Review
Genetics and epigenetics of adrenocortical tumors

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Highlights

  • Abnormal PKA activation is present in most of cortisol-producing tumors.

  • Abnormal membrane depolarization leading to increased cytosolic calcium levels is present in the majority of APAs.

  • Although ACCs are usually sporadic, they can be a manifestation of rare cancer syndromes.

  • Subgroups of ACCs divided according to genetic and epigenetic markers have different prognosis.

  • Molecular-targeted therapies are expected to improve clinical responses in advanced ACCs.

Abstract

Adrenocortical tumors are common neoplasms. Most are benign, nonfunctional and clinically irrelevant. However, adrenocortical carcinoma is a rare disease with a dismal prognosis and no effective treatment apart from surgical resection. The molecular genetics of adrenocortical tumors remain poorly understood. For decades, molecular studies relied on a small number of samples and were directed to candidate-genes. This approach, based on the elucidation of the genetics of rare genetic syndromes in which adrenocortical tumors are a manifestation, has led to the discovery of major dysfunctional molecular pathways in adrenocortical tumors, such as the IGF pathway, the Wnt pathway and TP53. However, with the advent of high-throughput methodologies and the organization of international consortiums to obtain a larger number of samples and high-quality clinical data, this paradigm is rapidly changing. In the last decade, genome-wide expression profile studies, microRNA profiling and methylation profiling allowed the identification of subgroups of tumors with distinct genetic markers, molecular pathways activation patterns and clinical behavior. As a consequence, molecular classification of tumors has proven to be superior to traditional histological and clinical methods in prognosis prediction. In addition, this knowledge has also allowed the proposal of molecular-targeted approaches to provide better treatment options for advanced disease. This review aims to summarize the most relevant data on the rapidly evolving field of genetics of adrenal disorders.

Introduction

Adrenocortical tumors (ACT) are common neoplasms, the prevalence of which increases with age, reaching a peak of 6% after 60 years. Most are benign cortical adenomas (ACA) and some are associated with endocrine syndromes (hypercortisolism in Cushing’s syndrome, hyperandrogenism in virilizing syndrome or mineralocorticoid excess in Conn’s syndrome) (Grumbach et al., 2003, Arnaldi and Boscaro, 2012). On the other hand, their malignant counterparts, adrenocortical carcinomas (ACC), are rare neoplasms with an incidence of 0.5–2/million per year (Fassnacht and Allolio, 2009). ACC is usually a very aggressive disease, with a dismal prognosis, with a 5-year survival rate of 16–44% (Fassnacht and Allolio, 2009). Surgical resection is the treatment of choice and the only therapeutic approach that significantly increases survival. Once ACC is not completely resectable, the available therapeutic options (which include the adrenolytic drug mitotane, systemic chemotherapy, radiation therapy, and, more recently, molecular-targeted therapies) have a small impact on survival (Fassnacht and Allolio, 2009). The differential diagnosis between ACA and localized ACC can be challenging, considering that clinical, laboratory, radiological, and pathological features can overlap to some extent. The accurate distinction between ACA and ACC is very important, since treatment is radically different (Fassnacht and Allolio, 2009). In recent years, considerable advances toward understanding the pathogenesis of ACT have been made. Different strategies have enabled these achievements:

  • 1.

    Identification of genetic alterations in rare familial syndromes and evaluation of whether the same defects are present in sporadic tumors.

  • 2.

    Investigation of signaling pathways that were proved important in other tumors types.

  • 3.

    Employment of high-throughput techniques such as genome wide expression profiling, methylation profiling and microRNA profiling to interrogate novel signaling pathways.

  • 4.

    Studies with animal models with one or more genetic defects in known signaling pathways.

Here we discuss the most relevant genetic aspects of ACTs. This review summarizes our current understanding of molecular pathogenesis of ACTs.

Section snippets

Lessons from rare genetic syndromes

ACTs, both benign (ACA) and malignant (ACC), may occur sporadically or in the setting of a heritable genetic syndrome. ACTs and adrenocortical hyperplasias are commonly a feature of multiple neoplasia syndromes (Table 1). The elucidation of the genetic basis of these syndromes has contributed to the identification of key signaling pathways that are dysregulated in sporadic ACTs. Clinical and molecular aspects of these genetic syndromes and their relationship to sporadic ACTs will be briefly

Carney complex (CC; OMIM 160980)

CC is a multiple neoplasia syndrome that is inherited in an autosomal dominant pattern and is characterized by spotty skin pigmentation and several tumors, including skin tumors, myxomas, schwannomas, liver, pancreatic, breast, and endocrine neoplasms such as follicular thyroid cancer, pituitary adenomas/hyperplasia and primary pigmented nodular adrenocortical hyperplasia (PPNAD) (Carney et al., 1985, Rothenbuhler and Stratakis, 2010). Linkage analysis of affected families has associated the

Chromosomal and sub-chromosomal alterations

Histological findings of adrenocortical tumors like nuclear aberrations, including a high nuclear grade, high mitotic counts and bizarre mitotic figures were recognized as a striking feature of ACC. With the advent of cytogenetic techniques, these gross morphological observations could be further characterized. Karyotyping studies of ACCs demonstrated that ACCs present a large number of chromosomal aberrations, including segmental duplications, rearrangements and aberrant chromosomes.

Molecular pathways dysregulated in sporadic ACTs

Epidermal Growth Factor Receptor (EGFR): The EGFR is a tyrosine kinase-coupled receptor, in which overexpression and activating somatic mutations have been documented in multiple human cancers, such as lung, colon, and breast (Salomon et al., 1995). The downstream targets of EGFR include the Ras/Raf/Mek/Erk pathway, which is involved in the regulation of fundamental biological processes, such as cell fate, proliferation, survival, cell cycle control, differentiation, and motility (Fig. 5) (

Genome-wide expression profiles

Global gene expression studies aim to identify biomarkers that could provide diagnostic and prognostic utility in addition to the classic histologic analyses and hold the promise of new potential targets for therapy. ACAs and ACCs have distinct expression profiles (Giordano et al., 2003, Giordano et al., 2009, de Fraipont et al., 2005, de Reynies et al., 2009). de Fraipont et al. identified a cluster of genes that could correctly discriminate ACAs and ACCs. According to their results, high

DNA methylation

DNA methylation involves the addition of a methyl group to the cytosine pyrimidine ring or adenine purine ring, occurring typically at CpG dinucleotides. In a normal cell, it acts as a regulatory mechanism for proper gene expression. There is growing evidence to suggest that DNA methylation, in addition to genetic modification, may cause altered patterns of gene expression resulting in tumorigenesis (Das and Singal, 2004, Wright and Gilbertson, 2010). Earlier studies on DNA methylation in ACTs

Molecular mechanisms of tumorigenesis and somatic evolution in ACTs – evidence from clinical, molecular data and animal models

In organs such as breast, colon, and skin, the carcinogenesis process appears to initiate from benign precursor lesions. Such lesions progressively accumulate genetic defects, culminating in malignant transformation. This fact is well demonstrated in colon carcinogenesis, in which invasive carcinomas clearly arise from tubular adenomas. For the adrenal gland, it is still a matter of debate as to whether ACCs arise from precursor benign lesions, such as ACAs or hyperplasias, or whether they

Conclusion remarks

In conclusion, much has been learned about the genetics and molecular classification of adrenocortical tumors over the past decade. Many of the key genes and pathways have been elucidated and are the current focus of therapeutic intervention (Fig. 5). It is expected that pangenomic and other global analyses that will be done in the upcoming years, will advance our understanding of adrenocortical tumorigenesis to a higher level. We believe that, in the near future, molecular markers will guide

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