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. Author manuscript; available in PMC: 2022 Aug 16.
Published in final edited form as: Endocr Relat Cancer. 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 Foust 1, Katrina Koc 1, Daniel W Bowles 7, Stephen Leong 7, Margaret E Wierman 1,8, Katja Kiseljak-Vassiliades 1,8
PMCID: PMC8384129  NIHMSID: NIHMS1730287  PMID: 34410225

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. 364 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.

INTRODUCTION

Adrenocortical carcinoma (ACC) is an orphan malignancy affecting individuals across a broad age spectrum with bimodal distribution from pediatric to adults. The rarity of the disease, limited preclinical models and lack of clinical trials have contributed to slow progress in the field and continued poor outcomes with 5-year survival rate of 35% (Else, et al. 2014; Icard, et al. 2001; Luton, et al. 1990).

Over the last decade, progress has been made in characterization of the genomic and genetic landscape of human adrenocortical carcinoma. Two large scale multi-omic studies confirmed that heterogonous molecular signatures underlying human ACC tumors are associated with variable genomic clusters and prognosis in patients (Assie, et al. 2014; Zheng, et al. 2016). These two comprehensive studies confirmed three known alterations in ACC including Insulin-like Growth Factor (IGF2) overexpression occurring in the majority of ACC tumors, and the Wnt and p53 pathways that are the most commonly altered in ACC (Giordano, et al. 2003; Tissier, et al. 2005). These studies have identified a few novel candidate driver genes including ZNRF3, RPL22, CCNE1 and TERF2; however, none of these are targetable to date (Assie et al. 2014; Zheng et al. 2016). Most studies to date show great variability in the phenotype and genotype of ACC.

For rare cancers, uncovering targetable genetic drivers and pathways in order to identify precision medicine approaches is especially important because of the difficulty in recruiting large number of subjects for clinical trials. Current therapies for ACC are limited. Mitotane, an adrenolytic drug, is the only FDA approved therapy with significant toxicity and limited effectiveness (Grubbs, et al. 2010; Megerle, et al. 2018; Terzolo, et al. 2007). In patients with advanced disease, EPD+M (etoposide, doxorubicin, cisplatin + mitotane) chemotherapy regiment is commonly used, but response rate is low at 23.2% with median progression-free survival of 5 months (Fassnacht, et al. 2012). No effective targeted therapy has been identified to date (Adam, et al. 2010; Berruti, et al. 2012; Fassnacht, et al. 2015; Gross, et al. 2006; Quinkler, et al. 2008; Weigel, et al. 2014; Wortmann, et al. 2010).

FoundationOne (Foundation Medicine Inc.; FMI, Cambridge, MA) is a next-generation sequencing-based platform that analyzes single nucleotide variants (SNV), indels, copy number alterations (CNA), and selected gene rearrangements in a targeted panel of cancer-associated genes (Frampton, et al. 2013). Here, we present genomic analysis of the largest known cohort of ACCs (N=364) genotyped with FoundationOne with the goal of identifying novel genetic alterations and understanding the percent targetable alterations for therapeutic intervention. Our analysis confirmed the commonly known pathway alterations in ACC and identified several novel somatic alterations. Importantly, we identified that 13.7% of ACC have alterations in the DNA mismatch repair gene pathway, which is higher than previously reported in adults with ACC (3–7%) (Lippert, et al. 2018; Raymond, et al. 2013; Zheng et al. 2016). Immune checkpoint inhibitor therapy was recently approved for MMR/MSI-H solid tumors (Lemery, et al. 2017), and may be a clinically relevant therapeutic option in a subset of patients with ACC.

METHODS

Data source

Genomic and limited demographic data for 364 ACCs from unique patients tested using FoundationOne (Frampton et al. 2013) through 2018 were provided by Foundation Medicine Inc. (FMI), Cambridge, MA (Supplementary Table 1 and 2; referred to as FMI dataset). Approval for this study, including a waiver of informed consent and Health Insurance Portability and Accountability Act waiver of authorization, was obtained from the Western Institutional Review Board (protocol #20152817). Prior to sequencing, all specimens were reviewed by the FMI pathologist for consistency with the previously established diagnosis of ACC. Data were generated as part of the clinical care; therefore, there may be ascertainment bias as some physicians may send all ACC tumors for analysis, whereas others may only send a subset from patients who have aggressive disease and are out of standard therapeutic options. Clinical information on stage, prior treatments and clinical course is not available. The FoundationOne baits version (T7 with 396 genes, T5a with 288 genes or D2 with 456 genes) used was accounted for when calculating the prevalence of alterations (Supplementary Table 3). There were 553 genes potentially investigated and 286 genes in common across all bait sets. Genes included in a specific bait set and assigned into annotation/pathway groups (Cancer Genome Atlas Research 2014; Landa, et al. 2016; Pozdeyev, et al. 2018) are listed in Supplementary Table 3.

Variant filtering and annotation

Germline DNA was not available for comparison. Therefore, to remove germline variants, synonymous variants and non-pathogenic variants, a stringent filtering strategy was used as described previously (Pozdeyev et al. 2018) and which are similar to the strategy used by the American Association for Cancer Research Project GENIE (Consortium 2017). In brief, germline variants reported by 1000 Genomes Project (Abecasis, et al. 2010) or present in any of the eight Exome Aggregation Consortium (Lek, et al. 2016) databases with the frequency of ≥ 0.00002 were excluded from further analysis. However, variants reported as “pathogenic”, “likely pathogenic” or of “uncertain significance” by ClinVar (Landrum, et al. 2016) were left in the database regardless of the frequency to prevent removal of the relatively frequent pathogenic germline variants causing cancer syndromes. Despite this rigorous filtering, it is possible that a few non-pathogenic or germline variants remained. After filtering, alterations were annotated using default settings in ANNOVAR (Wang, et al. 2010).

Mutation signature analysis

R package deconstructSigs was used to analyze mutation signatures in the adrenocortical cancers samples (Rosenthal, et al. 2016). Synonymous SNVs were included in this analysis only. COSMIC mutation signatures served as the reference (https://cancer.sanger.ac.uk/cosmic/signatures). Mutation signatures were evaluated only in specimens with at least 10 single nucleotide variants and small indels (71 tumors). As previously reported (Pozdeyev et al. 2018), this threshold was empirically identified as a minimum requirement to make reliable mutation signature calls. Mutation signature was assigned to a specific specimen when at least 60% of mutations were specific to a particular signature or mechanism (such as DNA mismatch repair deficit).

RESULTS

FoundationOne ACC cohort

Among 364 individual patient tumors analyzed, 222 were females and 141 were males (for 1 specimen the sex was unknown) (Figure 1A). The mean age (SD) was 48.6 (13.6) for females and 50.6 (12.20) for males with overall median age of 52 years at the time the specimens were submitted for genotyping, not different between sexes (Wilcoxon, p=0.44). Distribution by age and sex is shown in Figure 1B and is similar in distribution to the TCGA cohort (Zheng et al. 2016), although the bimodal distribution seen in TCGA female cohort was not observed in the FMI (Foundation Medicine Inc.) patient cohort.

Figure 1:

Figure 1:

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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

Genomic Landscape

A total of 3117 genomic alterations were found in 457 genes. The median number of alterations per tumor was 7 (range 1–56). SNVs and indels were the most common alterations (median=4), followed by CNA (median=1) and rearrangements (median=0) (Figure 2A) The distribution of types of genetic alterations associated with most frequently alerted genes is displayed in Figure 2B.

Figure 2:

Figure 2:

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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

The most frequently altered genes were TP53 (38%), CTNNB1 (28%), ZNRF3 (17%), CDKN2A (13%), RB1 (12%), MEN1 (12%), ATRX (11%), TERT promoter (10%), APC (10%) and NF1 (9%) (Figure 2B, Supplementary Figure 1). Of note, of the 138 TP53 alterations, 8 were found in the pediatric (<18 years old) cases (Supplementary Table 4). In addition, several novel recurrent alterations, not previously reported in ACC, were found affecting LRP1B (8%), IL7R (6%), FRS2 (4%), ARID1A1 (4%) and KRAS (3%).

Tumor suppressor genes (51%) and Wnt signaling pathway genes (51%) were commonly mutated (Figure 2C, Supplementary Figure 1). Epigenetic dysregulation plays a significant role in ACC tumorigenesis (Else, et al. 2008; Zheng et al. 2016). In our cohort, TERT, ATRX or DAXX were altered in 78 ACCs (21%); all were mutually exclusive except in one tumor, suggesting that mutation of any one gene in this pathway is sufficient to contribute to ACC development. Genes involved in histone modification, SWI/SNF (Switch/Sucrose Non-Fermentable) and DNA methylation were affected in 38%, 21 % and 8% of ACC, respectively (Figure 2C, Supplementary Figure 1).

Fifty ACCs (13.7%) exhibited 60 genomic alterations in MMR genes, MLH1, MSH2, MSH6 and PMS2 (Supplementary Table 2), which included 49 SNVs/indels, 10 CNAs (nine deletions, one amplification) and one MSH2-MSH2 truncating rearrangement. Eight of these are known pathogenic or likely pathogenic variants per ClinVar associated with Lynch syndrome (Supplementary Table 2). Overall, the 50 ACCs with MMR gene alterations had a significantly higher number of total SNV/indels compared to tumors with wild type MMR genes (Figure 3A, Wilcoxon test, p=1.14e-14). Interestingly, the majority (N=10/14) of MMR gene alterations in MMR altered tumors with low number (<10) of SNV/indels were still predicted damaging (predicted frameshifts, splice site variants or missense variants predicted damaging using in silico callers) (Supplementary Table 1 and 2). Surprisingly, 49 of the 50 ACC were microsatellite stable (Supplementary Table 1).

Figure 3:

Figure 3:

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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.

Mutational signature analysis (Alexandrov, et al. 2013) demonstrated, for the first time, that some ACC tumors display mutational signatures 6, 15 and 26, associated with defective MMR (Supplementary Figure 2). Eight of nine of these tumors had putative loss-of-function variants in MMR genes, supporting the functional significance of these variants (Figure 3B). None of the MMR altered tumors had a CTTNB1 hotspot mutation in exon 3, a known somatic ACC driver, observed in 66 other specimens (18.6 %) (Figure 3B). Mutational signature 1 caused by the spontaneous deamination of 5-methylcytosine (Alexandrov et al. 2013) associated with aging, was most prevalent in ACC. Surprisingly, these tumors were from younger patients (median age = 45 years) than the rest of the cohort (median age = 52 years, Wilcoxon, p=0.02).

Potentially actionable genomic alterations

Using OncoKB criteria (www.oncokb.org), this analysis identified 46 drug-targetable genetic alterations, with at least one found in 213 (58.5%) of samples in this cohort (Supplementary Table 5). Of these, the most common were found in CDKN2A (13.5%), NF1 (10.2%), CDK4 (7.7%) and MDM2 (5.8%), suggesting that drugs targeting components of cell cycle regulation might be helpful in subpopulations of ACC tumors (Supplementary Table 4). Most of the specific alterations found in each gene were not recurrent, with the exception of CDK4 R24L and NF1 R1276, which were found in two tumors each. Other recurrent alterations were found in PTCH1 S1203fs*52 in three tumors and KRAS G12C hotspot variant in two tumors. Also of interest, one tumor had a KIT/KDR/PDGFRA amplification, which is potentially druggable and was previously reported in anaplastic thyroid cancer (Pozdeyev et al. 2018). Fusion were rare and non-recurrent events in this cohort (N=13 fusions) confirming TCGA findings. FGFR2-CIT fusion reported in one tumor was likely oncogenic and a potential target for FGFR inhibitors.

DISCUSSION

This study represents the largest cohort of ACC to date and further establishes the prevalence of specific genomic alterations and identifies additional rare genomic events. A subset of this patient cohort has been previously published and described a series of 22 ACCs in which 76% featured at least 1 genomic alteration and there were 2.6 alterations per case (Ross, et al. 2014). In our current study of 364 ACC, there was an unexpectedly high prevalence of MMR gene alterations affecting 13.7% of ACCs, whereas prior studies found only 3–7% (Darabi, et al. 2020; Else et al. 2014; Lippert et al. 2018; Zheng et al. 2016). These tumors were associated with a greater mutation burden and MMR mutational signatures, supporting a functional significance. In addition, mutual exclusivity of MMR gene alterations and activating CTNNB1 mutations suggests that MMR gene loss is the primary carcinogenic event in this subset of tumors. Collectively, these findings are clinically relevant as immune checkpoint inhibitor therapy is approved for MMR-mutated and/or MSI-H solid tumors (Lemery et al. 2017).

We recently reported a positive response to immunotherapy in a patient with MMR pathway mutation and matched PDX mouse model of ACC, and we reported additional positive responses in a cohort of six patients with advanced ACC when immune checkpoint inhibitor was given in combination with mitotane (Head, et al. 2019; Lang, et al. 2020). Other data in the literature about the role of immunotherapy in ACC has been mixed (Carneiro, et al. 2019; Habra, et al. 2019; Le Tourneau, et al. 2018; Raj, et al. 2020). It is not yet clear if ACC tumors with MMR mutational signatures would have similar results to MMR–mutated solid tumors, but the correlation with tumor mutational burden implies that they might. Therefore, genomic profiling and selecting ACC tumors with high tumor mutation burden and MMR gene alterations might improve response to immunotherapy, offering a more personalized medicine approach.

Similar to prior studies (Assie et al. 2014; Juhlin, et al. 2015; Lippert et al. 2018; Zheng et al. 2016), this study confirmed that the Wnt/B-Catenin and p53 are the most commonly dysregulated pathways in ACC. Eight of the 138 TP53 gene alterations, detected in the cohort, were found within the subset of 12 pediatric cases. It is known that 50–80% of pediatric ACC are associated with Li Fraumeni syndrome caused by germline TP53 alterations (Rodriguez-Galindo, et al. 2005; Wagner, et al. 1994). The pediatric cases in this cohort represent a small subset of tumors, and do not significantly impact overall conclusions and alteration frequencies in the study cohort. We found that 10% (39/364) of ACC tumors carried an alteration in both CTNNB1 and TP53, and up to 30% (109/364) had alterations in both the p53 and Wnt signaling pathways, which is at higher frequencies than in prior studies (Lippert et al. 2018; Zheng et al. 2016). Our data is similar to previous work by Zheng et al (Zheng et al. 2016), showing alterations in ZNRF3 and CTNNB1 are almost always mutually exclusive, with only <1% (2/364) tumors containing alterations in both genes.

Recent studies also identified recurrent TERT promoter alterations in ACC tumors (Assie et al. 2014; Juhlin et al. 2015; Lippert et al. 2018; Zheng et al. 2016), and TCGA analysis found that TERT expression was significantly higher in the whole genome doubling tumor group (Zheng et al. 2016). We identified TERT alterations in 10% of ACC tumors. Collectively, alterations in telomere maintenance genes, TERT, ATRX or DAXX, were altered in 78 (21%) ACCs and all were mutually exclusive except in one tumor, suggesting that alterations in this pathway are oncogenic events.

Over half of the ACC tumors had potentially actionable alterations. Similar to published work, several potentially druggable alterations were identified in cell cycle and tumors suppressor genes, including alterations in CDK4, CDKN2A, NF1 and MDM2 gene. While limited therapeutic options are currently available for these dysregulated genes, targeting CDK4 using CDK4/6 inhibitors might be a relevant clinical option. Three CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib have recently been approved for hormone receptor positive and human epidermal growth factor receptor 2 (HER2) – negative metastatic breast cancer and are being investigated, alone or in combinations, in clinical trials in other solid tumors (Shah, et al. 2018). Several small clinical trials have also examined CDK4/6 inhibitors targeting solid tumors with CDKN2A loss, although responses have been modest (Ahn, et al. 2020; Al Baghdadi, et al. 2019). Furthermore, recent preclinical studies showed that ACC cell lines are sensitive to CDK4/6 inhibition (Fiorentini, et al. 2018; Hadjadj, et al. 2017; Liang, et al. 2020). CDK4 upregulation has been reported in 62% of ACC tumors (Liang et al. 2020), and in this study, CDK4 amplification occurred in in 6% of tumors and CDKN2A alterations occurred in 14%. Taken together, these data suggest that CDK4/6 inhibitors may have a place for novel treatment in ACC tumors.

A large subgroup of ACC had alterations in genes involved in epigenetic regulation, providing additional evidence of its importance in ACC tumorigenesis as previously reported (Zheng et al. 2016). Histone modification, telomere lengthening and SWI/SNF pathway genes were commonly altered (21–38%), while DNA methylation pathway gene alterations were observed in 8% of samples. Genetic alterations in ARID1A was another novel finding in our study for ACC, and has been shown in other endocrine tumors such as pituitary tumors (Bi, et al. 2017), thyroid cancers (Pozdeyev et al. 2018) and pheochromocytomas/paragangliomas (Toledo, et al. 2016). ARID1A acts as a tumor suppressor, where its loss disrupts SWI/SNF complex targeting of gene enhancers to alter gene expression and drive tumorigenesis (Mathur, et al. 2017). Although targeting epigenetic regulators for therapeutic intervention has shown only limited success so far (Shah, et al. 2006), alterations in this pathway may have prognostic implications (Davidson, et al. 2018; Seligson, et al. 2005; Weischer, et al. 2013; Zhou, et al. 2021). Furthermore, future studies on the impact of epigenome disruption might contribute to better understanding of environmental and genetic influences on ACC tumorigenesis.

Several other novel genetic alterations occurred in small subsets of ACC tumors. IL7R was mutated in 6% of samples and is normally expressed in immune cells and plays a role in the development and survival of immune cells (DeKoter, et al. 2007; Gregory, et al. 2007). Its absence results in combined immunodeficiency and overexpression results in T cell acute lymphoblastic leukemia (Oliveira, et al. 2019). IL7R is also amplified in squamous cell cancer of the esophagus and downregulation of IL7R decreased tumorigenicity in esophageal cell lines (Kim, et al. 2018). Taken together, mutations in IL7R might represent a novel potential therapeutic target in ACC. LRP1B a member of the low density lipoprotein (LDL) receptor family and interacts with multiple ligands including fibrinogen and apoE carrying lipoproteins (Liu, et al. 2000). Its promoter is hypermethylated in gastric cancer, oral squamous cell cancer, lung and ovarian cancer suggesting a role as a tumor suppressor gene (Beer, et al. 2016). LRP1B deletion is associated with poor prognosis in patients with glioblastomas (Tabouret, et al. 2015) and the gene is also downregulated in colon cancer where its loss increases cell growth and migration (Wang, et al. 2017). Perhaps novel therapeutics of this pathway may be future options for treatment of ACC. FRS2 in an adaptor protein that mediates FGFR signaling. FRS2 is ubiquitously expressed, and suppression of FRS2 expression decreases mitotgenic signaling in prostate cancer cells (Valencia, et al. 2011). FRS2 is amplified in various types of human cancer including liposarcomas, prostate and ovarian cancer (Jing, et al. 2018; Luo, et al. 2015; Valencia et al. 2011). Previous studies in ACC have identified FGFR signaling dysregulation and 57% of ACC with FGFR4 overexpression correlated with worse outcomes (Brito, et al. 2012). This study found four tumors with FGR4 amplification and one with FGFR2-CIT fusion predicted to be oncogenic. This suggests that FGFR pathway targeting might be relevant in a subset of ACC tumors.

Our study has several limitations. Targeted sequencing approaches may miss relevant genomic alterations. In addition, clinical data are not available and correlation with prior therapy and clinical outcomes could not be performed. Selection bias of the cohort may be present based on provider referral to the platform. However, FoundationOne is one of the most utilized platforms for clinical tumor genomic analysis adding to the relevance.

In summary, in the largest ACC cohort to date, analysis identified that 58.5% of ACC have at least one potentially actionable alteration, and importantly, a significant percentage of tumors (13.7%) have alterations in the MMR pathway. These data suggest that over half of ACC may have clinically relevant therapeutic options and a subset may respond to immunotherapy.

Supplementary Material

01

Supplementary Figure 1. Frequently altered genes and pathways in ACC.

02

Supplementary Figure 2. A heatmap of mutation signatures in ACCs with at least 10 SNPs and indels. The fractions of mutations belonging to a specific signature are shown on a heatmap.

03

Supplementary Table 1. Demographic and genotyping summary for patients in the ACC cohort. FoundationOne bait set, MSI status as well as number of genomic alterations of various types are listed.

04

Supplementary Table 2. Genomic alterations in ACC.

05

Supplementary Table 3. Genes included in FoundationOne panel bait sets and annotation group assignments.

06

Supplementary Table 4. Genomic alterations in pediatric ACC cohort.

07

Supplementary Table 5. All potentially actionable genomic alterations in ACC.

Table 1.

Potentially actionable genomic alterations in ACC found in more than 2% of ACC tumors

Gene Symbol Description Samples (%) Potential Targeted Therapy Level of Evidence
ALK Receptor tyrosine kinase 2.2 Crizotinib - F, M 1, R2
Alectinib - F, M 1, R2
Certinib - F 2
Lorlatinib - O 1
Brigatinib - O 1
ATM DNA damage repair related kinase 8 Olaparib - O 4
BRCA2 DNA damage involved TS 3.8 Rucaparib - O 1
Niraparib - O 1
Olaparib - O 2
Talazoparib - O 2
CDK4 Intracellular kinase 7.7 Abemaciclib - A 2
Palbociclib - A 2
CDKN2A Protein for cell growth and survival 13.5 Abemaciclib - O 4
Palbociclib - O 4
Ribociclib - O 4
EGFR Receptor tyrosine kinase 2.7 Afatinib - M, De, Du, I 1, R1
Erlotinib - De, M, I, Du 1, R1
Osimertinib - De, M 1, R2
Dacomitinib - De, M 1
Gefitinib - De, M,I , Du 1, R2
Poziotinib - I 3A
Lapatinib - A, M 4
KRAS GTPase regulator of MAPK and PI3K 2.7 Regorafenib - W 1
Cobimetinib - O 4, 3A
AMG-510 - M 3A
Cetuximab - W, O 1, R1
Panitumumab - W, O 1, R1
Binimetinib - O 4
Trametinib - O 4
MDM2 Ubiquitin ligase and p53 inhibitor 5.8 Milademetan Tosylate - A 3A
RO5045337 - A 3A
NF1 Negative regulator of RAS 10.2 Selumetinib - O 1
Cobimetinib - O 4
Trametinib - O 4
NTRK2 Receptor tyrosine kinase 2.5 Larotrectinib - F 1
Entrectinib - F 1
PDGFRA Receptor tyrosine kinase 4.7 Imatinib - F, O,M 1, R1
Avapritinib - M, De, I 1
Dasatinib - M 2
PTCH1 Inhibitor of the hedgehog pathway 4.1 Sonidegib - T 3A
Vismodegib - T 3A
TSC1 TS in the mTOR pathway 2.7 Everolimus - O 1
TSC2 TS in the mTOR pathway 2.7 Everolimus - O 1
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Abbreviations: Tumor suppressor (TS), Fusion (F), Missense mutation (M), Oncogenic mutation (O), Amplification (A), Deletion (De), Duplication (Du), Insertion (I), Wildtype (W).

Levels of significance are from OnkoKB website and denote the following: 1 - FDA recognized biomarker predictive of response to an FDA approved drug in this indication. 2 - Standard care biomarker recommended by the NCCN or other expert panels predictive of response to an FDA approved drug in this indication. 3A - Compelling clinical evidence supports the biomarker as being predictive of response to a drug in this indication. 3B - Standard care or investigational biomarker predictive of response to an FDA approved or investigational drug in another indication. 4 - Compelling biological evidence supports the biomarker as being predictive response to a drug. R1 - Standard care biomarker predictive of resistance to an FDA approved drug in this indication. R2 - Compelling clinical evidence supports the biomarker as being predictive of resistance to a drug.

Funding sources:

This work was supported by NIH K08CA222620 (to K.K.V.), Cancer League of Colorado Award (to K.K.V. and S.L.), Golfers Against Cancer (to K.K.V.), Veterans Affairs Merit Review Award 001 (to M.E.W.), American Cancer Society MRSG-15-063-01-TBG (to L.F.), NIH R01CA246586 (to L.F.), University of Colorado Cancer Center Support Grant P30-CA046934. The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data or in writing the manuscript.

Footnotes

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

REFERENCES

  1. Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME & McVean GA 2010. A map of human genome variation from population-scale sequencing. Nature 467 1061–1073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adam P, Hahner S, Hartmann M, Heinrich B, Quinkler M, Willenberg HS, Saeger W, Sbiera S, Schmull S, Voelker HU, et al. 2010Epidermal growth factor receptor in adrenocortical tumors: analysis of gene sequence, protein expression and correlation with clinical outcome. Mod Pathol 231596–1604. [DOI] [PubMed] [Google Scholar]
  3. Ahn ER, Mangat PK, Garrett-Mayer E, Halabi S, Dib EG, Haggstrom DE, Alguire KB, Calfa CJ, Cannon TL, Crilley PA, et al. 2020Palbociclib in Patients With Non–Small-Cell Lung Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study. JCO Precision Oncology 757–766. [DOI] [PubMed] [Google Scholar]
  4. Al Baghdadi T, Halabi S, Garrett-Mayer E, Mangat PK, Ahn ER, Sahai V, Alvarez RH, Kim ES, Yost KJ, Rygiel AL, et al. 2019Palbociclib in Patients With Pancreatic and Biliary Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study. JCO Precision Oncology 1–8. [DOI] [PubMed] [Google Scholar]
  5. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, et al. 2013Signatures of mutational processes in human cancer. Nature 500415–421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Assie G, Letouze E, Fassnacht M, Jouinot A, Luscap W, Barreau O, Omeiri H, Rodriguez S, Perlemoine K, Rene-Corail F, et al. 2014Integrated genomic characterization of adrenocortical carcinoma. Nat Genet 46607–612. [DOI] [PubMed] [Google Scholar]
  7. Beer AG, Zenzmaier C, Schreinlechner M, Haas J, Dietrich MF, Herz J & Marschang P 2016. Expression of a recombinant full-length LRP1B receptor in human non-small cell lung cancer cells confirms the postulated growth-suppressing function of this large LDL receptor family member. Oncotarget 7 68721–68733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Berruti A, Sperone P, Ferrero A, Germano A, Ardito A, Priola AM, De Francia S, Volante M, Daffara F, Generali D, et al. 2012Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma. European journal of endocrinology / European Federation of Endocrine Societies 166451–458. [DOI] [PubMed] [Google Scholar]
  9. Bi WL, Horowitz P, Greenwald NF, Abedalthagafi M, Agarwalla PK, Gibson WJ, Mei Y, Schumacher SE, Ben-David U, Chevalier A, et al. 2017 Landscape of Genomic Alterations in Pituitary Adenomas. Clin Cancer Res 231841–1851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Brito LP, Ribeiro TC, Almeida MQ, Jorge AA, Soares IC, Latronico AC, Mendonca BB, Fragoso MC & Lerario AM 2012. The role of fibroblast growth factor receptor 4 overexpression and gene amplification as prognostic markers in pediatric and adult adrenocortical tumors. Endocr Relat Cancer 19 L11–13. [DOI] [PubMed] [Google Scholar]
  11. Cancer Genome Atlas Research N 2014Integrated genomic characterization of papillary thyroid carcinoma. Cell 159676–690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Carneiro BA, Konda B, Costa RB, Costa RLB, Sagar V, Gursel DB, Kirschner LS, Chae YK, Abdulkadir SA, Rademaker A, et al. 2019Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2 Trial. J Clin Endocrinol Metab 1046193–6200. [DOI] [PubMed] [Google Scholar]
  13. Consortium APG 2017AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov 7818–831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Darabi S, Braxton DR, Eisenberg BL & Demeure MJ 2020. Molecular genomic profiling of adrenocortical cancers in clinical practice. Surgery. [DOI] [PubMed] [Google Scholar]
  15. Davidson J, Shen Z, Gong X & Pollack JR 2018. SWI/SNF aberrations sensitize pancreatic cancer cells to DNA crosslinking agents. Oncotarget 9 9608–9617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. DeKoter RP, Schweitzer BL, Kamath MB, Jones D, Tagoh H, Bonifer C, Hildeman DA & Huang KJ 2007. Regulation of the interleukin-7 receptor alpha promoter by the Ets transcription factors PU.1 and GA-binding protein in developing B cells. J Biol Chem 282 14194–14204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Else T, Giordano TJ & Hammer GD 2008. Evaluation of telomere length maintenance mechanisms in adrenocortical carcinoma. J Clin Endocrinol Metab 93 1442–1449. [DOI] [PubMed] [Google Scholar]
  18. Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, Jolly S, Miller BS, Giordano TJ & Hammer GD 2014. Adrenocortical carcinoma. Endocr Rev 35 282–326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Fassnacht M, Berruti A, Baudin E, Demeure MJ, Gilbert J, Haak H, Kroiss M, Quinn DI, Hesseltine E, Ronchi CL, et al. 2015Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol 16426–435. [DOI] [PubMed] [Google Scholar]
  20. Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, et al. 2012Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 3662189–2197. [DOI] [PubMed] [Google Scholar]
  21. Fiorentini C, Fragni M, Tiberio GAM, Galli D, Roca E, Salvi V, Bosisio D, Missale C, Terzolo M, Memo M, et al. 2018Palbociclib inhibits proliferation of human adrenocortical tumor cells. Endocrine 59213–217. [DOI] [PubMed] [Google Scholar]
  22. Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, Schnall-Levin M, White J, Sanford EM, An P, et al. 2013Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nature Biotechnology 311023–1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Giordano TJ, Thomas DG, Kuick R, Lizyness M, Misek DE, Smith AL, Sanders D, Aljundi RT, Gauger PG, Thompson NW, et al. 2003Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol 162521–531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, Caillier SJ, Ban M, Goris A, Barcellos LF, et al. 2007Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 391083–1091. [DOI] [PubMed] [Google Scholar]
  25. Gross DJ, Munter G, Bitan M, Siegal T, Gabizon A, Weitzen R, Merimsky O, Ackerstein A, Salmon A, Sella A, et al. 2006The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. Endocr Relat Cancer 13535–540. [DOI] [PubMed] [Google Scholar]
  26. Grubbs EG, Callender GG, Xing Y, Perrier ND, Evans DB, Phan AT & Lee JE 2010. Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane. Annals of surgical oncology 17 263–270. [DOI] [PubMed] [Google Scholar]
  27. Habra MA, Stephen B, Campbell M, Hess K, Tapia C, Xu M, Rodon Ahnert J, Jimenez C, Lee JE, Perrier ND, et al. 2019Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma. J Immunother Cancer 7253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Hadjadj D, Kim SJ, Denecker T, Ben Driss L, Cadoret JC, Maric C, Baldacci G & Fauchereau F 2017. A hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas. Aging (Albany NY) 9 2695–2716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Head L, Kiseljak-Vassiliades K, Clark TJ, Somerset H, King J, Raeburn C, Albuja-Cruz M, Weyant M, Cleveland J, Wierman ME, et al. 2019Response to Immunotherapy in Combination With Mitotane in Patients With Metastatic Adrenocortical Cancer. J Endocr Soc 32295–2304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Icard P, Goudet P, Charpenay C, Andreassian B, Carnaille B, Chapuis Y, Cougard P, Henry JF & Proye C 2001. Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 25 891–897. [DOI] [PubMed] [Google Scholar]
  31. Jing W, Lan T, Chen H, Zhang Z, Chen M, Peng R, He X & Zhang H 2018. Amplification of FRS2 in atypical lipomatous tumour/well-differentiated liposarcoma and de-differentiated liposarcoma: a clinicopathological and genetic study of 146 cases. Histopathology 72 1145–1155. [DOI] [PubMed] [Google Scholar]
  32. Juhlin CC, Goh G, Healy JM, Fonseca AL, Scholl UI, Stenman A, Kunstman JW, Brown TC, Overton JD, Mane SM, et al. 2015Whole-exome sequencing characterizes the landscape of somatic mutations and copy number alterations in adrenocortical carcinoma. J Clin Endocrinol Metab 100E493–502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kim MJ, Choi SK, Hong SH, Eun JW, Nam SW, Han JW & You JS 2018. Oncogenic IL7R is downregulated by histone deacetylase inhibitor in esophageal squamous cell carcinoma via modulation of acetylated FOXO1. Int J Oncol 53 395–403. [DOI] [PubMed] [Google Scholar]
  34. Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, Dogan S, Ricarte-Filho JC, Krishnamoorthy GP, Xu B, et al. 2016Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest 1261052–1066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Hoover J, et al. 2016ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Research 44D862–D868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Lang J, Capasso A, Jordan KR, French JD, Kar A, Bagby SM, Barbee J, Yacob BW, Head LS, Tompkins KD, et al. 2020Development of an Adrenocortical Cancer Humanized Mouse Model to Characterize Anti-PD1 Effects on Tumor Microenvironment. J Clin Endocrinol Metab 105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Le Tourneau C, Hoimes C, Zarwan C, Wong DJ, Bauer S, Claus R, Wermke M, Hariharan S, von Heydebreck A, Kasturi V, et al. 2018Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial. J Immunother Cancer 6111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, et al. 2016Analysis of protein-coding genetic variation in 60,706 humans. Nature 536285–291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Lemery S, Keegan P & Pazdur R 2017. First FDA Approval Agnostic of Cancer Site - When a Biomarker Defines the Indication. N Engl J Med 377 1409–1412. [DOI] [PubMed] [Google Scholar]
  40. Liang R, Weigand I, Lippert J, Kircher S, Altieri B, Steinhauer S, Hantel C, Rost S, Rosenwald A, Kroiss M, et al. 2020Targeted Gene Expression Profile Reveals CDK4 as Therapeutic Target for Selected Patients With Adrenocortical Carcinoma. Front Endocrinol (Lausanne) 11219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Lippert J, Appenzeller S, Liang R, Sbiera S, Kircher S, Altieri B, Nanda I, Weigand I, Gehrig A, Steinhauer S, et al. 2018Targeted Molecular Analysis in Adrenocortical Carcinomas: A Strategy Toward Improved Personalized Prognostication. J Clin Endocrinol Metab 1034511–4523. [DOI] [PubMed] [Google Scholar]
  42. Liu CX, Musco S, Lisitsina NM, Yaklichkin SY & Lisitsyn NA 2000. Genomic organization of a new candidate tumor suppressor gene, LRP1B. Genomics 69 271–274. [DOI] [PubMed] [Google Scholar]
  43. Luo LY, Kim E, Cheung HW, Weir BA, Dunn GP, Shen RR & Hahn WC 2015. The Tyrosine Kinase Adaptor Protein FRS2 Is Oncogenic and Amplified in High-Grade Serous Ovarian Cancer. Mol Cancer Res 13 502–509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, Laudat MH, Louvel A, Chapuis Y, Blondeau P, et al. 1990Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 3221195–1201. [DOI] [PubMed] [Google Scholar]
  45. Mathur R, Alver BH, San Roman AK, Wilson BG, Wang X, Agoston AT, Park PJ, Shivdasani RA & Roberts CW 2017. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet 49 296–302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Megerle F, Herrmann W, Schloetelburg W, Ronchi CL, Pulzer A, Quinkler M, Beuschlein F, Hahner S, Kroiss M, Fassnacht M, et al. 2018Mitotane Monotherapy in Patients With Advanced Adrenocortical Carcinoma. J Clin Endocrinol Metab 1031686–1695. [DOI] [PubMed] [Google Scholar]
  47. Oliveira ML, Akkapeddi P, Ribeiro D, Melao A & Barata JT 2019. IL-7R-mediated signaling in T-cell acute lymphoblastic leukemia: An update. Adv Biol Regul 71 88–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Pozdeyev N, Gay L, Sokol ES, Hartmaier RJ, Deaver KE, Davis SN, French JD, Vanden Borre P, LaBarbera DV, Tan AC, et al. 2018Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers. Clin Cancer Res. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Quinkler M, Hahner S, Wortmann S, Johanssen S, Adam P, Ritter C, Strasburger C, Allolio B & Fassnacht M 2008. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. The Journal of clinical endocrinology and metabolism 93 2057–2062. [DOI] [PubMed] [Google Scholar]
  50. Raj N, Zheng Y, Kelly V, Katz SS, Chou J, Do RKG, Capanu M, Zamarin D, Saltz LB, Ariyan CE, et al. 2020PD-1 Blockade in Advanced Adrenocortical Carcinoma. J Clin Oncol 3871–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Raymond VM, Everett JN, Furtado LV, Gustafson SL, Jungbluth CR, Gruber SB, Hammer GD, Stoffel EM, Greenson JK, Giordano TJ, et al. 2013Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol 313012–3018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Rodriguez-Galindo C, Figueiredo BC, Zambetti GP & Ribeiro RC 2005. Biology, clinical characteristics, and management of adrenocortical tumors in children. Pediatr Blood Cancer 45 265–273. [DOI] [PubMed] [Google Scholar]
  53. Rosenthal R, McGranahan N, Herrero J, Taylor BS & Swanton C 2016. deconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution. Genome Biology 17 31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Ross JS, Wang K, Rand JV, Gay L, Presta MJ, Sheehan CE, Ali SM, Elvin JA, Labrecque E, Hiemstra C, et al. 2014Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies. J Clin Pathol 67968–973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M & Kurdistani SK 2005. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435 1262–1266. [DOI] [PubMed] [Google Scholar]
  56. Shah M, Nunes MR & Stearns V 2018. CDK4/6 Inhibitors: Game Changers in the Management of Hormone Receptor-Positive Advanced Breast Cancer? Oncology (Williston Park) 32 216–222. [PMC free article] [PubMed] [Google Scholar]
  57. Shah MH, Binkley P, Chan K, Xiao J, Arbogast D, Collamore M, Farra Y, Young D & Grever M 2006. Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res 12 3997–4003. [DOI] [PubMed] [Google Scholar]
  58. Tabouret E, Labussiere M, Alentorn A, Schmitt Y, Marie Y & Sanson M 2015. LRP1B deletion is associated with poor outcome for glioblastoma patients. J Neurol Sci 358 440–443. [DOI] [PubMed] [Google Scholar]
  59. Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, et al. 2007Adjuvant mitotane treatment for adrenocortical carcinoma. The New England journal of medicine 3562372–2380. [DOI] [PubMed] [Google Scholar]
  60. Tissier F, Cavard C, Groussin L, Perlemoine K, Fumey G, Hagnere AM, Rene-Corail F, Jullian E, Gicquel C, Bertagna X, et al. 2005Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res 657622–7627. [DOI] [PubMed] [Google Scholar]
  61. Toledo RA, Qin Y, Cheng ZM, Gao Q, Iwata S, Silva GM, Prasad ML, Ocal IT, Rao S, Aronin N, et al. 2016Recurrent Mutations of Chromatin-Remodeling Genes and Kinase Receptors in Pheochromocytomas and Paragangliomas. Clin Cancer Res 222301–2310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Valencia T, Joseph A, Kachroo N, Darby S, Meakin S & Gnanapragasam VJ 2011. Role and expression of FRS2 and FRS3 in prostate cancer. BMC Cancer 11 484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Wagner J, Portwine C, Rabin K, Leclerc JM, Narod SA & Malkin D 1994. High frequency of germline p53 mutations in childhood adrenocortical cancer. J Natl Cancer Inst 86 1707–1710. [DOI] [PubMed] [Google Scholar]
  64. Wang K, Li M & Hakonarson H 2010. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38 e164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Wang Z, Sun P, Gao C, Chen J, Li J, Chen Z, Xu M, Shao J, Zhang Y & Xie J 2017. Down-regulation of LRP1B in colon cancer promoted the growth and migration of cancer cells. Exp Cell Res 357 1–8. [DOI] [PubMed] [Google Scholar]
  66. Weigel B, Malempati S, Reid JM, Voss SD, Cho SY, Chen HX, Krailo M, Villaluna D, Adamson PC & Blaney SM 2014. Phase 2 trial of cixutumumab in children, adolescents, and young adults with refractory solid tumors: a report from the Children’s Oncology Group. Pediatr Blood Cancer 61 452–456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Weischer M, Nordestgaard BG, Cawthon RM, Freiberg JJ, Tybjaerg-Hansen A & Bojesen SE 2013. Short telomere length, cancer survival, and cancer risk in 47102 individuals. J Natl Cancer Inst 105 459–468. [DOI] [PubMed] [Google Scholar]
  68. Wortmann S, Quinkler M, Ritter C, Kroiss M, Johanssen S, Hahner S, Allolio B & Fassnacht M 2010. Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma. European journal of endocrinology / European Federation of Endocrine Societies 162 349–356. [DOI] [PubMed] [Google Scholar]
  69. Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA, Lerario AM, Else T, Knijnenburg TA, Ciriello G, et al. 2016Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma. Cancer Cell 29723–736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Zhou M, Yuan J, Deng Y, Fan X & Shen J 2021. Emerging role of SWI/SNF complex deficiency as a target of immune checkpoint blockade in human cancers. Oncogenesis 10 3. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

01

Supplementary Figure 1. Frequently altered genes and pathways in ACC.

NIHMS1730287-supplement-01.pdf (322.9KB, pdf)
02

Supplementary Figure 2. A heatmap of mutation signatures in ACCs with at least 10 SNPs and indels. The fractions of mutations belonging to a specific signature are shown on a heatmap.

NIHMS1730287-supplement-02.pdf (28KB, pdf)
03

Supplementary Table 1. Demographic and genotyping summary for patients in the ACC cohort. FoundationOne bait set, MSI status as well as number of genomic alterations of various types are listed.

NIHMS1730287-supplement-03.csv (31.5KB, csv)
04

Supplementary Table 2. Genomic alterations in ACC.

NIHMS1730287-supplement-04.csv (2.2MB, csv)
05

Supplementary Table 3. Genes included in FoundationOne panel bait sets and annotation group assignments.

NIHMS1730287-supplement-05.csv (13.7KB, csv)
06

Supplementary Table 4. Genomic alterations in pediatric ACC cohort.

NIHMS1730287-supplement-06.xlsx (75.7KB, xlsx)
07

Supplementary Table 5. All potentially actionable genomic alterations in ACC.

NIHMS1730287-supplement-07.docx (26.7KB, docx)

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