Patterns of copy number alterations in primary breast tumors of South African patients and their impact on functional cellular pathways

Abstract

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.

A Review of Cancer Genetics and Genomics Studies in Africa

“…In the Tunisian population, Shan et al ( 154 ) and Hamdi et al ( 152 ) identified rs1219648, rs2981582, rs8051542, rs889312, and rs889312 as breast cancer susceptibility single nucleotide polymorphisms (SNPs), with rs9911630 as the SNP with the strongest effect on the expression of BRCA1 and two long non-coding RNAs (NBR2 and LINC008854). The genome-wide copy number alteration analysis of breast cancer in South African women ( 153 ) identified the amplification in Xp22.3 and 6p21-p25, and other regions that affect known cancer genes like CCND1 , CDKN1A , MDM2 , TP53 , and SMAD2 . Meanwhile, the whole-exome sequencing study by Hamdi et al ( 152 ) and Riahi et al ( 156 ) linked breast cancer in Tunisian women to alterations in MMS19 , DNAH3 , POLK , KATβ6 , and RCC1 in BRCA1/2 mutation-negative patients with familial breast cancer.…”

Molecular Cytogenomic Characterization of the Murine Breast Cancer Cell Lines C-127I, EMT6/P and TA3 Hauschka

“…The murine homologous band to human 19p13.1 is involved also in break events in all three studied cell lines, and this region was identified to comprise genes correlated for enhanced BC risk [ 29 , 31 , 47 ]. Furthermore, mutations in this region are strongly associated only with ER-negative BC subtypes [ 33 ]. Moreover, in TA3 Hauschka and C-127I, breakpoints homologous to human band 14q32 could be observed.…”

Cytogenomic characteristics of murine breast cancer cell line JC

“…Imbalances and breakpoints being observed in JC were determined according to aCGH and mcb data, and aligned to human homologous regions using Ensembl and the UCSC Genome Browser, as previously described [19]. The obtained data were compared to genetic changes known from human BCs according to literature [7,[20][21][22][23][24][25][26][27][28][29][30][31][32].…”