Germline DNA copy number variation in familial and early-onset breast cancer

Abstract

Introduction: Genetic factors predisposing individuals to cancer remain elusive in the majority of patients with a familial or clinical history suggestive of hereditary breast cancer. Germline DNA copy number variation (CNV) has recently been implicated in predisposition to cancers such as neuroblastomas as well as prostate and colorectal cancer. We evaluated the role of germline CNVs in breast cancer susceptibility, in particular those with low population frequencies (rare CNVs), which are more likely to cause disease."

Methods: Using whole-genome comparative genomic hybridization on microarrays, we screened a cohort of women fulfilling criteria for hereditary breast cancer who did not carry BRCA1/BRCA2 mutations.

Results: The median numbers of total and rare CNVs per genome were not different between controls and patients. A total of 26 rare germline CNVs were identified in 68 cancer patients, however, a proportion that was significantly different (P = 0.0311) from the control group (23 rare CNVs in 100 individuals). Several of the genes affected by CNV in patients and controls had already been implicated in cancer.

Conclusions: This study is the first to explore the contribution of germline CNVs to BRCA1/2-negative familial and early-onset breast cancer. The data suggest that rare CNVs may contribute to cancer predisposition in this small cohort of patients, and this trend needs to be confirmed in larger population samples.

Figure 1

Rare germline copy number variations detected in three unrelated breast cancer patients. (A) to (C) Top panels exhibit the array comparative genomic hybridization profiles of the chromosome regions (images based on the Genomic Workbench software) containing the selected copy number variation (CNV) (left) and the copy number of the corresponding sequences assessed by quantitative PCR in patients 3, 13 and 27 and control individuals (right). Bottom panels show the CNV positions in the chromosomes (small vertical red bars in the ideograms) and the corresponding genomic segments. The encompassed genes according to the Reference Sequence (RefSeq) collection are indicated by blue lines in the RefSeq genes track, and the CNVs loci reported in the general population are indicated by the blue (gain) and red (loss) bars in the Database of Genomic Variants (DGV) Struct Var track (data retrieved from the DGV) (images derived from the UCSC Genome Browser, freeze October 2011). Part (A) shows microdeletion at 1p31.1 of a 540 kb genomic segment containing the sequences of three genes. This alteration cosegregated with early-onset breast cancer in patient 3 and her sister. Part (B) shows microdeletion at 9p21.3 of a 137 kb genomic segment encompassing the gene KIA1797 and the microRNA MIR491 (patient 13). Part (C) shows microduplication at Xq13.1 of a 640 kb genomic segment affecting the FAM155B and EDA genes (patient 27).