DNA Copy Number Variation and BRCAx Hereditary Breast Cancer

Breast cancer is the second most deadly cancer for New Zealand (NZ) women aged between 25-75 years. Breast cancer generally exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. However, known susceptibility genes only account for less than 25% of the familial risk of breast cancer. The remaining genetic variance is likely to be due to variants conferring more moderate risks. To identify further breast cancer susceptibility alleles, 24 BRCAx (no pathogenic breast cancer 1, early onset (BRCA1) and breast cancer 2, early onset (BRCA2) mutations) probands from breast cancer families, 644 healthy female controls and 626 healthy male controls were fine-mapped for copy number variants (CNVs). Genome wide scanning of DNA germline CNVs was performed using Illumina Human1M-duo V3 beadchip single nucleotide polymorphism (SNP) array and the PennCNV calling algorithm; many novel CNVs were validated by quantitative PCR. In the array data, rare CNVs that were deletions were found only in the BRCAx cases, but not in the healthy controls. These rare deletions overlapped 15 genes (13 loci) that were all predicted to be disrupted: ANKRD45, DTX2, PDXDC1, PIK3C2G, PRAME, SLC9C2, RHD, TBC1D5, TMEM106B, UPK3B, CKM, KLKB1, SELP, SEMA7A and SPINT4. The first ten CNV events are suggested to be of low to moderate risk of breast cancer susceptibility. Many of these genes above belong to several biological pathways, for example TP53, oestrogen/progesterone signalling, and Fanconi Anemia (Fanconi Anemia is an autosomal recessive genetic disorder), and many of these genes have already been reported in relation to breast cancer pathogenesis and other cancers. These findings support an association between these rare CNVs and the genes they overlap. Further studies are warranted to assess definitively the role and susceptibility risk of these CNVs and genes in hereditary breast cancer development