Rare germline copy number variants (CNVs) and breast cancer risk.
Dennis J., Tyrer JP., Walker LC., Michailidou K., Dorling L., Bolla MK., Wang Q., Ahearn TU., Andrulis IL., Anton-Culver H., Antonenkova NN., Arndt V., Aronson KJ., Freeman LEB., Beckmann MW., Behrens S., Benitez J., Bermisheva M., Bogdanova NV., Bojesen SE., Brenner H., Castelao JE., Chang-Claude J., Chenevix-Trench G., Clarke CL., NBCS Collaborators ., Collée JM., CTS Consortium ., Couch FJ., Cox A., Cross SS., Czene K., Devilee P., Dörk T., Dossus L., Eliassen AH., Eriksson M., Evans DG., Fasching PA., Figueroa J., Fletcher O., Flyger H., Fritschi L., Gabrielson M., Gago-Dominguez M., García-Closas M., Giles GG., González-Neira A., Guénel P., Hahnen E., Haiman CA., Hall P., Hollestelle A., Hoppe R., Hopper JL., Howell A., ABCTB Investigators ., kConFab/AOCS Investigators ., Jager A., Jakubowska A., John EM., Johnson N., Jones ME., Jung A., Kaaks R., Keeman R., Khusnutdinova E., Kitahara CM., Ko Y-D., Kosma V-M., Koutros S., Kraft P., Kristensen VN., Kubelka-Sabit K., Kurian AW., Lacey JV., Lambrechts D., Larson NL., Linet M., Ogrodniczak A., Mannermaa A., Manoukian S., Margolin S., Mavroudis D., Milne RL., Muranen TA., Murphy RA., Nevanlinna H., Olson JE., Olsson H., Park-Simon T-W., Perou CM., Peterlongo P., Plaseska-Karanfilska D., Pylkäs K., Rennert G., Saloustros E., Sandler DP., Sawyer EJ., Schmidt MK., Schmutzler RK., Shibli R., Smeets A., Soucy P., Southey MC., Swerdlow AJ., Tamimi RM., Taylor JA., Teras LR., Terry MB., Tomlinson I., Troester MA., Truong T., Vachon CM., Wendt C., Winqvist R., Wolk A., Yang XR., Zheng W., Ziogas A., Simard J., Dunning AM., Pharoah PDP., Easton DF.
Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.