rare copy number variants observed in hereditary breast cancer cases disrupt genes in estrogen signaling and tp53 tumor suppression network罕见的拷贝数变异遗传性乳腺癌病例中观察到的破坏和tp53的肿瘤抑制基因在雌性激素信号网络.pdfVIP

Rare Copy Number Variants Observed in Hereditary Breast Cancer Cases Disrupt Genes in Estrogen Signaling and TP53 Tumor Suppression Network ¨ 1 1 1 2 3 Katri Pylkas , Mikko Vuorela , Meeri Otsukka , Anne Kallioniemi , Arja Jukkola-Vuorinen , Robert Winqvist1* 1 Laboratory of Cancer Genetics, Department of Clinical Genetics and Biocenter Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland, 2 Laboratory of Cancer Genetics, Institute of Biomedical Technology/BioMediTech, University of Tampere and Fimlab Laboratories, Tampere, Finland, 3 Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland Abstract Breast cancer is the most common cancer in women in developed countries, and the contribution of genetic susceptibility to breast cancer development has been well-recognized. However, a great proportion of these hereditary predisposing factors still remain unidentified. To examine the contribution of rare copy number variants (CNVs) in breast cancer predisposition, high-resolution genome-wide scans were performed on genomic DNA of 103 BRCA1, BRCA2, and PALB2 mutation negative familial breast cancer cases and 128 geographically matched healthy female controls; for replication an independent cohort of 75 similarly mutation negative young breast cancer patients was used. All observed rare variants were confirmed by independent methods. The studied breast cancer cases showed a consistent increase in the frequency of rare CNVs when compared to controls. Furthermore, the biological networks of the disrupted genes differed between the two groups. In familial cases the observed mutations disrupted genes, which were significantly overrepresented in cellular