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Published on: March 26, 2018
Molecular pathways of human adrenocortical carcinoma - translating cell signalling knowledge into diagnostic and
Paulina Szyszka, Ashley B Grossman, Salvador Diaz-Cano
1Department of Nuclear Medicine, Medical University of Gdansk, Gdansk, Poland; Department of Endocrinology and Medicine, King's College Hospital, London, United Kingdom; Guys Richard Dimbleby Department of Cancer Research, King's College London, London, United Kingdom. ddw@gumed.edu.pl.
Abstract:
Adrenocortical carcinoma is associated with a low cure rate and a high recurrence rate. The prognosis is poor, and at diagnosis 30-40% of cases are already metastatic. The current therapeutic options (surgical resection, followed by adjuvant mitotane treatment +/- chemotherapy) are limited, and the results remain unsatisfactory. Key molecular events that contribute to formation of adrenocortical cancer are IGF2 overexpression, TP53-inactivating mutations, and constitutive activation of the Wnt/b-catenin signalling pathway via activating mutations of the b-catenin gene. The underlying genetic causes of inherited tumour syndromes have provided insights into molecular pathogenesis. The increased occurrence of adrenocortical tumours in Li-Fraumeni and Beckwith-Wiedemann syndromes, and Carney complex, has highlighted the roles of specific susceptibility genes: TP53, IGF2, and PRKAR1A, respectively. Further studies have confirmed that these genes are also involved in sporadic tumour cases. Crucially, transcriptome-wide studies have determined the differences between malignant and benign adrenocortical tumours, providing potential diagnostic tools. In conclusion, enhancing our understanding of the molecular events of adrenocortical tumourigenesis, especially with regard to the signalling pathways that may be disrupted, will greatly contribute to improving a range of available diagnostic, prognostic, and treatment approaches. (Endokrynol Pol 2016; 67 (4): 427-440).
Insights
Adrenocortical carcinoma has poor outcomes and limited treatments. Understanding molecular changes like IGF2 overexpression and TP53 mutations is key to developing better diagnostic and therapeutic strategies for this cancer.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Adrenocortical carcinoma (ACC) presents a significant clinical challenge with low cure and high recurrence rates.
- Current therapeutic strategies, including surgery, mitotane, and chemotherapy, offer limited efficacy, especially in metastatic cases.
- Understanding the molecular underpinnings of ACC is crucial for improving patient outcomes.
Purpose of the Study:
- To review the key molecular events driving adrenocortical tumorigenesis.
- To highlight the role of genetic susceptibility in ACC development.
- To underscore the importance of molecular insights for diagnostic and therapeutic advancements.
Main Methods:
- Review of literature on adrenocortical carcinoma pathogenesis.
- Analysis of molecular events including gene mutations and signaling pathway activation.
- Examination of transcriptome-wide studies comparing malignant and benign tumors.
Main Results:
- Key molecular drivers identified include IGF2 overexpression, TP53 mutations, and Wnt/b-catenin pathway activation.
- Inherited tumor syndromes (Li-Fraumeni, Beckwith-Wiedemann, Carney complex) implicate TP53, IGF2, and PRKAR1A.
- Transcriptome-wide studies reveal molecular differences between malignant and benign adrenocortical tumors.
Conclusions:
- Enhanced understanding of adrenocortical tumorigenesis molecular events is vital.
- Focusing on disrupted signaling pathways can lead to improved diagnostic, prognostic, and treatment approaches.
- Further research into molecular pathogenesis promises to enhance ACC management.
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