PT  - JOURNAL ARTICLE
AU  - Owen J. Chen
AU  - Ester Castellsagué
AU  - Mohamed Moustafa-Kamal
AU  - Javad Nadaf
AU  - Barbara Rivera
AU  - Somayyeh Fahiminiya
AU  - Yilin Wang
AU  - Isabelle Gamache
AU  - Caterina Pacifico
AU  - Lai Jiang
AU  - Jian Carrot-Zhang
AU  - Leora Witkowski
AU  - Albert M. Berghuis
AU  - Stefan Schoenberger
AU  - Dominik Schneider
AU  - Susanne Bens
AU  - Reiner Siebert
AU  - Colin J. R. Stewart
AU  - Ziguo Zhang
AU  - William C. Chao
AU  - Celia M.T. Greenwood
AU  - David Barford
AU  - Marc Tischkowitz
AU  - Jacek Majewski
AU  - William D. Foulkes
AU  - Jose G. Teodoro
TI  - Germline Missense Variants in <em>CDC20</em> Result in Aberrant Mitotic Progression and Familial Cancer
AID  - 10.1101/2021.09.13.459529
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.09.13.459529
4099  - http://biorxiv.org/content/early/2021/09/14/2021.09.13.459529.short
4100  - http://biorxiv.org/content/early/2021/09/14/2021.09.13.459529.full
AB  - CDC20 is a co-activator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/CCDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic mutations have never been identified in humans. Using whole exome sequencing, we identified heterozygous missense CDC20 variants (L151R and N331K) that segregate with cancer in two families. Characterization of these mutants showed they retain APC/C activation activity but show reduced binding to BUBR1, a component of the SAC. Expression of L151R and N331K promoted mitotic slippage in HeLa cells and primary skin fibroblasts derived from carriers. CRISPR/Cas9 was used to generate mice carrying N331K. Homozygous mice carrying N331K were non-viable, however, heterozygotes displayed accelerated oncogenicity in Myc-driven cancers. These findings highlight an unappreciated role for CDC20 variants as tumor promoting genes in humans.Competing Interest StatementThe authors have declared no competing interest.