Sum of High-Risk Gene Mutation (SHGM): A Novel Attempt to Assist Differential Diagnosis for Adrenocortical Carcinoma with Benign Adenoma, Based on Detection of Mutations of Nine Target Genes

Guo-Yang Zheng,Xing-Cheng Wu,Jian-Hua Deng,Han-Zhong Li,Xue-Bin Zhang,Yu-Shi Zhang

doi:10.1007/s10528-021-10039-w

Abstract

There has been no research on applying gene detection to differential diagnosis of adrenocortical carcinoma (ACC). We attempted to explore a novel auxiliary method for differential diagnosis between ACC with benign adrenocortical adenoma (ACA), based on mutations of target genes in tissues. Nine genes were chosen as target genes, including TP53, CTNNB1, ARMC5, PRKAR1A, ZNRF3, RB1, APC, MEN1, and RPL22. Exons sequencing of target genes were performed in 98 cases of tissue samples by FastTarget technology, including 41 ACC tissues, 32 ACA tissues, and 25 normal adrenal gland tissues. Significant mutations were detected and identified, and the clinical information was collected, for further comparative analysis and application to assist differential diagnosis of ACC. We identified 132 significant gene mutations and 227 significant mutation sites in 37 ACC tissues, much more than ACA and normal adrenal gland tissues. Mutation rates of 6 genes in ACC tissues were obviously higher than ACA tissues, including ZNRF3, ARMC5, TP53, APC, RB1, and PRKAR1A, regarded as high-risk genes. The sum of mutated high-risk genes detected in each sample was denominated sum of high-risk gene mutation (SHGM), and the rates of SHGM > 0 and SHGM > 1 in ACC tissues were 73.0% and 62.2%, respectively, both obviously higher than those in ACA tissues, with significant statistic differences. Especially for 8 cases of ACC with diameter < 5 cm, SHGM > 0 and SHGM > 1 were found in 6 samples (75%) and 4 samples (50%), respectively. However, no relevance was found between SHGM and clinical characteristics of ACC. We identified 6 high-risk genes in ACC tissues, with significantly higher mutation rates than ACA or normal adrenal gland tissues. The sum of mutated high-risk genes detected in ACC tissues was denominated SHGM, which was potential to assist the differential diagnosis of ACC with ACA, especially for the small-size ACC.

Highlights

Adrenocortical carcinoma (ACC) is a rare epithelial malignant tumor, derived from adrenal cortical cells with a low annual incidence rate of approximately 0.7–2 people per million (Else et al 2014)
We expected to improve the accuracy of differential diagnosis for ACC and contribute to improve the prognosis of ACC patients who were misdiagnosed as benign adrenocortical adenoma (ACA), by using this novel genetic diagnostic method as supplement or combination of current diagnosis methods such as the Weiss system and Ki-67 index
The results showed that the mutation rates of 6 genes detected in ACC tissues were significantly higher than those in ACA and normal adrenal gland tissues, which were ZNRF3, TP53, ARMC5, APC, RB1, and PRKAR1A

Summary

Introduction

Adrenocortical carcinoma (ACC) is a rare epithelial malignant tumor, derived from adrenal cortical cells with a low annual incidence rate of approximately 0.7–2 people per million (Else et al 2014). Tumor stage is an important factor affecting the prognosis of ACC patients. Surgical resection of tumor is recommended as the preferred therapy for ACC, and the completeness of resection is another important influence factor of prognosis of ACC (Grubbs et al 2010; Crucitti et al 1996). It is sometimes difficult to differentiate ACC from benign adrenocortical adenoma (ACA), especially for small-size tumors, which may lead to inadequate surgical resection and poor survival prognosis. Present pathological examinations, including Weiss system and Ki-67 index, are not infallible for the differential diagnosis of ACC (Wein 2016), so some ACC patients misdiagnosed as ACA before operations might still miss the opportunities of postoperative salvage therapy to improve prognosis

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