RESUMO
CDC20 is a coactivator 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 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 Myc-driven cancers. These findings highlight an unappreciated role for CDC20 variants as tumor-promoting genes. SIGNIFICANCE: Two germline CDC20 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. See related commentary by Villarroya-Beltri and Malumbres, p. 3432.
Assuntos
Neoplasias , Fuso Acromático , Ciclossomo-Complexo Promotor de Anáfase/genética , Animais , Proteínas Cdc20/genética , Proteínas Cdc20/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Germinativas/metabolismo , Células HeLa , Humanos , Camundongos , Mitose/genética , Neoplasias/metabolismo , Ligação Proteica , Fuso Acromático/metabolismoRESUMO
The aim of the study performed was to test the quality and the appropriateness of nursing assessment in the light of the standards established by the American Nurses Association (ANA). For this purpose, we retrospectively reviewed our nursing documentation on a randomized sample of 300 patients (165 from the Clinical Oncology Division and 125 from the Women's Division of Cancer Institute , Bari). Statistical analysis was performed with SPSS vs 9. Data were analysed and compared with ANA standards. The results suggest that the collection of data regarding patients' health and demands is not systematic. A proposal to improve nursing data collection and assessment is therefore put forward.
