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Familial predisposition to adrenocortical tumors: Clinical and biological features and management strategies

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The incidence of adrenocortical tumors (ACTs) is increased in several familial cancer syndromes resulting from abnormalities in genes that encode transcription factors implicated in cell proliferation, differentiation, senescence, apoptosis, and genomic instability. These include P53, MEN1, APC, and PRKAR1A. Adenomas are the most common ACTs, but adrenocortical carcinomas occur rarely as well. The clinical manifestations of ACTs, which result from increased secretion of adrenocortical hormones, are similar in the familial and sporadic forms of the disease. However, their management may differ because of unique aspects of the constitutional syndromes. The analysis of gene expression profiles of ACTs in these constitutional syndromes have contributed to our understanding of adrenal tumorigenesis and revealed new molecular diagnostic and prognostic markers and candidate genes for targeted therapies. This chapter summarizes the clinical and biological features, pathogenesis, and management strategies for ACTs that develop in patients with familial cancer syndrome.

Introduction

Adrenocortical tumors (ACTs) are relatively common in clinical practice.1 Results from necropsy studies suggest that the average prevalence of ACTs is 2.3% (range, 1–8.7%).2 Consistent with these observations, a retrospective review of ACTs discovered incidentally during imaging evaluations for medical conditions not primarily associated with an adrenal pathology found a similar percentage (4.4%).3 Adrenocortical adenomas are the most common histopathologic diagnosis among these clinically silent adrenal masses (incidentalomas). Other histopathologic diagnoses include nodular hyperplasia, myelolipoma, lipoma, lymphoma, angiomyelolipoma, and adrenocortical carcinoma.4 Although most individuals who have ACTs do not suffer from other medical conditions, some tend to carry inherited gene mutations that predispose them to ACTs. These genetic abnormalities can cause a spectrum of clinical manifestations from endocrine syndromes to familial cancer syndromes.

Familial cancer syndromes are defined when multiple members of a family inherit gene mutations that predispose them to one or more types of cancer. In these families, adult-onset cancer develops at a younger age, and patients typically present with multiple primary sites of disease and/or bilateral involvement of paired organs.5 Familial cancer syndromes account for a relatively small percentage of all human cancers. For decades, clinicians suspected that certain tumors (i.e., those of the retina, breast, adrenal gland, and colon) had a genetic basis, because they showed Mendelian segregation in some families. More recently, extensive genome-wide linkage analysis led to the discovery of several specific germline mutations in tumor suppressor genes such as P53 that act according to Knudson’s “two hit” hypothesis (i.e., both alleles of the gene must be altered before cancer can arise)6 and explain familial cancer segregation. Remarkably, although persons carrying mutations in cancer-susceptibility genes have increased predisposition to cancer, most do not have other medical problems and lead normal productive lives including reproductive function.

Our increased understanding of the molecular pathways that trigger cancer and the development of novel methods that allow us to investigate those pathways and the function of cancer-susceptibility genes regulated by them has led to the discovery of a host of genes whose mutation could increase a person’s predisposition to cancer. Moreover, results from genotypic studies and cancer phenotypic association studies have revealed that some gene mutations and common genetic polymorphic variants might synergize to modulate cancer susceptibility. Thus, many tumors originally considered sporadic may also have an inherited basis. Finally, in constitutional syndromes such as Beckwith–Wiedemann syndrome (BWS), an increased susceptibility to ACTs has been also noted. In this chapter, we will describe the genetic and biologic features of ACTs and discuss their pathogenesis, management, and outcome and familial disorders associated with ACTs.

Section snippets

Epidemiology of ACTs in carriers of P53 mutations

In the late 1960s, Li et al. described four families with an autosomal-dominant pattern of several malignancies in the children and adults.5, 7 These families were classified as having Li–Fraumeni syndrome. Of the 44 cases of cancer that occurred among family members younger than 15 years, four (9%) were ACT.5 This frequency is much higher than that observed in the general population of persons younger than 15 years (0.3 cases per million), and ACTs account for less than 0.5% of all pediatric

Acknowledgements

This work was supported in part by grant CA-21765 from the National Institutes of Health (U.S. Department of Health and Human Services), by a Center of Excellence grant from the State of Tennessee, and by the American Lebanese Syrian Associated Charities (ALSAC). We thank Angela J. McArthur for expert scientific review of the manuscript.

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