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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

Breast Cancer Research 1/2017

Increased genomic burden of germline copy number variants is associated with early onset breast cancer: Australian breast cancer family registry

Breast Cancer Research > Ausgabe 1/2017
Logan C. Walker, John F. Pearson, George A. R. Wiggins, Graham G. Giles, John L. Hopper, Melissa C. Southey
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Electronic supplementary material

The online version of this article (doi:10.​1186/​s13058-017-0825-6) contains supplementary material, which is available to authorized users.



Women with breast cancer who have multiple affected relatives are more likely to have inherited genetic risk factors for the disease. All the currently known genetic risk factors for breast cancer account for less than half of the average familial risk. Furthermore, the genetic factor(s) underlying an increased cancer risk for many women from multiple-case families remain unknown. Rare genomic duplications and deletions, known as copy number variants (CNVs), cover more than 10% of a human genome, are often not assessed in studies of genetic predisposition, and could account for some of the so-called “missing heritability”.


We carried out a hypothesis-generating case-control study of breast cancer diagnosed before age 40 years (200 cases, 293 controls) using population-based cases from the Australian Breast Cancer Family Study. Genome-wide scanning for CNVs was performed using the Human610-Quad BeadChip and fine-mapping was conducted using PennCNV.


We identified deletions overlapping two known cancer susceptibility genes, (BRCA1 and BLM), and a duplication overlapping SMARCB1, associated with risk. The number of deletions across the genome was 1.5-fold higher for cases than controls (P = 10-16), and 2-fold higher when only rare deletions overlapping genes (frequency <1%) were assessed (P = 5 × 10-4). Association tests of CNVs, followed by experimental validation of CNV calls, found deletions overlapping the OR4C11 and OR4P4 genes were associated with breast cancer (P = 0.02 and P = 0.03, respectively).


These results suggest rare CNVs might have a role in breast cancer susceptibility, at least for disease at a young age.
Additional file 1: Figure S1. Study design for CNV discovery, quality control and analysis. Figure S2. The protocol use to define RefSeq gene boundaries. Figure S3. BLM deletions identified in a familial breast cancer pedigree. Male and female individuals are represented by squares and circles, respectively. The index case patient, who underwent genome-wide CNV profiling, is indicated by an arrow. Individuals with breast cancer are represented by closed circles. Other cancers are indicated by black shading in the lower left quadrant. Age at death, last known diagnosis or cancer diagnosis is indicated where known. Copy number genotype at the BLM locus is noted as BLM deletion (BLM del) or wildtype (wt) copy number. (DOCX 30 kb)
Additional file 2: Table S1. CNV data for cases and controls. Chromosome coordinates given according to Hg18. (XLSX 819 kb)
Additional file 3: Table S2. Taqman assays used for CNV assessment at 7 gene loci. Table S3. Cancer-predisposing genes disrupted by rare CNVs. Table S4. Results of Taqman assays carried across 7 gene loci. (DOCX 18 kb)
Additional file 4: Table S5. Results from a genome-wide association analysis of CNVs overlapping gene loci. (XLSX 205 kb)
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