CCNB2 and AURKA overexpression may cause atypical mitosis in Japanese cortisol-producing adrenocortical carcinoma with TP53 somatic variant
Open Access
- 14 April 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 15 (4), e0231665
- https://doi.org/10.1371/journal.pone.0231665
Abstract
Many genomic analyses of cortisol-producing adrenocortical carcinoma (ACC) have been reported, but very few have come from East Asia. The first objective of this study is to verify the genetic difference with the previous reports by analyzing targeted deep sequencing of 7 Japanese ACC cases using next-generation sequencing (NGS). The second objective is to compare the somatic variant findings identified by NGS analysis with clinical and pathological findings, aiming to acquire new knowledge about the factors that contribute to the poor prognosis of ACC and to find new targets for the treatment of ACC. DNA was extracted from ACC tissue of seven patients and two reference blood samples. Targeted deep sequencing was performed using the MiSeq system for 12 genes, and the obtained results were analyzed using MuTect2. The hypothesis was obtained by integrating the somatic variant findings with clinical and pathological data, and it was further verified using The Cancer Genome Atlas (TCGA) dataset for ACC. Six possible pathogenic and one uncertain significance somatic variants including a novel PRKAR1A (NM_002734.4):c.545C>A (p.T182K) variant were found in five of seven cases. By integrating these data with pathological findings, we hypothesized that cases with TP53 variants were more likely to show atypical mitotic figures. Using TCGA dataset, we found that atypical mitotic figures were associated with TP53 somatic variant, and mRNA expression of CCNB2 and AURKA was significantly high in TP53 mutated cases and atypical mitotic figure cases. We believe this is the first report that discusses the relationship between atypical mitotic figures and TP53 somatic variant in ACC. We presumed that overexpression of CCNB2 and AURKA mRNA may cause atypical mitosis in TP53 somatic mutated cases. Because AURKA is highly expressed in atypical mitotic cases, it may be an appropriate indicator for AURKA inhibitors.Funding Information
- Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province
This publication has 59 references indexed in Scilit:
- Targeted Sequencing of Cancer-Related Genes in Colorectal Cancer Using Next-Generation SequencingPLOS ONE, 2013
- Elevated cyclin B2 expression in invasive breast carcinoma is associated with unfavorable clinical outcomeBMC Cancer, 2013
- Investigation of the freely available easy-to-use software ‘EZR’ for medical statisticsBone Marrow Transplantation, 2012
- A Large Family with Carney Complex Caused by the S147G PRKAR1A Mutation Shows a Unique Spectrum of Disease Including Adrenocortical CancerJournal of Clinical Endocrinology & Metabolism, 2012
- ANNOVAR: functional annotation of genetic variants from high-throughput sequencing dataNucleic Acids Research, 2010
- Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an updateHuman Mutation, 2010
- Mutations in Regulatory Subunit Type 1A of Cyclic Adenosine 5′-Monophosphate-Dependent Protein Kinase (PRKAR1A): Phenotype Analysis in 353 Patients and 80 Different GenotypesJournal of Clinical Endocrinology & Metabolism, 2009
- Centrosome-associated regulators of the G2/M checkpoint as targets for cancer therapyMolecular Cancer, 2009
- Molecular Classification and Prognostication of Adrenocortical Tumors by Transcriptome ProfilingClinical Cancer Research, 2009
- An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinomaProceedings of the National Academy of Sciences of the United States of America, 2001