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. 2021 Aug 16;28(10):671-681.
doi: 10.1530/ERC-21-0040.

Targeted genomic analysis of 364 adrenocortical carcinomas

Nikita Pozdeyev  1   2 , Lauren Fishbein  1   2 , Laurie M Gay  3 , Ethan S Sokol  3 , Ryan Hartmaier  3 , Jeffrey S Ross  3   4 , Sourat Darabi  5 , Michael J Demeure  5   6 , Adwitiya Kar  1 , Lindsey J Foust  1 , Katrina Koc  1 , Daniel W Bowles  7 , Stephen Leong  7 , Margaret E Wierman  1   8 , Katja Kiseljak-Vassiliades  1   8
Affiliations

Targeted genomic analysis of 364 adrenocortical carcinomas

Nikita Pozdeyev et al. Endocr Relat Cancer. .

Abstract

Despite recent advances in elucidating molecular pathways underlying adrenocortical carcinoma (ACC), this orphan malignancy is associated with poor survival. Identification of targetable genomic alterations is critical to improve outcomes. The objective of this study was to characterize the genomic profile of a large cohort of patient ACC samples to identify actionable genomic alterations. Three hundred sixty-four individual patient ACC tumors were analyzed. The median age of the cohort was 52 years and 60.9% (n = 222) were female. ACC samples had common alterations in epigenetic pathways with 38% of tumors carrying alterations in genes involved in histone modification, 21% in telomere lengthening, and 21% in SWI/SNF complex. Tumor suppressor genes and WNT signaling pathway were each mutated in 51% of tumors. Fifty (13.7%) ACC tumors had a genomic alteration in genes involved in the DNA mismatch repair (MMR) pathway with many tumors also displaying an unusually high number of mutations and a corresponding MMR mutation signature. In addition, genomic alterations in several genes not previously associated with ACC were observed, including IL7R, LRP1B, FRS2 mutated in 6, 8 and 4% of tumors, respectively. In total, 58.5% of ACC (n = 213) had at least one potentially actionable genomic alteration in 46 different genes. As more than half of ACC have one or more potentially actionable genomic alterations, this highlights the value of targeted sequencing for this orphan cancer with a poor prognosis. In addition, significant incidence of MMR gene alterations suggests that immunotherapy is a promising therapeutic for a considerable subset of ACC patients.

Keywords: adrenocortical; analysis; carcinomas; genomics; targeted.

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Conflict of interest statement

Declaration of interest: The authors declare no potential conflicts of interest

Figures

Figure 1:
Figure 1:
Patients demographic distribution. A. Gender and age distribution in FMI cohort; B. Gender and age distribution by decades in FMI study (top) compared to TCGA (bottom). Red – female, blue- male
Figure 2:
Figure 2:
ACC genomic landscape, A. Distribution of genomic alteration by types; B. Frequency of the most altered genes and their genomic alterations; C. Frequency of tumor signaling pathway mutations
Figure 3:
Figure 3:
Mismatch repair (MMR) alterations in ACC A. Frequency of genomic alteration in tumors with MMR alterations compared to tumors with no MMR alterations; B. Number of somatic variants and mutational signatures in tumors with MMR gene alterations.
See this image and copyright information in PMC

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