Prevalence of Germline TP53 Mutations in a Prospective Series of Unselected Patients with Adrenocortical Carcinoma
Divisions of Molecular Medicine and Genetics (V.M.R., J.N.E., J.M.L.) and Metabolism, Endocrinology, and Diabetes (T.E., G.D.H.), Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-5419 The Journal of Clinical Endocrinology and Metabolism
(Impact Factor: 6.21).
11/2012; 98(1). DOI: 10.1210/jc.2012-2198
Adrenocortical carcinoma (ACC) is a hallmark cancer in families with Li Fraumeni syndrome (LFS) caused by mutations in the TP53 gene. The prevalence of germline TP53 mutations in children diagnosed with ACC ranges from 50-97%. Although existing criteria advocate for TP53 testing in all patients with ACC regardless of age at diagnosis, the overall prevalence of germline mutations in patients diagnosed with ACC has not been well studied.
Patients and methods:
A total of 114 patients with confirmed ACC evaluated in the University of Michigan Endocrine Oncology Clinic were prospectively offered genetic counseling and TP53 genetic testing, regardless of age at diagnosis or family history. Ninety-four of the 114 patients met with a genetic counselor (82.5%), with 53 of 94 (56.4%) completing TP53 testing; 9.6% (nine of 94) declined testing. The remainder (32 of 94; 34%) expressed interest in testing but did not pursue it for various reasons.
Four of 53 patients in this prospective, unselected series were found to have a TP53 mutation (7.5%). The prevalence of mutations in those diagnosed over age 18 was 5.8% (three of 52). There were insufficient data to estimate the prevalence in those diagnosed under age 18. None of these patients met clinical diagnostic criteria for classic LFS. Three of the families met criteria for Li Fraumeni-like syndrome; one patient met no existing clinical criteria for LFS or Li Fraumeni-like syndrome. Three of the four patients with mutations were diagnosed with ACC after age 45.
Genetic counseling and germline testing for TP53 should be offered to all patients with ACC. Restriction on age at diagnosis or strength of the family history would fail to identify mutation carriers.
Available from: Andreas G Moraitis
- "The prevalence of germline TP53 mutations in apparently sporadic ACT patients varies according to the age group. While in adults the prevalence is low, between 3–6% according to two recent studies (Herrmann, Heinze et al. 2012, Raymond, Else et al. 2012), among children, this proportion is significantly higher. Data from the USA and Europe indicates that the prevalence of germline TP53 mutations in pediatric patients is ∼50–80% (Wagner, Portwine et al. 1994, Varley, McGown et al. 1999). "
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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 aiming 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.
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ABSTRACT: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with often unfavorable prognosis. Here we summarize the knowledge about diagnosis, epidemiology, pathophysiology and therapy of ACC. Over the recent years multidisciplinary clinics have formed and the first international treatment trials have been conducted. This review focuses on evidence gained from recent basic science and clinical research and provides perspectives from the experience of a large multidisciplinary clinic dedicated to the care of patients with ACC.
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ABSTRACT: Purpose of review:
Adrenocortical cancer (ACC) is a rare and often aggressive malignancy. The overall 5-year survival rate of ACC is less than 30% in part owing to advanced stage of the disease at diagnosis and limited efficiency of therapies when initial surgery is not curative. So far, studies with large cohorts of patients affected by ACC were lacking because of the rarity of the disease; however, recent international and multicenter collaborative studies provide new insights in the management of ACC.
This review summarizes recent findings in the genetic, hormonal evaluation, imaging, and therapies of ACC in adults. There is new promise for the use of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography and metomidate in initial diagnosis and follow-up. Limited studies support benefit of specific surgical approaches such as loco-regional lymph node dissection and metastasectomy in specific subgroups. New developments in the use of mitotane therapy and its drug interactions, on adjuvant radiotherapy and prospective data on combined chemotherapy, have appeared recently.
These recent findings will provide more evidence-based recommendations in the future to better assist clinicians in the management of patients with ACC. However, there is still an important need to understand the molecular mechanisms underlying this disease to design better therapeutic approaches.
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