Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors

Sudheer Kumar Gara,Emerson Harris,Justin Lack,Margaret Cam,Electron Kebebew,Lisa Zhang

doi:10.1038/s41467-018-06366-z

Abstract

Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and high mortality due to metastatic disease. All reported genetic alterations have been in primary ACC, and it is unknown if there is molecular heterogeneity in ACC. Here, we report the genetic changes associated with metastatic ACC compared to primary ACCs and tumor heterogeneity. We performed whole-exome sequencing of 33 metastatic tumors. The overall mutation rate (per megabase) in metastatic tumors was 2.8-fold higher than primary ACC tumor samples. We found tumor heterogeneity among different metastatic sites in ACC and discovered recurrent mutations in several novel genes. We observed 37–57% overlap in genes that are mutated among different metastatic sites within the same patient. We also identified new therapeutic targets in recurrent and metastatic ACC not previously described in primary ACCs.

Highlights

Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and high mortality due to metastatic disease
Since the mutation rate was compared between primary ACC from the The Cancer Genome Atlas (TCGA) cohort to the metastatic cohort, we performed the same analysis in one matched primary ACC with a metastatic lung ACC tumor from the same patient
We found that metastatic lung ACC had a threefold higher mutation rate compared to the primary ACC (Fig. 1b)

Summary

Introduction

Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and high mortality due to metastatic disease. We report the genetic changes associated with metastatic ACC compared to primary ACCs and tumor heterogeneity. We found tumor heterogeneity among different metastatic sites in ACC and discovered recurrent mutations in several novel genes. It is evident that most of the advanced or late-stage cancers or treatment-resistant tumors adapt differently and gain additional mutations. Mutations analysis of late-stage cancer tumor sites and treatment-resistant tumors has shown biologically informative genomic alterations. It is important to understand the nature of recurrent and metastatic ACC to inform candidate genetic changes involved in cancer progression and to identify therapeutic targets. Our study objectives were to analyze the genomic landscape of metastatic ACC, the nature of different metastatic tumor sites (tumor heterogeneity), and their commonality and differences compared to primary ACC

Methods

Results

Conclusion