patients were negative for ER, PR and ERBB2 receptors. Race information was self-reported; 61.4% of the patients were from the Colored group, followed by 19.2% from the White and Black group, which are the three most predominant ethnic groups in South Africa. Array-CGH analysis was performed in microdissected tumor areas using the Agilent 8x60K oligo nucleotide array platform. Results: The average number of copy number alterations (CNAs) observed in these patients was 8.3±1.2 which was significantly associated with patients' tumor grade (P<0.01). The most frequent cytobands affected were Xp22.33-p21.1 (86.7% of the cases), 6p25.3-p21 (83.3%), 19p13.3-p13.11 (56.7%), 21p11.2-p11.1 (50%) and 16p13.3-p11.2 (43.3%), that except for the 21p region, were observed gained and/or amplified. From these commonly affected cytobands, gains on 6p was significantly associated with tumor grade (P<0.05). No significant association was observed among the average number of CNAs and/or the most frequent cytobands with other clinical-histopathological parameters and/or ethnic groups. Conclusions: Our results indicated that CNAs occur in South African breast cancer patients, in association with advanced tumor grades, but irrespectively of their ethnic descendance and other factors at diagnosis that are known to influence prognosis. Additional molecular studies, such as ours, that aim to determine the biologic contributions to breast-cancer risk in women in South Africa and other African countries are imperative. The understanding of the genetic determinants that are associated with the etiology of their tumors is a direction towards the reduction of their observed high mortality rates. Citation Format: Kamil Lupicki, Selene Elifio-Esposito, Aline S. Fonseca, Akanksha Mahajan, Silma R. Pereira, B Langa, Dhirendra Govender, Eugenio Panieri, Donavon Hiss, S Abdul-Rasool, Luciane R. Cavalli. Copy number profiling in South African breast cancer patients [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A14.