Data from Germline Missense Variants in <i>CDC20</i> Result in Aberrant Mitotic Progression and Familial Cancer

Abstract

<div>Abstract<p>CDC20 is a coactivator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/C<sup>CDC20</sup> is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of <i>CDC20</i> is common in many cancers, oncogenic mutations have never been identified in humans. Using whole-exome sequencing, we identified heterozygous missense <i>CDC20</i> variants (L151R and N331K) that segregate with ovarian germ cell tumors in two families. Functional characterization showed these mutants retain APC/C activation activity but have impaired binding to BUBR1, a component of the SAC. Expression of L151R and N331K variants promoted mitotic slippage in HeLa cells and primary skin fibroblasts derived from carriers. Generation of mice carrying the N331K variant using CRISPR-Cas9 showed that, although homozygous N331K mice were nonviable, heterozygotes displayed accelerated oncogenicity of <i>Myc</i>-driven cancers. These findings highlight an unappreciated role for <i>CDC20</i> variants as tumor-promoting genes.</p>Significance:<p>Two germline <i>CDC20</i> missense variants that segregate with cancer in two families compromise the spindle assembly checkpoint and lead to aberrant mitotic progression, which could predispose cells to transformation.</p><p><i><a href="https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-22-2400" target="_blank">See related commentary by Villarroya-Beltri and Malumbres, p. 3432</a></i></p></div>