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Wnt, TP53, and Cell-Cycle Dysregulation in ACC

Molecular Biology and Tumor Evolution

Wnt/β-catenin signaling, TP53 dysfunction, and broader cell-cycle dysregulation are recurring molecular features of adrenocortical carcinoma (ACC), a rare malignant tumor of the adrenal cortex with marked biologic and clinical heterogeneity.1 2 Within ACC, these pathways connect altered adrenal developmental programs to malignant progression by affecting proliferation, checkpoint control, chromosomal stability, and differentiation state.3 4 5

ACC is not defined by a single universal driver. Instead, integrated genomic and transcriptomic studies indicate that recurrent abnormalities in Wnt-pathway regulators, TP53/RB-associated checkpoints, and mitotic or proliferative programs help define major biologic subsets, usually alongside other changes such as IGF2 overexpression, epigenetic dysregulation, and structural genomic instability.6 7 8 These alterations are therefore best understood as pathway-level components of tumor evolution rather than isolated lesions with uniform clinical meaning.9 10

The evidence is strongest for recurrent association, prognostic stratification, and biologic plausibility, but weaker for direct clinical actionability. Most data come from retrospective tumor cohorts, multi-omic classification studies, and a limited number of laboratory models, especially H295R-derived systems, so causal interpretation and therapeutic generalization remain incomplete.11 12 13 Pediatric adrenocortical tumors, particularly those arising in germline TP53 predisposition settings, share some pathway labels with adult ACC but may differ in developmental context and genomic architecture, limiting straightforward extrapolation across age groups.14 15 16

Biological and Diagnostic Context

Early cytogenetic, loss-of-heterozygosity, and copy-number studies established ACC as a genomically unstable adrenal malignancy, with more numerous chromosomal abnormalities than adenoma and recurrent involvement of loci such as 11p15 and 17p.17 18 19 20 21 This supports a multistep model in which malignant transformation is accompanied by accumulating structural and regulatory defects rather than a single defining mutation.9 1

Modern multi-omic analyses refined this framework by identifying prognostically distinct ACC subgroups enriched for Wnt/β-catenin activation, TP53/Rb disruption, proliferative signatures, methylation abnormalities, and chromosomal instability.6 7 10 16 This subgrouping is relatively consistent across contemporary datasets, but the exact sequence of molecular events within an individual tumor remains uncertain. Clinically, the implication is that these pathways are useful for biologic classification and research stratification, while conventional staging, pathology, and surgical factors still anchor routine management.12 10

Major Molecular Phenotypes

Wnt/β-catenin activation

Aberrant Wnt/β-catenin signaling is one of the most reproducible pathway abnormalities in ACC. Reported mechanisms include activating CTNNB1 mutations, loss or deletion of Wnt repressors such as ZNRF3, less frequent APC-related events, and altered transcriptional cofactors that may enhance downstream signaling.22 6 23 24 Functional studies in ACC models support roles in proliferation, survival, invasion, and some aspects of steroidogenic regulation.13 25 26

However, Wnt activation is not specific to carcinoma, because CTNNB1 alterations and abnormal β-catenin signaling may also occur in adrenocortical adenomas.27 Mouse models suggest that β-catenin activation may be an early tumorigenic event that can drive hyperplasia and dysplasia, with additional alterations needed for overt malignant behavior.28 The reliable conclusion is that Wnt signaling is common and biologically important in ACC, but not sufficient by itself to define malignancy or predict behavior in all tumors. In practice, Wnt-pathway status may contribute to molecular subtyping and prognosis, but it is not a standalone diagnostic marker.29 30

TP53 and p53/Rb-cell-cycle disruption

TP53 pathway dysfunction is another central axis of ACC biology. Its importance was initially highlighted through hereditary cancer predisposition syndromes, particularly Li-Fraumeni syndrome and the Brazilian TP53 R337H founder variant associated with pediatric adrenocortical tumors.14 31 15 In adult sporadic ACC, TP53 alterations and broader p53/Rb-pathway abnormalities are repeatedly linked to higher proliferation, advanced stage, recurrence, and worse survival in retrospective cohorts.32 33

Cell-cycle dysregulation extends beyond TP53 itself. Aggressive ACC subsets often show overexpression of E2F-linked, G1/S, and G2/M programs, with candidate mediators involving cyclins, CDKs, mitotic regulators, and transcriptional networks such as EZH2-E2F1.34 35 36 These associations with aggressive biology are fairly consistent across molecular studies, but direct proof that any single lesion represents a validated therapeutic dependency remains limited. The practical implication is that p53/Rb and cell-cycle abnormalities currently inform prognosis and translational hypotheses more than standard treatment selection.37 10

Mitotic and chromosomal-instability programs

Broader mitotic dysregulation appears to accompany the most aggressive ACC phenotypes, fitting with the longstanding observation that carcinomas carry heavier structural genomic disruption than adenomas.17 19 5 More recent transcriptomic work has linked overexpression of kinetochore and chromosome-segregation programs, including CCAN-related genes, to poor outcome, but this evidence is largely correlative and in part derived from pan-cancer analyses rather than ACC-specific functional validation.38 36

This broader mitotic phenotype helps connect cell-cycle activation with chromosomal instability and adverse prognosis. It is a useful explanatory framework for aggressive disease biology, but it remains less reliable as an ACC-specific mechanistic category than recurrent Wnt- or TP53-pathway alterations.

Developmental and Lineage Context

The prominence of Wnt signaling in ACC likely reflects its normal role in adrenal zonation, progenitor maintenance, and cortical differentiation.3 4 39 ACC may therefore represent not only accumulated oncogenic damage but also distorted lineage-specific developmental signaling. Crosstalk with SF1/NR5A1, PKA, hedgehog, and related adrenal programs suggests that the biologic effect of a Wnt alteration depends on adrenal cellular context rather than mutation status alone.40 41 42

This developmental framing is supported by experimental systems and review-level synthesis, but the precise human cell of origin remains unsettled.43 39 Clinically, the implication is mainly interpretive: tumors with superficially similar pathway alterations may behave differently because lineage state, steroidogenic phenotype, and co-occurring alterations modify pathway output.44

Prognostic Associations and Integrated Subgroups

Integrated profiling studies consistently suggest that Wnt-pathway lesions and p53/Rb-cell-cycle defects are enriched in poor-prognosis ACC subgroups, especially when accompanied by high chromosomal instability, adverse methylation patterns, or whole-genome-doubling-like features.6 10 5 Some datasets support partly distinct aggressive subsets dominated by β-catenin-related versus p53-related programs, whereas others show substantial overlap and additional aggressive tumors without either canonical alteration.29 11 8

These prognostic correlations are among the more reproducible clinical contributions of the molecular literature, but they remain largely retrospective and cohort-dependent.12 16 The practical consequence is that molecular subclassification may refine biologic risk assessment and clinical-trial design, yet established management still relies primarily on surgery, stage, pathologic evaluation, and conventional proliferation markers.10 16

Limitations and Interpretive Pitfalls

Several limitations recur across this literature. Nuclear β-catenin staining does not always correspond to a canonical Wnt-pathway mutation, and some proposed regulators are rare, indirect, or of uncertain pathogenic significance.45 46 Likewise, association with poor prognosis does not establish druggability, and many mechanistic claims derive from a narrow set of cell models or in-silico analyses.47 13 48

Adult and pediatric adrenocortical tumors also should not be treated as biologically interchangeable. Shared labels such as “TP53-driven” or “Wnt-activated” may conceal important differences in developmental timing, mutation spectrum, and clinical behavior.49 15 Historical observations of chromosomal amplification and instability remain useful as context, but they contribute less to current pathway interpretation than integrated genomic studies.50 7

Role in Management and Research

At present, Wnt-, TP53-, and cell-cycle-related abnormalities are best established as explanatory and prognostic frameworks rather than routine therapeutic decision tools. Compared with surgery, which remains the principal curative treatment for localized ACC, and with conventional systemic approaches used in advanced disease, pathway-directed interventions remain investigational.51 10

These pathways nonetheless remain major translational targets. Current research explores β-catenin transcriptional cofactors, CDK-related vulnerabilities, apoptosis and DNA-damage dependencies, epigenetic regulators, and noncoding RNA networks that may converge on proliferative ACC subgroups.52 53 54 55 The most reliable overall conclusion is that Wnt activation and p53/Rb-cell-cycle failure are recurring features of aggressive ACC biology; what remains uncertain is how to translate that knowledge into validated, subgroup-specific therapies.56 16

Included Articles

  • PMID 2550179: Comparative constitutional-versus-tumor genotyping in a familial adrenocortical carcinoma case identified tumor-specific loss of 11p15.5 material consistent with a mitotic deletion between PTH and CALCA. The study supports involvement of the 11p15.5 region in ACC tumorigenesis and illustrates somatic chromosomal loss as an early molecular event.57
  • PMID 2566168: In three unrelated familial adrenocortical carcinoma cases, two tumors showed somatic loss of heterozygosity confined to chromosome 11p15.5. The study links familial ACC predisposition to the 11p15.5 region and suggests this locus may harbor a broader cancer-related gene involved in predisposition, tumor progression, or both.58
  • PMID 8640732: A case report of sporadic, nonfunctional synchronous bilateral ACC with mediastinal nodal metastasis found loss of heterozygosity at the p53 and RB loci in both adrenal primary tumors and metastatic tissue, while APC loss was not detected. The findings support involvement of p53 and RB pathway disruption in ACC tumorigenesis.59
  • PMID 9403053: The article maps a 2.5-Mb tumor-suppressor region at 11p15.5 that shows loss of heterozygosity in adrenocortical carcinoma and other cancers, refining its boundaries and cataloging known and novel genes within the interval. It supports 11p15.5 as a biologically important locus that may harbor tumor-suppressive drivers relevant to ACC.20
  • PMID 9694578: This review summarizes early molecular features of adrenocortical carcinoma, including recurrent involvement of TP53 and the 11p15.5 IGF-II locus, consistent monoclonality of carcinomas, and chromosomal imbalances that suggest adrenal-specific pathways of tumorigenesis distinct from other endocrine tumors.21
  • PMID 10514385: Comparative genomic hybridization of sporadic adrenocortical lesions found that carcinomas carry more chromosomal copy-number abnormalities than adenomas or hyperplasias, while gains involving chromosome 17 were seen in some hyperplasias and were common in adenomas, suggesting chromosome 17 gain as an early event in adrenocortical tumorigenesis.17
  • PMID 10574256: Interphase cytogenetic analysis of archival adrenocortical tumors found chromosomal gains to be more frequent in carcinomas than adenomas, supporting increasing genomic instability during tumor progression. Recurrent involvement of chromosomes 3, 9, and X in both adenomas and carcinomas suggests these changes may occur early in adrenocortical tumorigenesis.18
  • PMID 10824999: Comparative genomic hybridization in adrenocortical tumors found ACC to be dominated by recurrent chromosomal gains and multiple high-level amplifications, with distal 9p loss as the main recurring deletion. Larger adenomas shared some gains with carcinomas, while several amplifications appeared confined to malignant tumors, suggesting genomic events relevant to tumor progression and diagnostic separation.19
  • PMID 11786899: This news article highlights a germline TP53 R337H mutation linked to pediatric adrenocortical carcinoma in southern Brazil, describing it as a tissue-specific, low-penetrance predisposition allele. It emphasizes a proposed mechanism of pH-dependent destabilization of p53 tetramerization that may help explain adrenal-specific tumor susceptibility.14
  • PMID 12634062: This structural biology study links the pediatric ACC-associated TP53 R337H mutant to increased propensity for reversible amyloid-like ribbon formation by the p53 tetramerization domain under acidic conditions. The findings suggest a possible mechanism for mutant p53 nuclear accumulation in ACC cells.60
  • PMID 12956790: This review summarizes early molecular events implicated in adrenocortical tumorigenesis, highlighting 11p15.5 abnormalities with IGF2 overexpression and loss of CDKN1C and H19 expression, plus TP53 involvement in a subset of carcinomas. It also notes additional recurrent chromosomal regions that may harbor tumor suppressor genes or oncogenes.9
  • PMID 16140927: This study identifies frequent Wnt pathway activation in adrenocortical tumors through abnormal beta-catenin accumulation and somatic CTNNB1 exon 3 mutations. In ACC, diffuse cytoplasmic or nuclear beta-catenin staining was common, and functional data in H295R cells supported constitutive TCF-dependent transcriptional activation.22
  • PMID 17427106: This review highlights recurrent molecular features of ACC, including frequent IGF-II overexpression linked to dysregulation of the imprinted 11p15 locus, common chromosomal alterations affecting 17p13 and other regions, and less frequent TP53 mutations. It also connects hereditary syndromes such as Li-Fraumeni, Beckwith-Wiedemann, Carney complex, McCune-Albright, and MEN1 to mechanisms of adrenocortical tumorigenesis.31
  • PMID 18553255: This study examined WNT-4 mRNA expression across adrenocortical tumors and found reduced expression in virilizing carcinomas, while Conn’s adenomas showed increased WNT-4 and beta-catenin mRNA. In cultured cells, WNT-4 was hormonally regulated and responded differently in normal adrenal cells versus the NCI-H295R ACC cell line.61
  • PMID 19007854: This review frames ACC as a multistage tumorigenesis process driven by accumulated genetic and epigenetic alterations, linking hereditary-syndrome genes to sporadic disease. It highlights recurrent involvement of TP53, 11p15/IGF2 dysregulation, Wnt/beta-catenin signaling, and angiogenic pathways while noting that the initiating events remain unclear.1
  • PMID 19286162: This review frames dysregulated Wnt/beta-catenin signaling as a key mechanism linking normal adrenocortical stem or progenitor cell maintenance to ACC development. It highlights subcapsular Wnt/beta-catenin activity, roles in self-renewal and multipotency, and how pathway activation may drive abnormal growth and malignant transformation.3
  • PMID 19498322: Sequencing of 15 ACCs and 41 adenomas found CTNNB1 activating mutations in 20% of carcinomas and 20% of adenomas, supporting Wnt/beta-catenin pathway activation as an early and common event in adrenocortical tumorigenesis. BRAF V600E was identified in only one advanced nonfunctioning ACC, suggesting a rare molecular subset.27
  • PMID 19836496: This review highlights ACC molecular features including frequent IGF-2 overexpression, recurrent TP53 and 17p abnormalities, broad chromosomal gains and losses, and gene-expression signatures linked to prognosis. It also connects ACC risk to inherited syndromes such as Li-Fraumeni and Beckwith-Wiedemann.32
  • PMID 19863445: This pediatric ACC case links activating beta-catenin alteration and nuclear beta-catenin accumulation with more aggressive tumor behavior and metastasis in an infant with bilateral adrenal tumors and hepatic spread. The report supports Wnt-signaling involvement in pediatric ACC pathogenesis and possible tumor progression.49
  • PMID 20106872: This preclinical study supports constitutive Wnt/beta-catenin pathway activation as a driver of adrenocortical tumorigenesis. In adrenal-specific transgenic mice, beta-catenin activation caused progressive hyperplasia and dysplasia, altered zonal differentiation with hyperaldosteronism, and later malignant features including neovascularization and loco-regional invasion.28
  • PMID 20591784: This review summarizes major molecular mechanisms implicated in adrenocortical carcinoma pathogenesis, including IGF2 overexpression, Wnt/beta-catenin and cAMP-protein kinase A pathway activation, and TP53 and MEN1 alterations. It also links rare hereditary syndromes to sporadic ACC biology and highlights emerging molecular-bioinformatic pathways as potential therapeutic targets.51
  • PMID 20959480: Transcriptome analysis in adult sporadic ACC identified a poor-outcome molecular group enriched for largely mutually exclusive TP53 and CTNNB1 alterations, with distinct p53- and beta-catenin-driven expression subclusters and a third aggressive subgroup lacking either alteration, implying additional unidentified drivers.29
  • PMID 21252250: In ACTH-independent macronodular adrenal hyperplasia, larger nodules showed more chromosomal gains and enrichment of p53 signaling and cancer-related pathways than smaller nodules, which were enriched for metabolic pathways. These findings support stepwise genomic and transcriptomic progression toward greater tumorigenic potential within adrenal nodules.62
  • PMID 21386792: This review highlights core molecular alterations in ACC, emphasizing frequent IGF-2 overexpression from 11p15 abnormalities and constitutive Wnt/beta-catenin activation. It also links TP53-region loss, SF1 overexpression, and transcriptomic profiling to tumor development, recurrence risk, and emerging prognostic subclassification.63
  • PMID 21565795: This study links CTNNB1-mutated adrenocortical tumors, including one ACC and the H295R ACC line, to a Wnt/beta-catenin–associated expression program with upregulation of ISM1, RALBP1, PDE2A, and ENC1 and reduced PHYHIP. Beta-catenin/TCF inhibitors dose-dependently reduced several of these transcripts and proteins in H295R cells, supporting pathway-driven transcriptional deregulation.47
  • PMID 21733995: This study identified a recurrent 12-bp AXIN2 exon 7 deletion in a small subset of adrenocortical tumors, including 1 of 6 ACCs and the H295R ACC cell line. Tumors with AXIN2 alteration showed abnormal beta-catenin accumulation, supporting Wnt/beta-catenin pathway activation in adrenocortical tumorigenesis.45
  • PMID 22056416: This review summarizes transcriptomic evidence that ACC is molecularly distinct from adrenal adenoma and includes prognostically different ACC subgroups. It highlights dominant IGF2 overexpression, recurrent TP53 and Wnt/beta-catenin pathway alterations, and suggests p53-driven and beta-catenin-driven aggressive subsets.11
  • PMID 22427816: In ACC cell models, SF-1 and its coregulator RNF31 influence steroidogenesis-related transcription and show evidence of crosstalk with TGFβ and Wnt/β-catenin signaling. The study also reports that an SF-1 gene-expression profile can distinguish malignant from benign adrenocortical tumors.40
  • PMID 22539591: High-resolution SNP profiling of pediatric adrenocortical tumors identified recurrent copy number and LOH events, including chromosome 17 and 11p15 alterations, and focal lesions involving oncogenes, tumor suppressors, and LINC00290. TP53-mutated tumors showed more genomic rearrangements than TP53-wild-type tumors, supporting distinct oncogenic pathways in childhood ACT.15
  • PMID 22691887: This review summarizes molecular mechanisms linked to adrenocortical tumorigenesis, emphasizing cAMP/PKA pathway abnormalities, Wnt and beta-catenin activation, and microRNA dysregulation. It notes that beta-catenin pathway mutations are frequent in adrenocortical carcinoma and discusses these pathways as potential therapeutic targets.64
  • PMID 23812285: In a cohort of 49 sporadic adult ACCs, AXIN2 exon 8 alterations were rare and AXIN1 coding mutations were not detected in tumors with nuclear beta-catenin staining. The recurrent AXIN2 c2013_2024del12 variant appeared to be a germline non-pathogenic polymorphism rather than a major driver of Wnt/beta-catenin pathway activation in ACC.46
  • PMID 24220673: This review frames ACC as a rare aggressive adrenal cortical malignancy in which dysregulated IGF, Wnt, and TP53 pathways emerged from hereditary-syndrome studies and later high-throughput profiling. Expression, microRNA, and methylation analyses identified molecular subgroups with distinct clinical behavior and prognostic value beyond traditional histologic and clinical methods.12
  • PMID 24712566: This study identifies deregulated sonic hedgehog signaling in adrenocortical tumors, with adult ACC showing increased PTCH1, SMO, GLI3, and SUFU expression versus normal adult cortex, while pediatric tumors show a contrasting downregulated pattern. In an ACC cell line, SMO inhibition reduced GLI3, SFRP1, and CTNNB1 expression, decreased beta-catenin staining, and impaired cell viability.41
  • PMID 24747642: Integrated genomic profiling identified recurrent ACC alterations in Wnt/beta-catenin, p53/Rb, and chromatin-remodeling pathways, including frequent ZNRF3 loss or mutation. The study also defined two molecular subgroups with opposite outcomes, linking poor-prognosis tumors to heavier mutational and methylation burden and better-prognosis tumors to distinct microRNA dysregulation.6
  • PMID 25255746: This review summarizes adrenal embryologic development and highlights molecular regulators of cortical specification and maintenance, including SF1, Wnt4, WT1, beta-catenin, DAX1, PBX1, and GATA factors. It notes that adrenal capsular stem or progenitor populations may contribute to adrenocortical neoplasia.4
  • PMID 25490274: Whole-exome sequencing of 41 ACCs identified recurrent TP53 and CTNNB1 mutations, focal TERT amplification, and homozygous deletion of the Wnt repressors ZNRF3 and KREMEN1. The findings emphasize Wnt-pathway dysregulation as a central molecular theme and suggest largely mutually exclusive genomic routes in ACC tumor development.23
  • PMID 25823656: This preclinical study implicates Wnt/beta-catenin signaling in ACC cell growth and aggressiveness. In H295R models, beta-catenin silencing reduced MAPK and Akt activation, increased CDK inhibitors and apoptosis, reversed epithelial-to-mesenchymal transition, and suppressed xenograft growth and invasion.13
  • PMID 25931348: This review summarizes ACC molecular features including monoclonal origin, frequent chromosomal gains and losses, IGF2 overexpression, WNT/beta-catenin activation, DNA hypermethylation, and dysregulated microRNAs. It also notes that distinct gene-expression clusters correlate with histologic grade and clinical outcome.65
  • PMID 26106367: This review summarizes ACC as a molecularly heterogeneous malignancy in which recurrent alterations involve IGF2, TP53, CTNNB1, and newly identified ZNRF3, highlighting dysregulation of the Wnt/beta-catenin pathway. It also notes that genomic profiling has expanded understanding of ACC pathogenesis and may inform future diagnostic, prognostic, and therapeutic development.66
  • PMID 26214578: Combined transcriptomic and cell-line analyses identified AFF3 as a direct Wnt/beta-catenin target in ACC. AFF3 promoted H295R cell proliferation, reduced apoptosis, and was associated with poorer overall survival, supporting a role for beta-catenin-driven transcription and RNA-splicing programs in ACC biology.25
  • PMID 26421305: In adrenocortical tumor cell models, POD-1/TCF21 overexpression reduced SHP expression through promoter E-box binding, with associated increases in LRH-1 and, in hepatocarcinoma cells, Cyclin E1. The study suggests distinct regulatory effects of POD-1 on SF-1 versus LRH-1-related pathways relevant to adrenal tumor biology.67
  • PMID 26963385: This study links global DNA methylation abnormalities in ACC to altered expression of genes involved in TP53, WNT, and IGF signaling, and reports silencing of the tumor suppressor MARCKS. It also describes overall hypomethylation in ACC versus normal adrenal tissue alongside region-specific hypermethylation patterns.68
  • PMID 27387247: This review summarizes core molecular drivers of ACC, highlighting frequent IGF2 overexpression, TP53 inactivation, and Wnt/beta-catenin pathway activation, with additional roles for PKA and SF-1 signaling. It also notes transcriptomic differences between adenomas and carcinomas and links some alterations to prognosis and inherited tumor syndromes.69
  • PMID 27624192: This study identifies PKA as a tumor-suppressive regulator of adrenal cortical biology that represses WNT4 and downstream WNT/β-catenin signaling, linking zonation control to malignant transformation. In ACC, lower PKA activity and higher WNT pathway activity were associated with poorer prognosis, supporting WNT–PKA interplay as a core disease mechanism.42
  • PMID 27940298: This review links adrenal cortex stem/progenitor biology to ACC molecular pathogenesis, highlighting recurrent dysregulation of Wnt/beta-catenin signaling through CTNNB1, ZNRF3, and APC alterations and discussing possible contributions of hedgehog pathway crosstalk. It also notes differences between adult and pediatric tumors in Wnt-pathway alterations.43
  • PMID 28114280: This study identifies RARRES2 as a CpG-hypermethylation–silenced tumor suppressor in ACC. RARRES2 overexpression reduced proliferation, invasion, and xenograft growth while promoting β-catenin phosphorylation and degradation, suppressing Wnt/β-catenin signaling, and decreasing p38 MAPK phosphorylation through an immune-independent mechanism.70
  • PMID 28476230: This review links ACC to developmental signaling abnormalities, highlighting recurrent alterations in IGF2/11p15, Wnt/beta-catenin pathway genes including CTNNB1 and ZNRF3, TP53, and PKA-pathway genes such as PRKAR1A. It also connects these drivers to hereditary syndromes and emerging targeted-treatment concepts.71
  • PMID 29028646: This review summarizes ACC molecular alterations identified through genomic and related profiling, highlighting recurrent Wnt/beta-catenin pathway lesions, cell-cycle dysregulation involving TP53 and RB1, chromatin remodeling changes, TERT amplification, and epigenetic and transcriptomic signatures linked to malignant differentiation and prognosis.37
  • PMID 29080966: This review summarizes integrated genomic analyses showing that ACC comprises molecularly distinct subgroups defined by transcriptomic, methylation, microRNA, copy-number, and driver-gene alterations, with these patterns correlating with tumor aggressiveness and survival. It highlights recurrent pathways and lesions including IGF2 upregulation, Wnt/beta-catenin-related changes, CpG island methylator phenotypes, and chromosomal instability features.7
  • PMID 29428231: This study identifies BCL9 overexpression in adrenocortical carcinoma relative to normal adrenal tissue and adenoma, supporting BCL9 as a possible alternative activator of Wnt/beta-catenin signaling. BCL9 silencing reduced clonogenic growth in SW-13 cells but not in beta-catenin-mutant NCI-H295R cells, suggesting context-dependent pathway dependence.52
  • PMID 29581542: Targeted genomic profiling of 62 adult ACCs showed marked molecular heterogeneity, histotype-specific alteration patterns, and genomic change over progression between matched primary and recurrent or metastatic samples. Alterations in the p53/Rb1 pathway were linked to higher Ki-67, advanced stage, aggressive disease status, and shorter disease-free survival.33
  • PMID 29773584: This review synthesizes cell-cycle dysregulation in ACC, highlighting recurrent alterations in the p53/Rb1 pathway, CDK4/CDK2, cyclin E, ATR, and topoisomerase 2. It also notes that aggressive molecular subgroups show higher expression of cell-cycle genes and worse outcomes, supporting biologic stratification and candidate therapeutic targets.34
  • PMID 29803258: This commentary summarizes evidence that BCL9, a nuclear co-factor in Wnt/beta-catenin signaling, is overexpressed in a subset of ACC compared with adenoma and normal adrenal tissue, and that BCL9 knockdown reduced colony formation in at least one ACC cell line. It frames BCL9 as a possible molecular driver while emphasizing unresolved questions about mechanism and timing of overexpression.72
  • PMID 29872083: This study characterizes recurrent Wnt/beta-catenin pathway alterations in ACC, including hotspot CTNNB1 mutations, ZNRF3 homozygous deletions, APC alterations, and novel interstitial CTNNB1 deletions that produce functionally active truncated beta-catenin. These mutually exclusive pathway events were associated with downstream target activation and worse overall survival.24
  • PMID 30072419: This review links ACC pathogenesis to dysregulated adrenal self-renewal and stem/progenitor cell biology, highlighting molecular pathways including SHH, Wnt/beta-catenin, SF1, DLK1, and SOAT1. It frames next-generation sequencing and molecular profiling as central to understanding tumorigenesis and future personalized strategies.39
  • PMID 30402590: This review synthesizes genomics data showing that ACC comprises distinct molecular subtypes with different clinical outcomes and recurrent alterations involving IGF2, Wnt signaling, cell cycle control, chromosomal instability, DNA methylation, immune biology, and steroidogenesis. It frames these programs as central to ACC pathogenesis and as potential therapeutic entry points.10
  • PMID 30477734: This in-silico TCGA analysis proposes an ACC-specific mutation signature comprising ZFPM1, LRIG1, CRIPAK, ZNF517, GARS, and DGKZ, linked to proliferation marker FAM72 and intersecting with WNT/beta-catenin and MAPK signaling. The study frames these genes as candidate oncogenic drivers and potential prognostic or therapeutic leads rather than established clinical biomarkers.48
  • PMID 30978697: This review synthesizes evidence that ACC commonly shows anti-apoptotic dysregulation, including altered caspases, death-receptor signaling, BCL2-family members, IAPs such as survivin, and TP53 pathway abnormalities. These changes are linked to treatment resistance, aggressive behavior, and potential future therapeutic targeting of apoptosis pathways.53
  • PMID 31085769: This study identifies a noncoding RNA regulatory axis in ACC in which underexpressed miR-497 represses MALAT1, while overexpressed MALAT1 competes for miR-497 binding to EIF4E. In H295R cells, miR-497 overexpression or MALAT1 silencing reduced proliferation and induced cell cycle arrest, supporting a tumorigenic role for the miR-497-MALAT1/EIF4E pathway.54
  • PMID 31147626: This review summarizes multi-omics evidence that ACC comprises three major molecular subgroups with distinct outcomes and highlights recurrent drivers in the p53-RB and WNT-beta-catenin pathways. It also notes steroidogenic differentiation as a biologically distinctive feature and potential therapeutic target.8
  • PMID 31363169: This study suggests that EZH2 acts mainly as a transcriptional activator in ACC through cooperation with E2F1, driving cell cycle and mitotic genes including RRM2, PTTG1, and PRC1. High expression of this EZH2-E2F1 program was associated with poorer survival and aggressive tumor features, with RRM2 emerging as a potential therapeutic target in cell models.35
  • PMID 31522749: This study found that ACC has a distinct long non-coding RNA expression profile compared with adenoma and normal adrenal cortex. LINC00271 was downregulated in ACC, associated with shorter survival, and linked to WNT signaling, cell-cycle, and chromosome-segregation pathways.73
  • PMID 31970420: This case report describes a de novo activating CTNNB1 variant associated with pediatric adrenocortical adenoma and functional evidence of increased WNT/beta-catenin signaling due to reduced beta-catenin phosphorylation and stabilization. It supports a role for germline WNT-pathway activation in adrenocortical neoplasia.74
  • PMID 32147772: This small human tissue study found altered circadian clock-gene expression in ACC, with increased CRY1 and PER1 and decreased BMAL1, RORa, and Rev-ERB relative to normal adrenal tissue, alongside differences from cortisol-secreting adenomas. The findings suggest peripheral clock dysregulation may be involved in adrenocortical tumorigenesis.75
  • PMID 32507359: This review frames ACC as genetically linked mainly to dysregulation of Wnt-beta-catenin and p53 signaling and to IGF2 overexpression, with frequent alterations involving TP53, ZNRF3, CTNNB1, and 11p15. It also places these findings in the context of inherited syndromes such as Li-Fraumeni and Beckwith-Wiedemann that helped identify ACC driver pathways.2
  • PMID 33287648: Using the H295R adrenocortical carcinoma cell line, CTNNB1 knockdown reduced beta-catenin, AXIN2, LEF1, and cyclin D1 expression, inhibited proliferation, and decreased Ang II-stimulated aldosterone secretion with reduced CYP11B2 but not CYP11B1. These findings support a functional role for Wnt/beta-catenin signaling in adrenocortical tumor cell growth and steroidogenic regulation.26
  • PMID 34440096: This review frames ACC as a malignant adrenal cortical tumor whose pathogenesis is linked to mutations in tumor suppressor genes, Wnt-beta-catenin signaling components, and chromatin remodeling factors, with altered transcription factor regulation and epigenomic interactions also implicated.76
  • PMID 35117470: This review summarizes recurrent molecular alterations in ACC, highlighting TP53 abnormalities, IGF2 overexpression, Wnt/beta-catenin pathway activation including CTNNB1 and ZNRF3 changes, SF1 overexpression, chromosomal instability, methylation changes, and miRNA dysregulation as key contributors to tumorigenesis and aggressive behavior.56
  • PMID 35123514: This study identifies CENPF overexpression in ACC as associated with higher tumor stage and worse overall survival, and links CENPF to G2/M cell-cycle regulation, CDK1 interaction, and p53-related signaling. In vitro knockdown data suggest CENPF promotes ACC cell proliferation and progression-related behavior.36
  • PMID 35189247: This review frames ACC as driven by recurrent alterations in pathways including Wnt/beta-catenin, p53/Rb, chromatin remodeling, and cAMP/PKA, and proposes links between driver genes such as ZNRF3, CTNNB1, TP53, and PRKAR1A and PKM2-mediated glycolytic reprogramming. It highlights ZNRF3 loss as a tumor-suppressor defect that may activate Wnt signaling, increase c-Myc, GLUT1, and PKM2 expression, and support ACC progression.77
  • PMID 35483882: Whole-genome and transcriptome profiling of seven metastatic ACCs identified recurrent CTNNB1 and TP53 alterations, widespread loss of heterozygosity, and additional changes involving DNA repair, cell-cycle, telomere-maintenance, and epigenetic-regulation genes. A subset showed homologous recombination deficiency signatures and recurrent KDM5A copy gain with high expression, supporting biologically distinct molecular subsets.78
  • PMID 35765893: This study identifies LINC01234 as an upregulated, pathological stage-associated lncRNA in ACC, with higher expression linked to shorter overall and disease-free survival. Functional experiments suggest LINC01234 promotes ACC cell-cycle progression and growth through a miR-140-3p/BRD4 regulatory axis.79
  • PMID 37473498: This review summarizes how dysregulated miRNAs in ACC may shape tumor pathogenesis by modulating signaling pathways, including Wnt/beta-catenin and p53-related networks, and links altered miRNA expression with survival. It frames miRNAs as regulators of proliferation, apoptosis, metastasis, metabolism, and treatment resistance in ACC biology.55
  • PMID 37857840: This review summarizes major molecular features of ACC, highlighting recurrent pathway alterations involving WNT-beta-catenin, TP53-RB-cell cycle, chromatin remodeling, telomere maintenance, PKA, and IGF signaling. Integrated multi-omic classifications and genomic instability patterns such as whole-genome doubling are presented as biologically informative and prognostically relevant.5
  • PMID 38155952: This reanalysis of H295R ACC genomic and knockdown datasets argues that NR5A1 overexpression and beta-catenin activation mainly drive malignancy through parallel, largely distinct transcriptional programs rather than a dominant cooperative chromatin interaction. Beta-catenin binding was enriched at canonical TCF/LEF motifs, and overlap between NR5A1- and beta-catenin-regulated gene sets was limited.44
  • PMID 38269250: This review summarizes evidence that aberrant Wnt/β-catenin signaling is a major driver of ACC progression, linking CTNNB1/APC alterations and nuclear β-catenin activity to proliferative transcriptional programs, more aggressive pathologic features, advanced stage, and worse survival. It also outlines related regulators including WNT ligands, DKK3/FOXO1, and BCL9 as biologically relevant nodes.30
  • PMID 40633793: This review summarizes how multi-omic profiling in ACC defines biologically and prognostically distinct subgroups characterized by chromosomal instability, TP53 and Wnt/beta-catenin pathway alterations, IGF2 overexpression, methylation phenotypes, and miRNA patterns. It emphasizes that integrated molecular classification may refine prognosis and reveal therapeutic vulnerabilities, although routine clinical implementation remains limited.16
  • PMID 25171651: A non-ACC cancer study reported that DAX-1 can bind β-catenin and suppress β-catenin-dependent transcription, reducing proliferation and cell-cycle progression. Its relevance to ACC is indirect but conceptually relevant because DAX-1 is an adrenal developmental regulator that could modulate Wnt output in lineage-specific contexts.80
  • PMID 6888561: A classic neuroblastoma study noted that amplified oncogene-related DNA abnormalities had also been observed in a mouse adrenocortical tumor model, but it did not directly investigate human ACC or the Wnt/TP53/cell-cycle axis. It is therefore only indirectly relevant, mainly as historical context for gene amplification in adrenal tumor biology.50
  • PMID 35363173: A 2022 pan-cancer multi-omics study reported that altered expression of CCAN/kinetochore genes was associated with poor survival in ACC and linked these genes to broader pathway, microenvironment, and drug-sensitivity signals across tumors.38 For ACC, the relevance is supportive but indirect, mainly extending the note’s discussion of mitotic and chromosomal-instability programs rather than establishing a validated ACC-specific mechanism.38

References

Footnotes

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