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Germline Missense Variants in CDC20 Result in Aberrant Mitotic Progression and Familial Cancer

Owen J Chen1,2, Ester Castellsagué3,4,5, Mohamed Moustafa-Kamal1,2

  • 1Goodman Cancer Institute, McGill University, Montréal, Québec, Canada.

Cancer Research
|August 1, 2022
PubMed

Insights

Germline CDC20 variants (L151R and N331K) were identified in cancer families. These variants impair the spindle assembly checkpoint, promoting tumor development and highlighting CDC20’s role in oncogenesis.

Area of Science:

  • Cell biology
  • Genetics
  • Oncology

Background:

  • CDC20 is crucial for cell division by activating the anaphase promoting complex/cyclosome (APC/C).
  • The spindle assembly checkpoint (SAC) normally inhibits APC/CCDC20 to prevent errors in chromosome segregation.
  • While CDC20 overexpression is common in cancer, specific oncogenic mutations were previously unknown.

Purpose of the Study:

  • To investigate the role of CDC20 variants in hereditary cancer.
  • To functionally characterize novel CDC20 missense variants identified in cancer-prone families.

Main Methods:

  • Whole-exome sequencing to identify genetic variants.
  • Functional assays to assess APC/C activity and SAC binding.
  • Cellular studies using HeLa cells and patient-derived fibroblasts.
  • CRISPR-Cas9 gene editing in mice to model the N331K variant.

Main Results:

  • Two heterozygous missense CDC20 variants (L151R, N331K) were found to segregate with ovarian germ cell tumors in two families.
  • These variants maintain APC/C activation but exhibit reduced binding to BUBR1, a key SAC component.
  • Expression of L151R and N331K induced mitotic slippage in human cells.
  • Mice heterozygous for N331K showed accelerated Myc-driven cancer development.

Conclusions:

  • Germline CDC20 variants can compromise the spindle assembly checkpoint, leading to aberrant mitosis.
  • These findings reveal a novel mechanism by which CDC20 variants act as tumor-promoting genes.
  • This study identifies a new class of oncogenic drivers in hereditary cancer.

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