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.
Highlights
Adrenocortical carcinoma (ACC) is rare, with an annual incidence of 0.7–2.0 cases per million [1,2], but aggressive
We presumed that overexpression of CCNB2 and AURKA mRNA may cause atypical mitosis in TP53 somatic mutated cases
In cases with atypical mitotic figures, mRNA expression of CCNB1 (p = 0.068) was not significantly different from that of cases without atypical mitotic figures, the mRNA of CDK1 (p = 0.029), CCNB2 (p = 0.012), and AURKA (p = 0.018) was significantly highly expressed (Fig 4A, 4B, 4C and 4D). These results indicated that TP53 somatic variant and atypical mitotic figures are associated with high mRNA expression of CDK1, CCNB2, and AURKA
Summary
Adrenocortical carcinoma (ACC) is rare, with an annual incidence of 0.7–2.0 cases per million [1,2], but aggressive. Ki-67 is a proliferation index immunomarker that can help to refine the diagnosis and prognosis of ACC. It is established that ACC mostly shows a Ki-67 index 5% [6]. The association between cortisol-producing ACC and mortality shows a positive hazard ratio of 1.71 (95% confidence interval of 1.18–2.47) after adjusting for tumor stage. ENSAT guidelines define cortisol-producing ACC as a poor prognostic factor [9,10]. The mechanism by which patients with cortisol-producing ACC have a poor prognosis has not been elucidated. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
