Adrenocortical Carcinoma - Molecular Biology


Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (48)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

-RET and Adrenocortical Cancer
SDHB 1p36.13 IP, SDH, CWS2, PGL4, SDH1, SDH2, SDHIP -SDHB and Adrenocortical Cancer
SDHD 11q23.1 PGL, CBT1, CWS3, PGL1, QPs3, SDH4, cybS, CII-4 -SDHD and Adrenocortical Cancer
SDHC 1q23.3 CYBL, PGL3, QPS1, SDH3, CYB560 -SDHC and Adrenocortical Cancer
VHL 3p25.3 RCA1, VHL1, pVHL, HRCA1 -VHL and Adrenocortical Cancer
NF1 17q11.2 WSS, NFNS, VRNF -NF1 and Adrenocortical Cancer
MEN1 11q13.1 MEAI, SCG2 GWS
-MEN1 and Adrenocortical Cancer
TP53 17p13.1 P53, BCC7, LFS1, TRP53 GWS
-TP53 and Adrenocortical Carcinoma
PGLS 19p13.11 6PGL, HEL-S-304 -PGLS and Adrenocortical Cancer
ACCS 11p11.2 ACS, PHACS -ACCS and Adrenocortical Cancer
CAMP 3p21.31 LL37, CAP18, CRAMP, HSD26, CAP-18, FALL39, FALL-39 -CAMP and Adrenocortical Cancer
KCNJ5 11q24.3 CIR, GIRK4, KATP1, LQT13, KIR3.4 -KCNJ5 and Adrenocortical Cancer
CYP11B2 8q24.3 CPN2, ALDOS, CYP11B, CYP11BL, CYPXIB2, P450C18, P-450C18, P450aldo -CYP11B2 and Adrenocortical Cancer
SDHA 5p15.33 FP, PGL5, SDH1, SDH2, SDHF, CMD1GG -SDHA and Adrenocortical Cancer
TMEM127 2q11.2 -TMEM127 and Adrenocortical Cancer
SDHAF2 11q12.2 PGL2, SDH5, C11orf79 -SDHAF2 and Adrenocortical Cancer
CTNNB1 3p22.1 CTNNB, MRD19, armadillo GWS
-CTNNB1 and Adrenocortical Carcinoma
CYP11B1 8q24.3 FHI, CPN1, CYP11B, P450C11 -CYP11B1 and Adrenocortical Cancer
IGF2 11p15.5 GRDF, IGF-II, PP9974, C11orf43 -IGF2 Expression in Adrenocortical Carcinoma
NR5A1 9q33.3 ELP, SF1, FTZ1, POF7, SF-1, AD4BP, FTZF1, SPGF8, SRXY3, hSF-1 -NR5A1 and Adrenocortical Cancer
PDE11A 2q31.2 PPNAD2 -PDE11A and Adrenocortical Cancer
MAX 14q23.3 bHLHd4 -MAX and Adrenocortical Cancer
EGLN1 1q42.2 HPH2, PHD2, SM20, ECYT3, HALAH, HPH-2, HIFPH2, ZMYND6, C1orf12, HIF-PH2 -EGLN1 and Adrenocortical Cancer
EPAS1 2p21-p16 HLF, MOP2, ECYT4, HIF2A, PASD2, bHLHe73 -EPAS1 and Adrenocortical Cancer
CYP11A1 15q24.1 CYP11A, CYPXIA1, P450SCC -CYP11A1 and Adrenocortical Cancer
GDNF 5p13.2 ATF, ATF1, ATF2, HSCR3, HFB1-GDNF -GDNF and Adrenocortical Cancer
HSD3B2 1p12 HSDB, HSD3B, SDR11E2 -HSD3B2 and Adrenocortical Cancer
EGLN3 14q13.1 PHD3, HIFPH3, HIFP4H3 -EGLN3 and Adrenocortical Cancer
ZNRF3 22q12.1 RNF203, BK747E2.3 GWS
-ZNRF3 and Adrenocortical Cancer
RB1 13q14.2 RB, pRb, OSRC, pp110, p105-Rb, PPP1R130 GWS
-RB1 and Adrenocortical Carcinoma
NR0B1 Xp21.2 AHC, AHX, DSS, GTD, HHG, AHCH, DAX1, DAX-1, NROB1, SRXY2 -NR0B1 and Adrenocortical Cancer
-TERT and Adrenocortical Carcinoma
GATA6 18q11.2 -GATA6 and Adrenocortical Cancer
RBP3 10q11.22 IRBP, RBPI, RP66, D10S64, D10S65, D10S66 -RBP3 and Adrenocortical Cancer
KIF1B 1p36.22 KLP, CMT2, CMT2A, CMT2A1, HMSNII, NBLST1 -KIF1B and Adrenocortical Cancer
GNRHR 4q13.2 HH7, GRHR, LRHR, LHRHR, GNRHR1 -GNRHR and Adrenocortical Cancer
CDKN2A 9p21.3 ARF, MLM, P14, P16, P19, CMM2, INK4, MTS1, TP16, CDK4I, CDKN2, INK4A, MTS-1, P14ARF, P19ARF, P16INK4, P16INK4A, P16-INK4A GWS
-CDKN2A and Adrenocortical Carcinoma
AVPR1A 12q14.2 V1aR, AVPR1, AVPR V1a -AVPR1A and Adrenocortical Cancer
NR4A2 2q22-q23 NOT, RNR1, HZF-3, NURR1, TINUR -NR4A2 and Adrenocortical Cancer
MC2R 18p11.21 ACTHR -MC2R and Adrenocortical Cancer
AGTR2 Xq23 AT2, ATGR2, MRX88 -AGTR2 and Adrenocortical Cancer
CCN5 20q13.12 CT58, WISP2, CTGF-L -WISP2 and Adrenocortical Cancer
LHCGR 2p21 HHG, LHR, LCGR, LGR2, ULG5, LHRHR, LSH-R, LH/CGR, LH/CG-R -LHCGR and Adrenocortical Cancer
DAXX 6p21.32 DAP6, EAP1, BING2 GWS
-DAXX and Adrenorortical Carcinoma
KCNQ1OT1 11p15.5 LIT1, Kncq1, KvDMR1, KCNQ10T1, KCNQ1-AS2, KvLQT1-AS, NCRNA00012 -KCNQ1OT1 and Adrenocortical Cancer
-MED12 and Adrenocortical Carcinoma
AVPR1B 1q32.1 V1bR, AVPR3 -AVPR1B and Adrenocortical Cancer
NR3C2 4q31.23 MR, MCR, MLR, NR3C2VIT -NR3C2 and Adrenocortical Cancer

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

GWS - Genome/Exome Wide Study, large-scale/significant (selected):
Assié G et al. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet. 2014; 46(6):607-12

Latest Publications

Longui CA
Rev Paul Pediatr. 2019 Jan-Mar; 37(1):2-3 [PubMed] Free Access to Full Article Related Publications

Mota JM, Sousa LG, Braghiroli MI, et al.
Pembrolizumab for metastatic adrenocortical carcinoma with high mutational burden: Two case reports.
Medicine (Baltimore). 2018; 97(52):e13517 [PubMed] Free Access to Full Article Related Publications
RATIONALE: In the setting of metastatic or locally advanced adrenocortical carcinoma, a limited number of therapies are available and their efficacy is generally below modest. The backbone of treatment remains surgery, even for metastatic disease, whenever it is possible, and mitotane. Chemotherapy can be used with limited results. A small subset of patients with adrenocortical carcinoma may have high mutational burden and harbor mutations in mismatch-repair genes.
PATIENT CONCERNS: We report a 40-year old and a 28-year-old female patients with metastatic adrenocortical carcinoma refractory to multiple treatments.
DIAGNOSIS: Next-generation sequencing detected high mutational burden (>10 mutations/megabase) in both patients, one of them with MSH2 mutation.
INTERVENTIONS: They were treated with pembrolizumab (100 to 200 mg every 3 weeks).
OUTCOMES: The patient harboring a MSH2 mutation experienced a long-term complete response after pembrolizumab, while the patient with high mutational burden and absence of mismatch repair deficiency did not have any response.
LESSONS: To the best of our knowledge, this is the first report in the literature of a durable complete response after pembrolizumab in a patient with metastatic adrenocortical carcinoma. Differences in therapy sequencing, possibly abscopal effect related to multiple previous radiotherapy exposition, predictive values of high mutational burden and mutations in mismatch-repair genes are discussed.

Rahane CS, Kutzner A, Heese K
Establishing a human adrenocortical carcinoma (ACC)-specific gene mutation signature.
Cancer Genet. 2019; 230:1-12 [PubMed] Related Publications
Adrenocortical carcinoma (ACC) is a rare and aggressive tumor whose molecular signaling pathways are not fully understood. Using an in-silico clinical data analysis approach we retrieved human gene mutation data from the highly reputed Cancer Genome Atlas (TCGA). ACC-specific gene mutations were correlated with proliferation marker FAM72 expression and Mutsig along with the algorithmic implementation of the 20/20 rule were used to validate their oncogenic potential. The newly identified oncogenic driver gene set (ZFPM1, LRIG1, CRIPAK, ZNF517, GARS and DGKZ), specifically and most repeatedly mutated in ACC, is involved in tumor suppression and cellular proliferation and thus could be useful for the prognosis and development of therapeutic approaches for the treatment of ACC.

Gara SK, Lack J, Zhang L, et al.
Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors.
Nat Commun. 2018; 9(1):4172 [PubMed] Free Access to Full Article Related Publications
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.

Doyle MR, Johnston JM
A novel p.Gly187Arg TP53 variant appears to result in Li-Fraumeni syndrome.
Pediatr Hematol Oncol. 2018; 35(3):203-207 [PubMed] Related Publications
Li-Fraumeni syndrome is an autosomal dominant cancer syndrome characterized by pathogenic variants in the TP53 gene on chromosome 17. The most common cancers in Li-Fraumeni kindreds include sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma. We report a 9-month-old male who was diagnosed with an adrenocortical tumor and later found to harbor a novel TP53 c.559 G > C germline variant, resulting in p.Gly187Arg. Family history included early-onset breast cancer in his paternal grandmother and paternal great-grandfather, as well as colon cancer at age 31 in a paternal cousin. The same TP53 variant was later confirmed in his paternal grandmother. Based on this information, his father (age 28, obligate carrier for the variant) was referred for colonoscopic screening and found to have multiple adenomatous polyps. This previously undescribed variant lies at an exon/intron boundary and is predicted to decrease splice site efficiency with resulting altered splicing or exon skipping. Our patient's family history provides limited evidence that this variant is a cause of Li-Fraumeni syndrome.

Petr EJ, Else T
Adrenocortical carcinoma (ACC): When and why should we consider germline testing?
Presse Med. 2018 Jul - Aug; 47(7-8 Pt 2):e119-e125 [PubMed] Related Publications
Adrenocortical carcinoma (ACC), particularly when occurring during childhood, has been a traditional component of the tumor spectrum of Li-Fraumeni syndrome. Recent research has defined a significant risk increase of ACC with other familial cancer syndromes, such as Lynch syndrome and multiple endocrine neoplasia. ACC patients can serve as index patients for a new family diagnosis of a hereditary syndrome, allowing for further family cascade genetic testing, impacting the care and surveillance for patients and at risk family members. Individuals carrying pathogenic genetic variants can embark on a regular preventive screening and surveillance protocol likely reducing morbidity and mortality. Although several of these hereditary predisposition syndromes lead to a very high relative risk increase for ACC, the absolute risk most often does not reach a level to recommend general screening for ACC in carriers of pathogenic mutations. The larger value lies in the ability to screen for other commonly associated tumors in pathogenic variant carriers, such as colon cancer with Lynch syndrome. Here, we review the risk for ACC associated with hereditary syndromes and suggest an approach for genetic evaluation for ACC patients.

Decmann A, Perge P, Nyíro G, et al.
MicroRNA Expression Profiling in Adrenal Myelolipoma.
J Clin Endocrinol Metab. 2018; 103(9):3522-3530 [PubMed] Related Publications
Introduction: Adrenal myelolipoma (AML) is the second most common and invariably benign primary adrenal neoplasm. Due to the variable proportion of fat and hematopoietic elements and its often large size, it can cause differential diagnostic problems. Several reports confirmed the utility of miRNAs in the diagnosis of tumors, but miRNA expression in AML has not yet been investigated.
Materials and Methods: Next-generation sequencing (NGS) was performed on 30 formalin-fixed, paraffin-embedded (FFPE) archived tissue samples [10 each of AML, adrenocortical adenoma (ACA), and adrenocortical carcinoma (ACC)]. Validation was performed by real-time quantitative reverse transcription polymerase chain reaction on a cohort containing 41 further FFPE samples (15 AML, 14 ACA, and 12 ACC samples). Circulating miRNA counterparts of significantly differentially expressed tissue miRNAs were studied in 33 plasma samples (11 each of ACA, ACC, and AML).
Results: By NGS, 256 significantly differentially expressed miRNAs were discovered, and 8 of these were chosen for validation. Significant overexpression of hsa-miR-451a, hsa-miR-486-5p, hsa-miR-363-3p, and hsa-miR-150-5p was confirmed in AML relative to ACA and ACC. hsa-miR-184, hsa-miR-483-5p, and hsa-miR-183-5p were significantly overexpressed in ACC relative to ACA but not to AML. Circulating hsa-miR-451a and hsa-miR-363-3p were significantly overexpressed in AML, whereas circulating hsa-miR-483-5p and hsa-miR-483-3p were only significantly overexpressed in ACC vs ACA.
Conclusions: We have found significantly differentially expressed miRNAs in AML and adrenocortical tumors. Circulating hsa-miR-451a might be a promising minimally invasive biomarker of AML. The lack of significantly different expression of hsa-miR-483-3p and hsa-miR-483-5p between AML and ACC might limit their applicability as diagnostic miRNA markers for ACC.

Svahn F, Paulsson JO, Stenman A, et al.
TERT promoter hypermethylation is associated with poor prognosis in adrenocortical carcinoma.
Int J Mol Med. 2018; 42(3):1675-1683 [PubMed] Related Publications
Telomere maintenance, most commonly achieved by telomerase activation through induction of the telomerase reverse transcriptase (TERT) gene, is required for cell immortalization, a hallmark of cancer. Adrenocortical carcinoma (ACC) is an endocrine tumor for which TERT promoter mutations and telomerase activation have been reported. The present study assessed alterations of the TERT gene locus and telomere length in relation to clinical characteristics in ACC. In total, 38 cases of ACC with known TERT promoter mutational status were included. TERT promoter methylation densities were assessed by pyrosequencing, and TERT copy numbers and telomere length were determined by quantitative polymerase chain reaction analysis, followed by comparison of the mRNA expression of TERT and clinical parameters. The ACC tissue samples showed increased TERT copy numbers, compared with normal adrenal tissue (NAT) samples (P=0.001). Mutually exclusive TERT copy number gains or promoter mutation were present in 70% of the ACC samples. The ACC tissues exhibited higher levels of CpG promoter methylation of all eight CpG sites investigated within the ‑578 to ‑541 bp (Region A), compared with the NATs (P=0.001). High methylation density at this region was associated with metastatic disease and/or relapse, poor survival rates and higher European Network for the Study of Adrenal Tumor stage (P<0.05). The mRNA expression of TERT was inversely correlated with methylation density at ‑162 to ‑100 bp (Region B). Correlation was observed between relative telomere length and the gene expression of TERT. It was concluded that epigenetic alterations of the TERT promoter are frequent and associated with advanced disease and poorer clinical outcome in ACC.

Chortis V, Taylor AE, Doig CL, et al.
Nicotinamide Nucleotide Transhydrogenase as a Novel Treatment Target in Adrenocortical Carcinoma.
Endocrinology. 2018; 159(8):2836-2849 [PubMed] Free Access to Full Article Related Publications
Adrenocortical carcinoma (ACC) is an aggressive malignancy with poor response to chemotherapy. In this study, we evaluated a potential new treatment target for ACC, focusing on the mitochondrial reduced form of NAD phosphate (NADPH) generator nicotinamide nucleotide transhydrogenase (NNT). NNT has a central role within mitochondrial antioxidant pathways, protecting cells from oxidative stress. Inactivating human NNT mutations result in congenital adrenal insufficiency. We hypothesized that NNT silencing in ACC cells will induce toxic levels of oxidative stress. To explore this, we transiently knocked down NNT in NCI-H295R ACC cells. As predicted, this manipulation increased intracellular levels of oxidative stress; this resulted in a pronounced suppression of cell proliferation and higher apoptotic rates, as well as sensitization of cells to chemically induced oxidative stress. Steroidogenesis was paradoxically stimulated by NNT loss, as demonstrated by mass spectrometry-based steroid profiling. Next, we generated a stable NNT knockdown model in the same cell line to investigate the longer lasting effects of NNT silencing. After long-term culture, cells adapted metabolically to chronic NNT knockdown, restoring their redox balance and resilience to oxidative stress, although their proliferation remained suppressed. This was associated with higher rates of oxygen consumption. The molecular pathways underpinning these responses were explored in detail by RNA sequencing and nontargeted metabolome analysis, revealing major alterations in nucleotide synthesis, protein folding, and polyamine metabolism. This study provides preclinical evidence of the therapeutic merit of antioxidant targeting in ACC as well as illuminating the long-term adaptive response of cells to oxidative stress.

Vatrano S, Volante M, Duregon E, et al.
Detailed genomic characterization identifies high heterogeneity and histotype-specific genomic profiles in adrenocortical carcinomas.
Mod Pathol. 2018; 31(8):1257-1269 [PubMed] Related Publications
Molecular characterization of adrenocortical carcinoma has been recently established, but the correlation between molecular profiles and clinical and pathological characteristics is still poorly defined with no data available about genetic heterogeneity along disease progression. In this scenario, a detailed molecular profile was correlated with clinical and pathological characteristics in adrenocortical carcinoma patients to identify potentially novel biomarkers. Targeted next-generation sequencing and copy number variation analyses for 18 most frequently altered genes in adrenocortical carcinoma were assessed on 62 adult cases (including 10 with matched primary and metastatic/recurrence samples) and results correlated with major clinical and pathological characteristics of tumors. A total of 433 somatic deleterious genetic alterations (328 gene mutations and 105 copy number variations) were identified in 57/62 cases, five resulted wild type for all genes tested. TERT, CDK4, ZNRF3,and RB1 were altered in more than 30% of cases. Among histological variants genotypes were significantly different. Lowest mutation burden was found in the oncocytic type (p = 0.006), whereas the highest with a prevalence of RB1 (p = 0.001) and CDK4 (p = 0.002) was found in the conventional and myxoid ones, respectively. None of the 10 cases with matched samples showed a stable genotype along tumor progression, although allelic frequencies or percentages of altered nuclei at fluorescence in situ hybridization were in most cases similar among different tumor samples for genes that were stable along tumor progression. Among individual genes, an altered p53/Rb1 pathway was the strongest adverse molecular signature, being associated with high Ki-67 index, high tumor stage, aggressive disease status, and shorter disease-free survival. The genomic signature in adrenocortical carcinoma is changing along tumor progression and is associated with specific clinical and pathological features, including histological variant and prognosis.

Hui W, Liu S, Zheng J, et al.
Nutlin-3a as a novel anticancer agent for adrenocortical carcinoma with CTNNB1 mutation.
Cancer Med. 2018; 7(4):1440-1449 [PubMed] Free Access to Full Article Related Publications
Adrenocortical carcinoma (ACC) is a rare malignancy, and CTNNB1 is frequently mutated in ACC. Our study aims to screen for effective agents with antineoplastic activity against ACC with CTNNB1 mutation. In-silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database was conducted. Drug sensitivity in cells with CTNNB1 mutation was analyzed and further in vitro and in vivo studies were performed using the compound. Only one compound, Nutlin-3a, an MDM2 inhibitor, was significantly sensitive in 18 cancer cells with CTNNB1 mutation. Further analysis of the 18 cells revealed no significant efficacy between cells with both CTNNB1 and TP53 mutations indicating concomitant TP53 mutation did not impact on drug efficacy. We verified that Nutlin-3a inhibited cellular proliferation in ACC cell line NCI-H295R which harbored CTNNB1 mutation but not in SW13 cells which did not. Nutlin-3a induced cell apoptosis and G1 cell-cycle arrest in NCI-H295R cells. Nutlin-3a also decreased cellular migration and inhibited epithelial-to-mesenchymal transition (EMT) process in terms of EMT index. Nutlin-3a resulted in decreased β-catenin level independent of p53 level in NCI-H295R but not SW13 cells. We also evaluated the effect of Nutlin-3a on hormonal secretion of NCI-H295R cells and found it resulted in decreased levels of cortisol, androgen, and progesterone. Nutlin-3a treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Our study has revealed that Nutlin-3a potently inhibits ACC with CTNNB1 mutation. How p53/MDM2 axis coordinates with Wnt/beta-Catenin signaling in ACC warrants further study.

Kieler M, Müllauer L, Koperek O, et al.
Analysis of 10 Adrenocortical Carcinoma Patients in the Cohort of the Precision Medicine Platform MONDTI.
Oncology. 2018; 94(5):306-310 [PubMed] Related Publications
OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare disease with a dismal prognosis. We aimed to evaluate if a personalized medicine approach may be useful for matching patients with ACC to targeted therapies.
METHODS: This is an analysis of 10 molecularly profiled ACCs that were progressing under standard of care treatment. The profile consisted of a 50-gene next-generation sequencing panel, immunohistochemistry (IHC), and fluorescence in situ hybridization for several proteins or chromosomal aberrations.
RESULTS: In 6 (60%) tumor samples, no somatic mutation was detected, while in 3 (30%) tumors 1 mutation was detected and in 1 (10%) tumor 2 mutations were detected. These mutations were CTNNB1 (2 samples), TP53 (1 sample), RB1 (1 sample) and APC (1 sample). Expression of phospho-mTOR and of EGFR was commonly detected by IHC (87.5 and 62.5%). In 4 (50%) samples, IHC revealed a weak expression of progesterone receptor. Less frequent alterations were expression of PDGFR-α, c-KIT, and estrogen receptor, each in 1 case.
CONCLUSIONS: Based on the molecular profile, no recommendation for targeted therapy was made by the multi-disciplinary team. Currently, ACC might not be suitable for a precision medicine approach according to our tests.

Nagy Z, Decmann Á, Perge P, Igaz P
[Pathogenic and diagnostic roles of microRNAs in adrenocortical tumours].
Orv Hetil. 2018; 159(7):245-251 [PubMed] Related Publications
Adrenocortical tumours are quite prevalent. Most of these tumours are benign, hormonally inactive adrenocortical adenomas. Rare hormone-secreting adrenocortical adenomas are associated with severe clinical consequences, whereas the prognosis of the rare adrenocortical cancer is rather poor in its advanced stages. The pathogenesis of these tumours is only partly elucidated. MicroRNAs are small, non-coding RNA molecules that are pivotal in the regulation of several basic cell biological processes via the posttranscriptional regulation of gene expression. Their altered expression has been described in many tumours. Several tissue microRNAs, such as miR-483-5p, miR-503, miR-210, miR-335 and miR-195 were found to be differentially expressed among benign and malignant adrenocortical tumours, and these could also have pathogenic relevance. Due to their tissue specific and stable expression, microRNAs can be exploited in diagnostics as well. As the histological diagnosis of adrenocortical malignancy is difficult, microRNAs might be of help in the establishment of malignancy. Novel data show that microRNAs are secreted in various body fluids, projecting their applicability as biomarkers as part of liquid biopsy. In this review, we attempt to present a synopsis on the pathogenic relevance of microRNAs in adrenocortical tumours and their potential diagnostic applicability. Orv Hetil. 2018; 159(7): 245-251.

Hadjadj D, Kim SJ, Denecker T, et al.
A hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas.
Aging (Albany NY). 2017; 9(12):2695-2716 [PubMed] Free Access to Full Article Related Publications
High proliferation rate and high mutation density are both indicators of poor prognosis in adrenocortical carcinomas. We performed a hypothesis-driven association study between clinical features in adrenocortical carcinomas and the expression levels of 136 genes involved in DNA metabolism and G1/S phase transition. In 79 samples downloaded from The Cancer Genome Atlas portal, high

Bonnet-Serrano F, Bertherat J
Genetics of tumors of the adrenal cortex.
Endocr Relat Cancer. 2018; 25(3):R131-R152 [PubMed] Related Publications
This review describes the molecular alterations observed in the various types of tumors of the adrenal cortex, excluding Conn adenomas, especially the alterations identified by genomic approaches these last five years. Two main forms of bilateral adrenocortical tumors can be distinguished according to size and aspect of the nodules: primary pigmented nodular adrenal disease (PPNAD), which can be sporadic or part of Carney complex and primary bilateral macro nodular adrenal hyperplasia (PBMAH). The bilateral nature of the tumors suggests the existence of an underlying genetic predisposition. PPNAD and Carney complex are mainly due to germline-inactivating mutations of

Garinet S, Nectoux J, Neou M, et al.
Detection and monitoring of circulating tumor DNA in adrenocortical carcinoma.
Endocr Relat Cancer. 2018; 25(3):L13-L17 [PubMed] Related Publications

Nicolson NG, Man J, Carling T
Advances in understanding the molecular underpinnings of adrenocortical tumors.
Curr Opin Oncol. 2018; 30(1):16-22 [PubMed] Related Publications
PURPOSE OF REVIEW: Adrenocortical tumors are divided into benign adenomas and malignant carcinomas. The former is relatively common and carries a favorable prognosis, whereas the latter is rare and frequently presents at an advanced stage, with poor outcomes. Advances in next-generation sequencing, genome analysis, and bioinformatics have allowed for high-throughput molecular characterization of adrenal tumorigenesis.
RECENT FINDINGS: Although recent genomic, epigenomic, and transcriptomic studies in large tumor cohorts have confirmed the central roles of aberrant Wnt/ß-catenin signaling, constitutive protein kinase A pathway activation, cell cycle dysregulation, and ion channelopathies in adrenal tumorigenesis, these studies also revealed novel signature events underlying malignant differentiation of adrenocortical carcinomas.
SUMMARY: Recent advances in understanding of the molecular mechanisms underlying adrenocortical tumorigenesis provide new molecular diagnostic and prognostic tools and opportunities for novel therapeutic approaches. These findings are particularly important in adrenocortical carcinoma, for which current treatment options are limited.

Creemers SG, Korpershoek E, Atmodimedjo PN, et al.
Identification of Mutations in Cell-Free Circulating Tumor DNA in Adrenocortical Carcinoma: A Case Series.
J Clin Endocrinol Metab. 2017; 102(10):3611-3615 [PubMed] Related Publications
Context: The disease course of adrenocortical carcinoma (ACC) patients is heterogeneous. A marker for prognosis and treatment response would facilitate choices for diagnosis and therapy. In other cancer types, circulating cell-free tumor DNA predicted tumor dynamics.
Case Descriptions: The present pilot study included six patients. Next-generation sequencing (NGS) showed mutations in three ACC cases. From these patients, blood was drawn before (1 to 2 weeks) and after surgery and cell-free circulating DNA (cfDNA) was isolated. Tumor-specific mutations were found in the cfDNA of one of the three patients, with metastasized ACC at diagnosis. NGS of the tumor showed an NRAS mutation (c.182A>G:p.Q61R) in 78%, a TP53 mutation (c.856G>A:p.E286K) in 60%, and a TERT gene mutation (1295250C>T) in 28% of the reads. The preoperative cfDNA showed the same mutations at a frequency of 64%, 32%, and 2%, respectively. The postoperative cfDNA showed the same mutations but at lower frequencies (52%, 16%, and 3%, respectively). The patient was postoperatively treated with mitotane and chemotherapy. No mutations were detected in the corresponding leukocyte DNA or in the cfDNA from the two other patients.
Conclusions: To the best of our knowledge, we report for the first time mutations occurring at high levels in cfDNA collected before and after surgery from one of three patients, after previous identification in the tumor. However, in the cfDNA from two patients with known mutations, we were unable to reliably detect mutations in the cfDNA. Our results indicate that mutation detection in cfDNA can vary among ACC patients, and other approaches might be required to detect the tumor response and monitor progressive disease.

Franceschi S, Spugnesi L, Aretini P, et al.
Whole-exome analysis of a Li-Fraumeni family trio with a novel TP53 PRD mutation and anticipation profile.
Carcinogenesis. 2017; 38(9):938-943 [PubMed] Related Publications
Li-Fraumeni syndrome is a clinically heterogeneous familial cancer predisposition syndrome with autosomal-dominant inheritance caused by heterozygous germline mutations in the TP53 gene. We here analyze the genetic background of a family with a 4-year-proband presented with a Li-Fraumeni tumor. The mother developed breast cancer at age 37 and the proband died at age 8. We performed Sanger sequencing and whole-exome sequencing on peripheral blood DNA from proband and relatives. Data analysis selected only high-quality score and depth reads, rare variants and protein impact involving missense, non-sense, frameshift and splice disrupt mutations. Disease implicated variants and predicted deleterious alterations were also chosen. TP53 genetic testing revealed a never reported TP53 deletion arose as de novo mutation in the mother and inherited by the proband. We then performed whole-exome analysis of the trio to uncover inherited variants from the father that potentially worsen the already altered genetic background in the proband. No pathogenic variants were inherited in autosomal recessive, de novo dominant or X-linked recessive manner. Comparing proband and father exome we detected 25 predicted deleterious variants including a nonsense mutation in ERCC3. Those inherited mutations are possible candidate modifiers linked to TP53, explaining the proband accelerated tumor onset compared to the mother and providing a possible explanation of the genetic anticipation event in this Li-Fraumeni family.

Jonker PKC, Meyer VM, Kruijff S
Epigenetic dysregulation in adrenocortical carcinoma, a systematic review of the literature.
Mol Cell Endocrinol. 2018; 469:77-84 [PubMed] Related Publications
Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with a poor prognosis. Diagnosis and treatment of this tumor remains challenging. The Weiss score, the current gold standard for the histopathological diagnosis of ACC, lacks diagnostic accuracy of borderline tumors (Weiss score 2 or 3) and is subject to inter observer variability. Furthermore, adjuvant and palliative systemic therapy have limited effect and no proven overall survival benefit. A better insight in the molecular background of ACC might identify markers that improve diagnostic accuracy, predict treatment response or even provide novel therapeutic targets. This systematic review of the literature aims to provide an overview of alterations in DNA methylation, histone modifications and their potential clinical relevance in ACC.

Else T, Lerario AM, Everett J, et al.
Adrenocortical carcinoma and succinate dehydrogenase gene mutations: an observational case series.
Eur J Endocrinol. 2017; 177(5):439-444 [PubMed] Related Publications
OBJECTIVE: Germline loss-of-function mutations in succinate dehydrogenase (
PATIENTS AND RESULTS: We report four unrelated patients with ACC and
CONCLUSIONS: We observed truncating mutations in

Macedo GS, Vieira IA, Vianna FSL, et al.
p53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers.
Fam Cancer. 2018; 17(2):269-274 [PubMed] Related Publications
Li-Fraumeni and Li-Fraumeni-like syndrome (LFS/LFL) are clinically heterogeneous cancer predisposition syndromes characterized by diagnosis of early-onset and often multiple cancers with variable tumor patterns and incomplete penetrance. To date, the genetic modifiers described in LFS/LFL have been shown to map to either TP53 or its main negative regulator, MDM2. Additionally, all studies were focused on families with different TP53 germline mutations. Hence, in this study we explored the effect of the most studied polymorphisms of p53 pathway genes on clinical manifestations of individuals carrying the founder TP53 mutation R337H (n = 136) and controls (n = 186). Cancer-affected carriers had been diagnosed either with adrenocortical carcinoma (ACC, n = 29) or breast cancer (BC, n = 43). Allelic discrimation using TaqMan assay was used for genotyping MDM2 SNP 309 (rs2279744) as well as MDM4 (rs1563828) and USP7 (rs1529916) polymorphisms. We found significantly higher MDM2 SNP 309 GG genotype and G allele frequencies in the LFS cohort than in controls. Furthermore, median age at first diagnosis was earlier in MDM2 SNP309 GG carriers when compared to other genotypes for both cancers (ACC: age 1 vs. 2 years; BC: age 35 vs. 43 years, respectively), although not statistically different. The allelic and genotypic frequencies for all SNPs did not differ between cancer affected and unaffected carriers, neither between patients with ACC or BC. In conclusion, our results suggest that MDM2 SNP 309 may contribute to the LFL phenotype and also to an earlier age at diagnosis of ACC and BC cancer in carriers of the R337H founder mutation.

Bulzico D, Torres DC, Ferreira GM, et al.
A Novel TP53 Mutation Associated with TWIST1 and SIP1 Expression in an Aggressive Adrenocortical Carcinoma.
Endocr Pathol. 2017; 28(4):326-331 [PubMed] Related Publications
Adrenocortical carcinomas (ACC) are very rare tumors related to TP53 mutations mostly in childhood onset cases. Epithelial-mesenchymal transition (EMT) transcription factors TWIST1 and Smad interacting protein 1 (SIP1) are related to poorer outcomes in other malignancies, but their role in ACC is unknown. We describe a case of an advanced metastatic ACC (Weiss-score of 9) in a patient at age 76. After primary tumor resection, mitotane therapy was started as palliation to low-volume liver metastasis. After a 2-year period of stable disease, the patient died due to brain metastasis. Somatic gene sequencing revealed a novel TP53 mutation in DNA extracted from paraffin-embedded tissue, a deletion of 8bp in exon 8 (c.811_818del8; GAGGTGCG/-) in homo or hemizygosis causing a subsequent frameshift and premature stop codon at position 302. Immunohistochemistry of P53 and p-Ser-15 P53 showed absent tumoral staining. In addition, immunohistochemical analysis showed an increased expression of the mesenchymal markers vimentin and fibronectin. At last, EMT transcription factors TWIST1 and SIP1 were also overexpressed in tumoral cells. This case report describes an aggressive ACC with not only a novel somatic mutation, but also a novel International Agency for Research on Cancer database 8 base-pair deletion in TP53 exon 8. In addition, the expression of EMT inducers TWIST1 and SIP1 have been reported for the first time in an ACC case. Further investigation is needed to clarify the biologic significance of this new TP53 mutation and its role in the EMT process.

Ruggiero C, Doghman-Bouguerra M, Sbiera S, et al.
Dosage-dependent regulation of
Sci Signal. 2017; 10(469) [PubMed] Related Publications
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis. Genomic studies have enabled progress in our understanding of the molecular bases of ACC, but factors that influence its prognosis are lacking. Amplification of the gene encoding the transcription factor steroidogenic factor-1 (SF-1; also known as NR5A1) is one of the genetic alterations common in ACC. We identified a transcriptional regulatory mechanism involving increased abundance of VAV2, a guanine nucleotide exchange factor for small GTPases that control the cytoskeleton, driven by increased expression of the gene encoding SF-1 in ACC. Manipulating SF-1 and VAV2 abundance in cultured ACC cells revealed that VAV2 was a critical factor for SF-1-induced cytoskeletal remodeling and invasion in culture (Matrigel) and in vivo (chicken chorioallantoic membrane) models. Analysis of ACC patient cohorts indicated that greater VAV2 abundance robustly correlated with poor prognosis in ACC patients. Because VAV2 is a druggable target, our findings suggest that blocking VAV2 may be a new therapeutic approach to inhibit metastatic progression in ACC patients.

Pilati C, Shinde J, Alexandrov LB, et al.
Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas.
J Pathol. 2017; 242(1):10-15 [PubMed] Related Publications
Germline alterations in DNA repair genes are implicated in cancer predisposition and can result in characteristic mutational signatures. However, specific mutational signatures associated with base excision repair (BER) defects remain to be characterized. Here, by analysing a series of colorectal cancers (CRCs) using exome sequencing, we identified a particular spectrum of somatic mutations characterized by an enrichment of C > A transversions in NpCpA or NpCpT contexts in three tumours from a MUTYH-associated polyposis (MAP) patient and in two cases harbouring pathogenic germline MUTYH mutations. In two series of adrenocortical carcinomas (ACCs), we identified four tumours with a similar signature also presenting germline MUTYH mutations. Taken together, these findings demonstrate that MUTYH inactivation results in a particular mutational signature, which may serve as a useful marker of BER-related genomic instability in new cancer types. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Murtha TD, Brown TC, Rubinstein JC, et al.
Overexpression of cytochrome P450 2A6 in adrenocortical carcinoma.
Surgery. 2017; 161(6):1667-1674 [PubMed] Related Publications
BACKGROUND: Cytochrome P450-mediated metabolism of chemotherapeutic agents contributes to chemotherapy resistance in multiple malignancies. Adrenocortical carcinoma is known to have a poor response to adjuvant therapies; however, the mechanism remains unknown. Recent comprehensive genetic analyses of adrenocortical carcinomas demonstrated recurrent copy number gains in multiple cytochrome P450 genes prompting investigation into whether cytochrome P450 overexpression potentiates adrenocortical carcinoma chemoresistance.
METHODS: We determined the expression patterns of 6 cytochrome P450 genes (CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2S1, and CYP4F2) predicted to be amplified in adrenocortical carcinoma (n = 29) relative to normal adrenal cortex (n = 10). Gene copy numbers were determined with the TaqMan copy number assay. Gene silencing was performed via small interfering RNA (siRNA) in the adrenocortical carcinoma cell line NCI-H295R and treated with mitotane and cisplatin.
RESULTS: Of the 6 cytochrome P450 genes tested, CYP2A6 was overexpressed with a 55-fold mean increase compared to normal adrenal samples (P < .05). Immunohistochemical analysis confirmed protein overexpression. Copy gains of CYP2A6 were found in 26% (7/27) of adrenocortical carcinoma specimens. Silencing of CYP2A6 in NCI-H295R cells resulted in decreased cell viability and increased chemosensitivity (P < .05).
CONCLUSION: Frequent upregulation in adrenocortical carcinomas and the reversal of chemoresistance in adrenocortical carcinoma cells via enforced silencing suggest a role for CYP2A6 in adrenocortical malignancy.

Hassan N, Zhao JT, Sidhu SB
The role of microRNAs in the pathophysiology of adrenal tumors.
Mol Cell Endocrinol. 2017; 456:36-43 [PubMed] Related Publications
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression in a sequence-specific manner. Due to its association with an assortment of diseases, miRNAs have been extensively studied in the last decade. In this review, the current understanding of the role of miRNAs in the pathophysiology of adrenal tumors is discussed. The recent contributions of high-throughput miRNA profiling studies have identified miRNAs that have functional and molecular roles in adrenal tumorigenesis. With respect to the biological heterogeneity of adrenal tumors and the limitations of the current treatments, an improved understanding of miRNAs may hold potential diagnostic and therapeutic value to facilitate better clinical management.

Jouinot A, Assie G, Libe R, et al.
DNA Methylation Is an Independent Prognostic Marker of Survival in Adrenocortical Cancer.
J Clin Endocrinol Metab. 2017; 102(3):923-932 [PubMed] Related Publications
Context: Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival.
Objective: The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort.
Design: Methylation was measured by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA).
Setting: MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers.
Patients: The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors).
Main Outcome Measures: DFS and OS.
Results: In the training cohort, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) was the strongest methylation marker. In the validation cohort, methylation was a significant prognostic factor of DFS (P < 0.0001) and OS (P < 0.0001). Methylation, Ki67, and ENSAT stage were combined in multivariate models. For DFS, methylation (P = 0.0005) and stage (P < 0.0001) but not Ki67 (P = 0.19) remained highly significant. For OS, methylation (P = 0.0006), stage (P < 0.0001), and Ki67 (P = 0.024) were independent prognostic factors.
Conclusions: Tumor DNA methylation emerges as an independent prognostic factor in ACC. MS-MLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.

Pereira SS, Máximo V, Coelho R, et al.
Telomerase and N-Cadherin Differential Importance in Adrenocortical Cancers and Adenomas.
J Cell Biochem. 2017; 118(8):2064-2071 [PubMed] Related Publications
Adrenocortical carcinomas (ACC) are most frequently highly aggressive tumors. We assessed the telomerase reverse transcriptase (TERT) and N-cadherin role in the biology of ACC and their potential utility as molecular biomarkers, in different types of tumoral adrenocortical tissue. A total of 48 adrenal cortex samples (39 tumoral and 9 normal adrenal glands) were studied. TERT promoter mutations were searched by PCR and Sanger sequencing in two hotspots positions (-124 and -146). Also, telomerase and N-cadherin expression were evaluated by immunohistochemistry. TERT promoter mutations were not detected in any of the samples either malignant or benign. Telomerase nuclear expression was present in 26.6% of ACC and in 45.5% of non-functioning adenomas. It was absent in benign Cushing's lesions and in normal adrenal glands. Contrarily, N-cadherin was always expressed in the cellular membranes of benign adenomas or normal adrenals but no expression was detected in the majority of ACC. Nuclear telomerase and membrane N-cadherin expression were positively correlated in ACCs. We conclude that in ACC, the loss of N-cadherin is a frequent phenomenon while the existence of TERT promoter mutations is not and nuclear telomerase expression is present in only a minority of cases. Since the loss of N-cadherin expression was identified in both high and low proliferative ACC, this marker should be considered important for diagnostic application. Our study also suggests the existence of a TERT non-canonical function in cell adhesion. J. Cell. Biochem. 118: 2064-2071, 2017. © 2017 Wiley Periodicals, Inc.

Murtha TD, Korah R, Carling T
Suppression of cytochrome P450 4B1: An early event in adrenocortical tumorigenesis.
Surgery. 2017; 161(1):257-263 [PubMed] Related Publications
BACKGROUND: Adrenocortical carcinoma is a rare neoplasm with a poor prognosis. Conversely, adrenocortical adenomas are common and benign. Despite their shared histologic origin, little evidence exists to suggest that adrenocortical adenoma arises from adrenocortical carcinoma. Recent genetic analyses of adrenocortical carcinoma have shown recurrent gene copy deletion of CYP4B1, a cytochrome P450 isozyme. This study investigates a potential role for CYP4B1 in modulating adrenocortical tumorigenesis and/or conferring chemoresistance to adrenocortical carcinomas.
METHODS: Using TaqMan, real-time quantitative polymerase chain reaction techniques, we investigated CYP4B1 expression in normal adrenal cortex (n = 10), histologically confirmed adrenocortical adenomas (n = 10), and adrenocortical carcinomas (n = 10). Adrenocortical carcinoma cell lines were enforced to express CYP4B1, and effects on cell death and enhanced mitotane and cisplatin sensitivity were tested.
RESULTS: Gene expression analyses demonstrated suppression of CYP4B1 in 100% of both the adrenocortical adenomas (10/10) and adrenocortical carcinomas (10/10) tested. Average relative expression of CYP4B1 was decreased at 0.19 (0.01-0.50; P < .01) in adrenocortical adenomas and nearly absent in adrenocortical carcinomas (0.01; 0.00-0.05; P < .01). Protein expression correlated with mRNA expression. Ectopic expression of CYP4B1 promoted cytotoxicity and increased chemosensitivity in adrenocortical carcinoma cell lines.
CONCLUSION: CYP4B1 is silenced in both benign and malignant adrenocortical tumors and may contribute to tumorigenesis and chemoresistance. Sensitization of adrenocortical carcinoma cells engineered to overexpress CYP4B1 further supports this notion.

Recurrent Chromosome Abnormalities

Selected list of common recurrent structural abnormalities

Abnormality Type Gene(s)
11p15 Abnormalities in Adrenocortical CarcinomaDeletion

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

11p15 Abnormalities in Adrenocortical Carcinoma

Gicquel C, Raffin-Sanson ML, Gaston V, et al.
Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors.
J Clin Endocrinol Metab. 1997; 82(8):2559-65 [PubMed] Related Publications
Abnormalities of the 11p15 region with overexpression of the normally imprinted insulin-like growth factor II (IGF-II) gene have been implicated in the pathogenesis of adrenocortical tumors. We evaluated the frequency and distribution of 11p15 loss of heterozygosity (LOH) and IGF-II gene overexpression in a series of 82 sporadic adrenocortical tumors, screened for pathological functional imprinting of the 11p15 region in tumors not exhibiting LOH and evaluated the expression of H19 gene in these tumors. Abnormalities of the 11p15 region as LOH (loss of the maternal allele and duplication of the paternal allele) and/or IGF-II gene overexpression are frequent features of the malignant state and were found in 27 of 29 (93.1%) of the malignant tumors and in only 3 of 35 (8.6%) of the benign tumors. Tumors without abnormality of the 11p15 region (mainly benign tumors) did not exhibit pathological functional imprinting. In tumors with mosaicism for 11p15 LOH, biallelic expression of the IGF-II gene was constant in the tumor cell contingent not undergoing LOH. Abrogation of H19 expression correlated with the loss of the maternal allele (LOH or pathological imprinting), but did not always correlate with overexpression of the IGF-II gene. These data indicate the involvement of dysregulation of the 11p15 region in late steps of adrenocortical tumorigenesis and provide us with new molecular markers for a better diagnostic and prognostic evaluation of adrenocortical tumors.

Gicquel C, Bertagna X, Schneid H, et al.
Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors.
J Clin Endocrinol Metab. 1994; 78(6):1444-53 [PubMed] Related Publications
Little is known about the pathophysiology of sporadic adrenocortical tumors in adults. Because loss of heterozygosity at the 11p15 locus has been described in childhood tumors, particularly, in adrenocortical tumors, associated with the Beckwith-Wiedemann syndrome and because insulin-like growth factor-II (IGF-II) is a crucial regulator of fetal adrenal growth, we looked for structural analysis at the 11p15 locus and IGF-II gene expression in 23 sporadic adrenocortical adult tumors: 6 carcinomas (5 with Cushing's syndrome and 1 nonsecreting) and 17 benign adenomas (13 with Cushing's syndrome, 1 pure androgen secreting, and 3 nonsecreting). Twenty-one patients were informative at the 11p15 locus, and six (four carcinomas and two adenomas) of them (28.5%) exhibited 11p15 structural abnormalities in tumor DNA (five, an uniparental disomy and one, a mosaicism). In a single case that could be further studied, a paternal isodisomy was observed. Very high IGF-II mRNA contents were detected in seven tumors (30%; 5 of the 6 carcinomas and 2 of the 17 adenomas). They were particularly found in tumors with uniparental disomy at the 11p15 locus. Overall, a strong correlation existed between IGF-II mRNA contents and DNA demethylation at the IGF-II locus. These data show that genetic alterations involving the 11p15 locus were highly frequent in malignant tumors, but found only in rare adenomas. These results in combination with evidence for overexpression of IGF-II from the 11p15.5 locus suggest that abnormalities in structure and/or expression of the IGF-II gene play a role as a late event of a multistep process of tumorigenesis.

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