Germline Mutations in the Spindle Assembly Checkpoint Genes BUB1 and BUB3 Are Risk Factors for Colorectal Cancer

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 145; no. 3; pp. 544 - 547
• Main Authors: de Voer, Richarda M, Geurts van Kessel, Ad, Weren, Robbert D.A, Ligtenberg, Marjolijn J.L, Smeets, Dominique, Fu, Lei, Vreede, Lilian, Kamping, Eveline J, Verwiel, Eugène T.P, Hahn, Marc–Manuel, Ariaans, Maayke, Spruijt, Liesbeth, van Essen, Ton, Houge, Gunnar, Schackert, Hans K, Sheng, Jian Q, Venselaar, Hanka, van Ravenswaaij–Arts, Conny M.A, van Krieken, J. Han J.M, Hoogerbrugge, Nicoline, Kuiper, Roland P
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2013
• Subjects: Adult; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer Predisposition; Case-Control Studies; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Gastroenterology and Hepatology; Genome-Wide Association Study; Germ-Line Mutation; Humans; Mosaic Variegated Aneuploidy; Poly-ADP-Ribose Binding Proteins; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Risk Factors; Spindle Assembly Checkpoint; Mosaic Variegated Aneuploidy; Cancer Predisposition; Spindle Assembly Checkpoint; colorectal cancer; SAC; CRC; MVA
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2013.06.001

The spindle assembly checkpoint controls proper chromosome segregation during mitosis and prevents aneuploidy—an important feature of cancer cells. We performed genome-wide and targeted copy number and mutation analyses of germline DNA from 208 patients with familial or early-onset (40 years of age or younger) colorectal cancer; we identified haploinsufficiency or heterozygous mutations in the spindle assembly checkpoint genes BUB1 and BUB3 in 2.9% of them. Besides colorectal cancer, these patients had variegated aneuploidies in multiple tissues and variable dysmorphic features. These results indicate that mutations in BUB1 and BUB3 cause mosaic variegated aneuploidy and increase the risk of colorectal cancer at a young age.