PTTG1 overexpression in adrenocortical cancer is associated with poor survival and represents a potential therapeutic target

Demeure, Michael J.; Coan, Kathryn E.; Grant, Clive S.; Komorowski, Richard; Stephan, Elizabeth; Sinari, Shripad; Mount, David W.; Bussey, Kimberly J.

doi:10.1016/j.surg.2013.06.058

Cited by 61 publications

(59 citation statements)

References 25 publications

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“…Other factors which are reported to associate with poor prognosis in patients with ACC include overexpression of the pituitary tumor transforming gene 1 (PTTG) (Demeure et al 2013), low expression of the transforming growth factor b signaling mediator SMAD and diminished expression of GATA-6 (Parviainen et al 2013), and cyclin E overproduction (Tissier et al 2004).…”

Section: Prognostic and Predictive Markersmentioning

confidence: 99%

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Creemers¹,

Hofland²,

Korpershoek³

et al. 2015

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with the current gold standard being the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins are promising not only as it comes to identifying malignancy but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.

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Section: Prognostic and Predictive Markersmentioning

confidence: 99%

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Creemers¹,

Hofland²,

Korpershoek³

et al. 2015

Endocrine-Related Cancer

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“…Overexpression of PTTG1, encoding a securin, a negative regulator of TP53 was reported in 84% of ACC and appeared to be a marker of poor survival (Demeure et al 2013). Loss of the retinoblastoma protein pRb in immunochemistry, secondary to deleterious mutation or allelic loss was found in 27% of ACC, all these tumors being aggressive .…”

Section: Signaling Pathways Involved In Adrenal Malignant Carcinogenementioning

confidence: 99%

Genetics of tumors of the adrenal cortex

Bonnet-Serrano

Bertherat

2018

Endocrine-Related Cancer

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This review describes the molecular alterations observed in the various types of tumors of the adrenal cortex, excluding Conn adenomas, especially the alterations identified by genomic approaches these last five years. Two main forms of bilateral adrenocortical tumors can be distinguished according to size and aspect of the nodules: primary pigmented nodular adrenal disease (PPNAD), which can be sporadic or part of Carney complex and primary bilateral macro nodular adrenal hyperplasia (PBMAH). The bilateral nature of the tumors suggests the existence of an underlying genetic predisposition. PPNAD and Carney complex are mainly due to germline-inactivating mutations of PRKAR1A, coding for a regulatory subunit of PKA, whereas PBMAH genetic seems more complex. However, genome-wide approaches allowed the identification of a new tumor suppressor gene, ARMC5, whose germline alteration could be responsible for at least 25% of PBMAH cases. Unilateral adrenocortical tumors are more frequent, mostly adenomas. The Wnt/beta-catenin pathway can be activated in both benign and malignant tumors by CTNNB1 mutations and by ZNRF3 inactivation in adrenal cancer (ACC). Some other signaling pathways are more specific of the tumor dignity. Thus, somatic mutations of cAMP/PKA pathway genes, mainly PRKACA, coding for the catalytic alpha-subunit of PKA, are found in cortisol-secreting adenomas, whereas IGF-II overexpression and alterations of p53 signaling pathway are observed in ACC. Genomewide approaches including transcriptome, SNP, methylome and miRome analysis have identified new genetic and epigenetic alterations and the further clustering of ACC in subgroups associated with different prognosis, allowing the development of new prognosis markers.

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“…PTTG1 overexpression has been reported in a variety of endocrine-related tumors, particularly pituitary, thyroid, breast, ovarian and uterine tumors, as well as non-endocrine-related cancers involving the central nervous, pulmonary and gastrointestinal systems. PTTG1 levels were found to be correlated with tumor invasiveness (14) and PTTG1 has been identified as a key signature gene associated with tumor metastasis (10).…”

Section: Pttg1 Was Isolated From Rat Pituitary Tumor Cells In 1997 Anmentioning

confidence: 99%

High expression of pituitary tumor-transforming gene-1 predicts poor prognosis in clear cell renal cell carcinoma

Wei

Yang

et al. 2014

Molecular and Clinical Oncology

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Abstract. Pituitary tumor-transforming gene-1 (PTTG1) is a recently identified oncogene involved in the progression of malignant tumors; however, the expression level of PTTG1 in clear cell renal cell carcinoma (ccRCC) and its potential value as a novel prognostic marker for ccRCC remains unclear. In this study, PTTG1 mRNA and protein levels were assessed in 44 paired ccRCC tissues and adjacent normal tissues by quantitative polymerase chain reaction (qPCR) and immunohistochemistry, respectively. Further immunohistochemical analysis was implemented in 192 samples of ccRCC to evaluate the associations between PTTG1 levels and the clinical characteristics in ccRCC. Reverse transcription qPCR and immunohistochemical analysis demonstrated that the PTTG1 mRNA and protein levels were significantly higher in ccRCC compared to normal tissues. In addition, the PTTG1 protein level in 192 ccRCC samples was found to be significantly correlated with T stage, N classification, metastasis, recurrence and Fuhrman grade, whereas it was not associated with age and gender. Patients with low PTTG1 levels exhibited a better survival outcome compared to those with a higher PTTG1 level. PTTG1 expression and N stage were identified as independent prognostic factors for the overall survival of ccRCC patients. The results suggested that the overexpression of PTTG1 indicates a poor prognosis in ccRCC patients and, therefore, PTTG1 may serve as a novel prognostic marker for ccRCC. IntroductionRenal cell carcinoma (RCC) is one of the leading causes of urological cancer-related mortality and clear cell renal cell carcinoma (ccRCC) is the most common type of RCC, accounting for 82% of RCC cases (1). Early-stage ccRCC is usually asymptomatic and difficult to accurately diagnose; in addition, ccRCC is resistant to conventional chemotherapeutic drugs and the overall clinical outcome is poor (2). The treatment of advanced ccRCC remains a major challenge for clinicians and ccRCC is responsible for ~35% of RCC-related mortality cases (1). Thus, there is an urgent need for diagnostic and prognostic biomarkers in ccRCC. However, there are currently no biomarkers for ccRCC in routine clinical practice. Over the last few years, prognostic markers for ccRCC, such as senescence-associated protein p400 (3), glyoxalase-1 (4), transforming growth factor-β-activated kinase-1 (5) and serum miR-210 (6), have emerged; however, their large-scale clinical application is not feasible. Therefore, novel diagnostic and prognostic markers of ccRCC would be valuable in high-risk individuals and in those with existing disease.Pituitary tumor-transforming gene-1 (PTTG1) was first isolated from rat pituitary tumor cells in 1997 and was identified as an oncogene, as PTTG1 overexpression was found to induce cellular transformation in vitro and tumor formation in nude mice (7). As a human securin, PTTG1 is involved in the mitotic spindle checkpoint pathway and inhibits sister chromatid separation to ensure chromosomal stability (7,8). In contrast to its restricted expression...

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PTTG1 overexpression in adrenocortical cancer is associated with poor survival and represents a potential therapeutic target

Cited by 61 publications

References 25 publications

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Genetics of tumors of the adrenal cortex

High expression of pituitary tumor-transforming gene-1 predicts poor prognosis in clear cell renal cell carcinoma

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