Mutation of the Cell Cycle Regulator p27kip1 Drives Pseudohypoxic Pheochromocytoma Development

Mohr, Hermine; Ballke, Simone; Bechmann, Nicole; Gulde, Sebastian; Malekzadeh-Najafabadi, Jaber; Peitzsch, Mirko; Ntziachristos, Vasilis; Steiger, Katja; Wiedemann, Tobias; Pellegata, Natalia S.

doi:10.3390/cancers13010126

Cited by 10 publications

(11 citation statements)

References 51 publications

(39 reference statements)

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“…In addition, CDKN1B has been recognized as a potential driver mutation in the development of breast cancer and prostate cancer ( 31 ). Recent studies have also highlighted the predisposition of Cdkn1b-mutated rats in developing pheochromocytoma ( 32 ), although no cases have been reported in humans yet.…”

Section: Discussionmentioning

confidence: 99%

Case Report: New CDKN1B Mutation in Multiple Endocrine Neoplasia Type 4 and Brief Literature Review on Clinical Management

et al. 2022

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BackgroundThe fourth type of multiple endocrine neoplasia (MEN) is known as a rare variant of MEN presenting a MEN1-like phenotype and originating from a germline mutation in CDKN1B. However, due to the small number of cases documented in the literature, the peculiar clinical features of MEN4 are still largely unknown, and clear indications about the clinical management of these patients are currently lacking. In order to widen our knowledge on MEN4 and to better typify the clinical features of this syndrome, we present two more cases of subjects with MEN4, and through a review of the current literature, we provide some possible indications on these patients’ management.Case PresentationThe first report is about a man who was diagnosed with a metastatic ileal G2-NET at the age of 34. Genetic analysis revealed the mutation p.I119T (c.356T>C) of exon 1 of CDKN1B, a mutation already reported in the literature in association with early-onset pituitary adenomas. The second report is about a 76-year-old woman with a multifocal pancreatic G1-NET. Genetic analysis identified the CDKN1B mutation c.482C>G (p.S161C), described here for the first time in association with MEN4 and currently classified as a variant of uncertain significance. Both patients underwent biochemical and imaging screening for MEN1-related diseases without any pathological findings.ConclusionsAccording to the cases reported in the literature, hyperparathyroidism is the most common clinical feature of MEN4, followed by pituitary adenoma and neuroendocrine tumors. However, MEN4 appears to be a variant of MEN with milder clinical features and later onset. Therefore, these patients might need a different and personalized approach in clinical management and a peculiar screening and follow-up strategy.

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Section: Discussionmentioning

confidence: 99%

Case Report: New CDKN1B Mutation in Multiple Endocrine Neoplasia Type 4 and Brief Literature Review on Clinical Management

et al. 2022

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“…An age-dependent association between the CD4/CD8 ratio and frailty has been noted in patients with HIV, which are also prone to develop cachexia [ 16 ]; however, this seemed not to be the case in our mouse models of cancer cachexia. In addition, tumor vascularization and endothelial permeability are tightly linked with inflammation [ 35 ] and may influence circulating cachexia mediators, yet the expression of vascularization marker genes (Epas1, Tie2, Vegfr2, Pecam1 (CD31) [ 36 ] was not different between young and aged mice across all experiments (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Aging Aggravates Cachexia in Tumor-Bearing Mice

Geppert

Walth

Expósito

et al. 2021

Cancers

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Background: Cancer is primarily a disease of high age in humans, yet most mouse studies on cancer cachexia are conducted using young adolescent mice. Given that metabolism and muscle function change with age, we hypothesized that aging may affect cachexia progression in mouse models. Methods: We compare tumor and cachexia development in young and old mice of three different strains (C57BL/6J, C57BL/6N, BALB/c) and with two different tumor cell lines (Lewis Lung Cancer, Colon26). Tumor size, body and organ weights, fiber cross-sectional area, circulating cachexia biomarkers, and molecular markers of muscle atrophy and adipose tissue wasting are shown. We correlate inflammatory markers and body weight dependent on age in patients with cancer. Results: We note fundamental differences between mouse strains. Aging aggravates weight loss in LLC-injected C57BL/6J mice, drives it in C57BL/6N mice, and does not influence weight loss in C26-injected BALB/c mice. Glucose tolerance is unchanged in cachectic young and old mice. The stress marker GDF15 is elevated in cachectic BALB/c mice independent of age and increased in old C57BL/6N and J mice. Inflammatory markers correlate significantly with weight loss only in young mice and patients. Conclusions: Aging affects cachexia development and progression in mice in a strain-dependent manner and influences the inflammatory profile in both mice and patients. Age is an important factor to consider for future cachexia studies.

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“…One cluster of PCC related mutant genes is highly related to hypoxia pathway (18). These genes activate hypoxia inducible factor (HIF) and then transcribe several genes related to angiogenesis and cell growth.…”

Section: Discussionmentioning

confidence: 99%

COX4I2 is a novel biomarker of blood supply in adrenal tumors

Mao¹,

Ma²,

Zhuo³

et al. 2021

Transl Androl Urol

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Background: Previous study has been reported that COX4I2 expression level demonstrated a positive correlation with microvessel density in pheochromocytomas (PCC) samples, suggesting that the expression of COX4I2 maybe related to blood supply level in other adrenal tumors as well. The aim of this study is to clarify the correlation of COX4I2 expression and blood supply in adrenal tumors. Methods: A total of 84 patients were recruited, among which 46 was diagnosed as adrenocortical adenoma (ACA) and 38 was diagnosed as PCC. Contrast-enhanced CT values were used to evaluate the blood supply levels in those patients. The expression of mRNA was examined by quantitative real-time polymerase chain reaction (qPCR) and protein was detected by immunohistochemistry (IHC).Results: The COX4I2 expression level in PCC group is significantly higher than that in ACA group (P<0.01). The expression of angiogenesis-related genes EPAS1, VEGFA and KDR mRNA in PCC group is higher than that of ACA group (P<0.05). Correlation analysis shows COX4I2 expression level is correlated with CT values (P<0.001), intraoperative blood loss (P<0.05) and operation time (P<0.05), and the expression of COX4I2 mRNA is correlated with EPAS1, VEGFA and KDR mRNA (P<0.05). Conclusions:The results displayed a distinct expression level of COX4I2 between ACA and PCC, suggesting that COX4I2 is a novel biomarker of blood supply in adrenal tumors. This research also opens the possibility for further research on COX4I2 as a novel target for anti-tumor angiogenesis.

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Mutation of the Cell Cycle Regulator p27kip1 Drives Pseudohypoxic Pheochromocytoma Development

Cited by 10 publications

References 51 publications

Case Report: New CDKN1B Mutation in Multiple Endocrine Neoplasia Type 4 and Brief Literature Review on Clinical Management

Case Report: New CDKN1B Mutation in Multiple Endocrine Neoplasia Type 4 and Brief Literature Review on Clinical Management

Aging Aggravates Cachexia in Tumor-Bearing Mice

COX4I2 is a novel biomarker of blood supply in adrenal tumors

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