Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors

Gara, Sudheer Kumar; Lack, Justin; Zhang, Lisa; Harris, E. L.; Cam, Margaret C.; Kebebew, Electron

doi:10.1038/s41467-018-06366-z

Cited by 62 publications

(46 citation statements)

References 53 publications

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“…This is considered a hallmark of cancer and provides selective advantage for the survival of tumour cells either in a dormant phase or as a rapidly progressing disease (Jin et al 2018). Tissue heterogeneity in melanoma is key to the survival and evolutionary versatility of the disease (Hwang et al 2018), and some clinical studies have shown that reduced heterogeneity is linked to a longer survival of the cancer patients (Gara et al 2018;Hanahan and Weinberg 2011;Szász et al 2017). To some extent, heterogeneity exists in all types of malignant tumours.…”

Section: Pathological Characterisation Of Melanomamentioning

confidence: 99%

Clinical protein science in translational medicine targeting malignant melanoma

et al. 2019

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Melanoma of the skin is the sixth most common type of cancer in Europe and accounts for 3.4% of all diagnosed cancers. More alarming is the degree of recurrence that occurs with approximately 20% of patients lethally relapsing following treatment. Malignant melanoma is a highly aggressive skin cancer and metastases rapidly extend to the regional lymph nodes (stage 3) and to distal organs (stage 4). Targeted oncotherapy is one of the standard treatment for progressive stage 4 melanoma, and BRAF inhibitors (e.g. vemurafenib, dabrafenib) combined with MEK inhibitor (e.g. trametinib) can effectively counter BRAFV600E-mutated melanomas. Compared to conventional chemotherapy, targeted BRAFV600E inhibition achieves a significantly higher response rate. After a period of cancer control, however, most responsive patients develop resistance to the therapy and lethal progression. The many underlying factors potentially causing resistance to BRAF inhibitors have been extensively studied. Nevertheless, the remaining unsolved clinical questions necessitate alternative research approaches to address the molecular mechanisms underlying metastatic and treatment-resistant melanoma. In broader terms, proteomics can address clinical questions far beyond the reach of genomics, by measuring, i.e. the relative abundance of protein products, post-translational modifications (PTMs), protein localisation, turnover, protein interactions and protein function. More specifically, proteomic analysis of body fluids and tissues in a given medical and clinical setting can aid in the identification of cancer biomarkers and novel therapeutic targets. Achieving this goal requires the development of a robust and reproducible clinical proteomic platform that encompasses automated biobanking of patient samples, tissue sectioning and histological examination, efficient protein extraction, enzymatic digestion, mass spectrometry-based quantitative protein analysis by label-free or labelling technologies and/or enrichment of peptides with specific PTMs. By combining data from, e.g. phosphoproteomics and acetylomics, the protein expression profiles of different melanoma stages can provide a solid framework for understanding the biology and progression of the disease. When complemented by proteogenomics, customised protein sequence databases generated from patient-specific genomic and transcriptomic data aid in interpreting clinical proteomic biomarker data to provide a deeper and more comprehensive molecular characterisation of cellular

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Section: Pathological Characterisation Of Melanomamentioning

confidence: 99%

Clinical protein science in translational medicine targeting malignant melanoma

et al. 2019

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“…This gene has been associated with myeloproliferative disorders, as shown by its fusions with platelet-derived growth factor receptor beta gene (PDGFRB) [33]. In addition, PDE4DIP variants are one of the most frequent in metastatic adrenocortical carcinomas in adults [34]. Of note, all four of our patients with an inactivating variant in PDE4DIP also harbor the hypomorphic widespread TP53 p.R337H founder allele [35][36][37].…”

Section: Discussionmentioning

confidence: 74%

Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors

Pinto

Faucz

Paza³

et al. 2020

Cancers

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Phosphodiesterases (PDEs) form a superfamily of enzymes that catalyze the hydrolysis of cyclic nucleotides adenosine 3′5′-cyclic monophosphate (cAMP) and guanosine 3′5′-cyclic monophosphate (cGMP) to their inactive 5′ monophosphates. cAMP plays a critical role as a second messenger in endocrine tissues, and activation of cAMP signaling has been reported in endocrine tumors. Germline variants in PDEs have been associated with benign cortisol-secreting adrenocortical adenomas and testicular germ cell cancer but not adrenocortical carcinoma. We performed whole genome sequencing (WGS) and whole exome sequencing (WES) of paired blood and tumor samples from 37 pediatric adrenocortical tumors (ACTs). Germline inactivating variants in PDEs were observed in 9 of 37 (24%) patients. Tumor DNA analysis revealed loss of heterozygosity, with maintenance of the mutated allele in all cases. Our results suggest that germline variants in PDEs and other regulators of the cAMP-signaling pathway may contribute to pediatric adrenocortical tumorigenesis, perhaps by cooperating with germline hypomorphic mutant TP53 alleles and uniparental disomy of chromosome 11p15 (Beckwith–Wiedemann syndrome).

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“…It is intriguing to note that a recent study of metastatic ACC tumours has identified an enrichment of driver mutations in RA pathway genes, possibly lending further support to the inactivation of this pathway being a crucial step in ACC progression. 56 In addition, alterations in the retinoic acid pathway have also been linked recently to benign adrenocortical tumours secreting aldosterone. 57 In conclusion, our results offer human genetic evidence for the importance of the druggable RA pathway in ACC onset and extend its relevance to progression of both paediatric and adult ACC.…”

Section: Discussionmentioning

confidence: 99%

A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence

et al. 2020

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BACKGROUND: Genome-wide association studies (GWASs) have enriched the fields of genomics and drug development. Adrenocortical carcinoma (ACC) is a rare cancer with a bimodal age distribution and inadequate treatment options. Paediatric ACC is frequently associated with TP53 mutations, with particularly high incidence in Southern Brazil due to the TP53 p.R337H (R337H) germline mutation. The heterogeneous risk among carriers suggests other genetic modifiers could exist. METHODS: We analysed clinical, genotype and gene expression data derived from paediatric ACC, R337H carriers, and adult ACC patients. We restricted our analyses to single nucleotide polymorphisms (SNPs) previously identified in GWASs to associate with disease or human traits. RESULTS: A SNP, rs971074, in the alcohol dehydrogenase 7 gene significantly and reproducibly associated with allelic differences in ACC age-of-onset in both cohorts. Patients homozygous for the minor allele were diagnosed up to 16 years earlier. This SNP resides in a gene involved in the retinoic acid (RA) pathway and patients with differing levels of RA pathway gene expression in their tumours associate with differential ACC progression. CONCLUSIONS: These results identify a novel genetic component to ACC development that resides in the retinoic acid pathway, thereby informing strategies to develop management, preventive and therapeutic treatments for ACC.

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Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors

Cited by 62 publications

References 53 publications

Clinical protein science in translational medicine targeting malignant melanoma

Clinical protein science in translational medicine targeting malignant melanoma

Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors

A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence

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