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Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
New role for ZFX in oncogenesis a
Andrew Arnold & Chen-Pang Soong
a
a
University of Connecticut School of Medicine; Farmington, CT USA Published online: 10 Dec 2014.
Click for updates To cite this article: Andrew Arnold & Chen-Pang Soong (2014) New role for ZFX in oncogenesis, Cell Cycle, 13:22, 3465-3466, DOI: 10.4161/15384101.2014.980693 To link to this article: http://dx.doi.org/10.4161/15384101.2014.980693
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
EDITORIALS: CELL CYCLE FEATURES Cell Cycle 13:22, 3465--3466; November 15, 2014; © 2014 Taylor & Francis Group, LLC
New role for ZFX in oncogenesis Andrew Arnold* and Chen-Pang Soong
Downloaded by [University of Sunderland] at 13:37 22 December 2014
University of Connecticut School of Medicine; Farmington, CT USA
Parathyroid adenomas are common endocrine neoplasms. They occur in both sexes and are especially frequent in postmenopausal women. The estimated prevalence is 1–4 cases per 1000 persons overall, and up to 20 cases per 1000 women between ages 55–75.1 True malignancies of the parathyroid glands do occur but they are rare, while typical parathyroid adenomas are benign, causing morbidity through their metabolic activity. The excessive secretion of parathyroid hormone (PTH) from these tumors can result in hypercalcemia, osteoporosis, fractures, and kidney stones. In addition, parathyroid adenomas also constitute an important model system whose study has already yielded fundamental insights. For example, one of modes in which the cyclin D1 gene (PRAD1, CCND1) was originally discovered, and the way cyclins were first directly linked to human neoplasia, was by its identification as a parathyroid adenoma oncogene activated by DNA rearrangement with the upstream regulatory region of the PTH gene.2 Of great interest are the stillunknown reasons why cyclin D1 activation in the parathyroid typically yields benign neoplasia, while the same oncogene drives malignant neoplasia in other cell types such as breast, B-lymphoid, and squamous cells. Interest in parathyroid adenomas as potentially holding keys to understanding, reversing, or preventing the development of malignant properties in tumors is heightened by evidence that typical parathyroid adenomas almost never evolve into malignant parathyroid carcinomas,2 contrasting with well-known models for such progression e.g., colorectal cancer.
Beyond cyclin D1, which is overexpressed in 20–40% of parathyroid adenomas, their molecular pathogenesis is only partially understood. Tumor suppressor gene MEN1 is also a fully established driver, subject to biallelic inactivation in 12–20%.2 Germline and somatic mutations of tumor suppressor HRPT2/ CDC73 are important in parathyroid carcinoma, but not in typical adenomas. Infrequent mutations in other candidate tumor genes, most notably EZH2 in 1% of adenomas,3 have been detected through whole-exome sequencing, but have not yet been shown to drive hyperparathyroidism in vivo. Of great interest from a cell cycle perspective is the special role of cyclindependent kinase inhibitor (CDKI) genes in parathyroid and other endocrine tumors. Germline mutation in the gene encoding p27kip1 causes multiple endocrine tumors in rodents and humans; variants in the p15, p18, and p21 genes are associated with similar human phenotypes, and are also found in sporadic parathyroid adenomas, suggesting that germline CDKI mutations may confer a low-penetrance predisposition to hyperparathyroidism.2 Such findings, including the identification of p27 mutations in small intestine neuroendocrine tumors4 and the dearth of such mutations in most human cancers, suggest that the endocrine cell context provides an enhanced susceptibility to tumorigenesis and selective advantage when a CDKI mutation occurs. Future studies of emerging cell cycle-targeting therapeutic agents such as CDK4/6 inhibitors, may find selected tumors of endocrine-related tissue types to be especially responsive. Given the need for a more comprehensive and integrated view of the molecular landscape responsible for parathyroid
tumors, the recent report in Oncoscience implicating transcription factor ZFX in parathyroid tumorigenesis is significant.5 Starting with a cohort of parathyroid adenomas subjected to whole exome sequencing, ZFX mutations were identified in nearly 5% of tumors (6/130), one of the more fruitful outcomes of unbiased sequencing approaches in this disease. ZFX, best known for its role in regulating stem cell renewal and differentiation, belongs to the Krueppel C2H2-type zinc finger protein family and contains 13 zinc finger subdomains. Striking in their specificity, each mutation affected one of just 2 consecutive, highly conserved, arginine residues located in the 13th zinc finger subdomain, converting positively charged R767 or R768 to glutamine, threonine, or leucine. Mutations were somatic in all cases when this could be determined, and their clonality, predicted damage to protein function, and absence from lists of normal variants, all suggest that they contributed a tumorigenic selective advantage and are not passenger alterations. Furthermore, the narrow spectrum of affected codons, and the presence in females of heterozygous mutation of this X-linked but non-X-inactivated gene, suggests that mutant ZFX is functioning as a direct-acting dominant oncogene, conferring a gain-of-function which might involve accentuation of normal transcriptional activities or a qualitative change in target genes.5 Regarding these questions of how ZFX mutation may drive neoplasia, other intriguing links between ZFX and tumorigenesis have been reported. In addition to its required role in self-renewal of haematopoietic and embryonic stem cells, ZFX contributes to MYC or NOTCH-induced leukemia induction in mice, and ZFX was
*Correspondence to: Andrew Arnold; Email: [email protected] Submitted: 09/24/2014; Accepted: 10/11/2014 http://dx.doi.org/10.4161/15384101.2014.980693 Comment to: Soong C, Arnold A. Recurrent ZFX mutations in human sporadic parathyroid adenomas. Oncoscience 2014; 1:360-6.
www.landesbioscience.com
Cell Cycle
3465
also identified as a crucial regulator of specific Hedgehog-induced malignancies in vivo.6 Whether these pathways are involved in parathyroid neoplasia merits further study, as does the question of how often similar mutations will be encountered in other types of human tumors – interestingly, an identical ZFX mutation References
trigger further studies of the biochemical and oncologic consequences of ZFX mutations in relevant experimental systems, and their outcome may well impact the future of personalized/precision medicine.
3. Cromer MK, et al. J Clin Endocrinol Metab 2012; 97: E1774-81; PMID:22740705; http://dx.doi.org/ 10.1210/jc.2012-1743 4. Francis JM, et al. Nat Genet 2013; 45:1483-6; PMID:24185511; http://dx.doi.org/10.1038/ng.2821 5. Soong C, Arnold A. Oncoscience 2014; 1:360-6
6. Palmer CJ, et al. Cancer Res 2014; 74:5914-24; PMID:25164012; http://dx.doi.org/10.1158/00085472.CAN-14-0834; pii:canres.0834.2014 7. Casimiro MC, et al. J Clin Invest 2012; 122:833-43; PMID:22307325; http://dx.doi.org/10.1172/JCI60256
Downloaded by [University of Sunderland] at 13:37 22 December 2014
1. Marcocci C, Cetani F. N Engl J Med 2011; 365:2389-97; P M I D : 2 21 8 79 8 6 ; h ttp: / / d x . d oi . o r g / 1 0 . 10 5 6 / NEJMcp1106636 2. Costa-Guda J, Arnold A. Mol Cell Endocrinol 2014; 386:46-54; PMID:24035866; http://dx.doi.org/ 10.1016/j.mce.2013.09.005
in an endometrial carcinoma, of previously uncertain significance in COSMIC, can now be viewed as probably pathogenetic. Finally, ZFX is a transcriptional target of cyclin D1,7 directly linking ZFX to an established parathyroid oncogenic pathway and to cell cycle regulation. Thus, the Oncoscience report will certainly
3466
Cell Cycle
Volume 13 Issue 22
Cell Cycle Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kccy20
New role for ZFX in oncogenesis a
Andrew Arnold & Chen-Pang Soong
a
a
University of Connecticut School of Medicine; Farmington, CT USA Published online: 10 Dec 2014.
Click for updates To cite this article: Andrew Arnold & Chen-Pang Soong (2014) New role for ZFX in oncogenesis, Cell Cycle, 13:22, 3465-3466, DOI: 10.4161/15384101.2014.980693 To link to this article: http://dx.doi.org/10.4161/15384101.2014.980693
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
EDITORIALS: CELL CYCLE FEATURES Cell Cycle 13:22, 3465--3466; November 15, 2014; © 2014 Taylor & Francis Group, LLC
New role for ZFX in oncogenesis Andrew Arnold* and Chen-Pang Soong
Downloaded by [University of Sunderland] at 13:37 22 December 2014
University of Connecticut School of Medicine; Farmington, CT USA
Parathyroid adenomas are common endocrine neoplasms. They occur in both sexes and are especially frequent in postmenopausal women. The estimated prevalence is 1–4 cases per 1000 persons overall, and up to 20 cases per 1000 women between ages 55–75.1 True malignancies of the parathyroid glands do occur but they are rare, while typical parathyroid adenomas are benign, causing morbidity through their metabolic activity. The excessive secretion of parathyroid hormone (PTH) from these tumors can result in hypercalcemia, osteoporosis, fractures, and kidney stones. In addition, parathyroid adenomas also constitute an important model system whose study has already yielded fundamental insights. For example, one of modes in which the cyclin D1 gene (PRAD1, CCND1) was originally discovered, and the way cyclins were first directly linked to human neoplasia, was by its identification as a parathyroid adenoma oncogene activated by DNA rearrangement with the upstream regulatory region of the PTH gene.2 Of great interest are the stillunknown reasons why cyclin D1 activation in the parathyroid typically yields benign neoplasia, while the same oncogene drives malignant neoplasia in other cell types such as breast, B-lymphoid, and squamous cells. Interest in parathyroid adenomas as potentially holding keys to understanding, reversing, or preventing the development of malignant properties in tumors is heightened by evidence that typical parathyroid adenomas almost never evolve into malignant parathyroid carcinomas,2 contrasting with well-known models for such progression e.g., colorectal cancer.
Beyond cyclin D1, which is overexpressed in 20–40% of parathyroid adenomas, their molecular pathogenesis is only partially understood. Tumor suppressor gene MEN1 is also a fully established driver, subject to biallelic inactivation in 12–20%.2 Germline and somatic mutations of tumor suppressor HRPT2/ CDC73 are important in parathyroid carcinoma, but not in typical adenomas. Infrequent mutations in other candidate tumor genes, most notably EZH2 in 1% of adenomas,3 have been detected through whole-exome sequencing, but have not yet been shown to drive hyperparathyroidism in vivo. Of great interest from a cell cycle perspective is the special role of cyclindependent kinase inhibitor (CDKI) genes in parathyroid and other endocrine tumors. Germline mutation in the gene encoding p27kip1 causes multiple endocrine tumors in rodents and humans; variants in the p15, p18, and p21 genes are associated with similar human phenotypes, and are also found in sporadic parathyroid adenomas, suggesting that germline CDKI mutations may confer a low-penetrance predisposition to hyperparathyroidism.2 Such findings, including the identification of p27 mutations in small intestine neuroendocrine tumors4 and the dearth of such mutations in most human cancers, suggest that the endocrine cell context provides an enhanced susceptibility to tumorigenesis and selective advantage when a CDKI mutation occurs. Future studies of emerging cell cycle-targeting therapeutic agents such as CDK4/6 inhibitors, may find selected tumors of endocrine-related tissue types to be especially responsive. Given the need for a more comprehensive and integrated view of the molecular landscape responsible for parathyroid
tumors, the recent report in Oncoscience implicating transcription factor ZFX in parathyroid tumorigenesis is significant.5 Starting with a cohort of parathyroid adenomas subjected to whole exome sequencing, ZFX mutations were identified in nearly 5% of tumors (6/130), one of the more fruitful outcomes of unbiased sequencing approaches in this disease. ZFX, best known for its role in regulating stem cell renewal and differentiation, belongs to the Krueppel C2H2-type zinc finger protein family and contains 13 zinc finger subdomains. Striking in their specificity, each mutation affected one of just 2 consecutive, highly conserved, arginine residues located in the 13th zinc finger subdomain, converting positively charged R767 or R768 to glutamine, threonine, or leucine. Mutations were somatic in all cases when this could be determined, and their clonality, predicted damage to protein function, and absence from lists of normal variants, all suggest that they contributed a tumorigenic selective advantage and are not passenger alterations. Furthermore, the narrow spectrum of affected codons, and the presence in females of heterozygous mutation of this X-linked but non-X-inactivated gene, suggests that mutant ZFX is functioning as a direct-acting dominant oncogene, conferring a gain-of-function which might involve accentuation of normal transcriptional activities or a qualitative change in target genes.5 Regarding these questions of how ZFX mutation may drive neoplasia, other intriguing links between ZFX and tumorigenesis have been reported. In addition to its required role in self-renewal of haematopoietic and embryonic stem cells, ZFX contributes to MYC or NOTCH-induced leukemia induction in mice, and ZFX was
*Correspondence to: Andrew Arnold; Email: [email protected] Submitted: 09/24/2014; Accepted: 10/11/2014 http://dx.doi.org/10.4161/15384101.2014.980693 Comment to: Soong C, Arnold A. Recurrent ZFX mutations in human sporadic parathyroid adenomas. Oncoscience 2014; 1:360-6.
www.landesbioscience.com
Cell Cycle
3465
also identified as a crucial regulator of specific Hedgehog-induced malignancies in vivo.6 Whether these pathways are involved in parathyroid neoplasia merits further study, as does the question of how often similar mutations will be encountered in other types of human tumors – interestingly, an identical ZFX mutation References
trigger further studies of the biochemical and oncologic consequences of ZFX mutations in relevant experimental systems, and their outcome may well impact the future of personalized/precision medicine.
3. Cromer MK, et al. J Clin Endocrinol Metab 2012; 97: E1774-81; PMID:22740705; http://dx.doi.org/ 10.1210/jc.2012-1743 4. Francis JM, et al. Nat Genet 2013; 45:1483-6; PMID:24185511; http://dx.doi.org/10.1038/ng.2821 5. Soong C, Arnold A. Oncoscience 2014; 1:360-6
6. Palmer CJ, et al. Cancer Res 2014; 74:5914-24; PMID:25164012; http://dx.doi.org/10.1158/00085472.CAN-14-0834; pii:canres.0834.2014 7. Casimiro MC, et al. J Clin Invest 2012; 122:833-43; PMID:22307325; http://dx.doi.org/10.1172/JCI60256
Downloaded by [University of Sunderland] at 13:37 22 December 2014
1. Marcocci C, Cetani F. N Engl J Med 2011; 365:2389-97; P M I D : 2 21 8 79 8 6 ; h ttp: / / d x . d oi . o r g / 1 0 . 10 5 6 / NEJMcp1106636 2. Costa-Guda J, Arnold A. Mol Cell Endocrinol 2014; 386:46-54; PMID:24035866; http://dx.doi.org/ 10.1016/j.mce.2013.09.005
in an endometrial carcinoma, of previously uncertain significance in COSMIC, can now be viewed as probably pathogenetic. Finally, ZFX is a transcriptional target of cyclin D1,7 directly linking ZFX to an established parathyroid oncogenic pathway and to cell cycle regulation. Thus, the Oncoscience report will certainly
3466
Cell Cycle
Volume 13 Issue 22
