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Faranoush M, Naseripour M, Faranoush P, Davoodi‐Moghaddam Z, Jahandideh A, Sadighnia N, Daneshjou D, Shams P, Sedaghat A, Mirshahi R, Ravanbod S, Nasirnejad F, Elahinia A, Bashash D. Delving Into Retinoblastoma Genetics: Discovery of Novel Mutations and Their Clinical Impact: Retrospective Cohort Study. Cancer Med 2025; 14:e70922. [PMID: 40317918 PMCID: PMC12046630 DOI: 10.1002/cam4.70922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 04/12/2025] [Accepted: 04/21/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND Retinoblastoma (Rb) is a rare intraocular malignancy that originates in the retina of children under 5 years of age. Approximately one-third of children diagnosed with retinoblastoma are associated with germline mutations in one of the RB1 alleles. In this study, we aim to identify RB1 mutations in retinoblastoma patients using Sanger sequencing in combination with multiplex ligation-dependent probe amplification (MLPA). METHOD The genomic DNA of 167 Rb patients was isolated from peripheral blood and their clinical information was extracted from medical records. The mutations in the RB1 gene were identified through PCR sequencing. Negative results from the PCR sequencing were further analyzed using MLPA reactions. RESULTS RB1 mutations were identified in 56 of the 167 (33.5%) patients. The common mutation types were frameshift mutations (n = 19), followed by nonsense (n = 20), splicing (n = 8), missense (n = 5), and whole exon deletion (n = 2). The overall survival rate was 98.2%, with an average follow-up duration of 59 months. Moreover, germline RB1 mutation's correlation with enucleation rates is less pronounced in unilateral cases (12.1%) compared to bilateral cases (65.5%). A total of 13 novel mutations have been identified, of which four are specifically associated with enucleation. CONCLUSION This study provides a comprehensive analysis of RB1 germline mutations in a group of cases with Rb, leading to the identification of 13 novel mutations in Rb patients at a referral center in Iran. We expect that our findings will yield valuable insights to inform the management and genetic counseling of Rb patients, as well as their relatives who are at a higher risk.
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Affiliation(s)
- Mohammad Faranoush
- Pediatric Growth and Development Research CenterInstitute of Endocrinology and Metabolism, Iran University of Medical SciencesTehranIran
| | - Masood Naseripour
- Eye Research CenterThe Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical SciencesTehranIran
| | - Pooya Faranoush
- Pediatric Growth and Development Research CenterInstitute of Endocrinology and Metabolism, Iran University of Medical SciencesTehranIran
- Iranian Hemophilia and Thrombophilia Association (MAHTA)TehranIran
| | - Zeinab Davoodi‐Moghaddam
- Department of Hematology and Blood BankingSchool of Allied Medical Sciences, Shahid Beheshti University of Medical SciencesTehranIran
| | - Alireza Jahandideh
- Department of Clinical ScienceFaculty of Specialized Veterinary Sciences, Science and Research Branch, Islamic Azad UniversityTehranIran
| | - Negin Sadighnia
- Pediatric Growth and Development Research CenterInstitute of Endocrinology and Metabolism, Iran University of Medical SciencesTehranIran
| | - Delbar Daneshjou
- Pediatric Growth and Development Research CenterInstitute of Endocrinology and Metabolism, Iran University of Medical SciencesTehranIran
| | - Parisa Shams
- Cell and Developmental Biology DepartmentFaculty of Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECRTehranIran
| | - Ahad Sedaghat
- Eye Research CenterThe Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical SciencesTehranIran
| | - Reza Mirshahi
- Eye Research CenterThe Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical SciencesTehranIran
| | - Shirin Ravanbod
- Iranian Hemophilia and Thrombophilia Association (MAHTA)TehranIran
| | | | - Ali Elahinia
- Pediatric Growth and Development Research CenterInstitute of Endocrinology and Metabolism, Iran University of Medical SciencesTehranIran
| | - Davood Bashash
- Department of Hematology and Blood BankingSchool of Allied Medical Sciences, Shahid Beheshti University of Medical SciencesTehranIran
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Nag A, Khetan V. Genetics of Retinoblastoma - An Update. Semin Ophthalmol 2025:1-9. [PMID: 40235228 DOI: 10.1080/08820538.2025.2492287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 03/27/2025] [Accepted: 04/07/2025] [Indexed: 04/17/2025]
Abstract
PURPOSE The purpose of this review article is to provide an exhaustive overview of the genetic and epigenetic changes involved in retinoblastoma (RB) tumorigenesis along with their real-world applications. METHODS We searched the Pubmed database using keywords: retinoblastoma, genetics, epigenetics, oncogenes, tumor suppressor genes and target genes. RESULTS RB oncogenesis is triggered by biallelic RB1 gene mutation but progression involves additional genetic and epigenetic events. Commonly seen genetic mutations include nonsense, small insertions/deletions and splice mutations. Additional changes include copy number alterations, single nucleotide polymorphisms and epigenetic alterations (dysregulation of microRNAs, differential methylations). These pathways have led to the identification of several potential target genes that can play a role in future in precision therapy. CONCLUSIONS Genetic testing, counseling and risk stratification are integral to the management of RB. The latest genetic advancements herald the dawn of a new era with potential therapeutic approaches to RB and improved treatment outcomes.
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Affiliation(s)
- Adwaita Nag
- Vitreoretina & Ocular Oncology, Susrut Eye Foundation & Research Centre, Kolkata, West Bengal, India
| | - Vikas Khetan
- Vitreoretina, Ocular Oncology and Ocular Genetics, Flaum Eye Institute, Rochester, NY, USA
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Simonini S. Regulation of cell cycle in plant gametes: when is the right time to divide? Development 2025; 152:dev204217. [PMID: 39831611 PMCID: PMC11829769 DOI: 10.1242/dev.204217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Cell division is a fundamental process shared across diverse life forms, from yeast to humans and plants. Multicellular organisms reproduce through the formation of specialized types of cells, the gametes, which at maturity enter a quiescent state that can last decades. At the point of fertilization, signalling lifts the quiescent state and triggers cell cycle reactivation. Studying how the cell cycle is regulated during plant gamete development and fertilization is challenging, and decades of research have provided valuable, yet sometimes contradictory, insights. This Review summarizes the current understanding of plant cell cycle regulation, gamete development, quiescence, and fertilization-triggered reactivation.
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Affiliation(s)
- Sara Simonini
- Department of Plant and Microbial Biology, University of Zurich, Zollikerstrasse 107, CH8008, Zurich, Switzerland
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Jun SY, Hong SM, Jang KT. Prognostic Value of Retinoblastoma in Small Intestinal Adenocarcinoma: A Multicenter Retrospective Study. J Korean Med Sci 2024; 39:e335. [PMID: 39742876 DOI: 10.3346/jkms.2024.39.e335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/19/2024] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND The retinoblastoma (RB) protein which is encoded by RB gene selectively provides a cell type-specific function in malignancies. In colorectal carcinoma, RB has been highly expressed and related cyclin/cyclin-dependent kinase 4/6 inhibitors have shown improved therapeutic effects in some patients. However, little is known about RB in small intestinal adenocarcinoma (SIAC). METHODS Here, we conducted a multi-institutional study of RB expression in 229 surgically resected SIACs to explore the clinicopathologic and prognostic implications and the relationship with microsatellite instability (MSI) status and KRAS mutations. RESULTS High RB expression (RBHigh) was more commonly observed in SIACs (76/229, 33%) than in normal small intestinal mucosa (27/188, 14%; P < 0.001). RBHigh was associated with nodular growth patterns (P = 0.028), the absence of lymphovascular (P = 0.001) and perineural invasion (P = 0.048), and a lower T category (P = 0.042) and indicated better overall survival (P = 0.003). In multivariate analysis, RBHigh (P = 0.049) was an independent prognostic predictor of better prognosis, along with younger patient age (P = 0.049), the absence of retroperitoneal seeding (P = 0.004), lower tumor stage (P < 0.001), and MSI (P = 0.005). The prognostic impact of RB expression was consistently observed regardless of MSI status and specifically persistent in SIACs with lower stages (stages I and II). CONCLUSION RBHigh was related to favorable clinicopathologic SIAC characteristics and indicated better patient prognosis. The prognostic predictability of RB was found in SIACs with lower stages, independent of MSI status. RB expression is a reliable and potent prognostic indicator for SIAC and may aid in selecting chemotherapy for patients.
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Affiliation(s)
- Sun-Young Jun
- Department of Pathology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kee-Taek Jang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Carley H, Kulkarni A. Reproductive decision-making in cancer susceptibility syndromes. Best Pract Res Clin Obstet Gynaecol 2024; 96:102527. [PMID: 38987108 DOI: 10.1016/j.bpobgyn.2024.102527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 06/12/2024] [Indexed: 07/12/2024]
Abstract
Cancer susceptibility syndromes confer an increased lifetime risk of cancer and occur due to germline likely-pathogenic or pathogenic variants in a cancer susceptibility gene. Clinical Genetics services advise patients of ways to manage their future cancer risks, often prefaced with uncertainties due to poor understandings of individualised risk. For individuals/couples whose future offspring are at risk of a cancer susceptibility syndrome, different options are available depending on their preferences and circumstances, including prenatal diagnosis and preimplantation genetic testing. This review provides an overview of the most common cancer susceptibility syndromes, available reproductive options and a genetic counselling framework recommended to support individuals/couples in their decision-making. We describe complexities of decision-making involving moderate penetrance and sex-specific variable penetrance genes and explore associated ethical issues arising in this complex area of medicine.
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Affiliation(s)
- Helena Carley
- Clinical Genetics, 7(th) Floor Borough Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK; Clinical Ethics, Law, & Society Group, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, Roosevelt Drive, Oxford, OX3 7BN, UK.
| | - Anjana Kulkarni
- Clinical Genetics, 7(th) Floor Borough Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK; Guy's & St Thomas NHS Foundation Trust, UK.
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Ravi J, Samart K, Zwolak J. Modeling the START transition in the budding yeast cell cycle. PLoS Comput Biol 2024; 20:e1012048. [PMID: 39093881 PMCID: PMC11324117 DOI: 10.1371/journal.pcbi.1012048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 08/14/2024] [Accepted: 04/02/2024] [Indexed: 08/04/2024] Open
Abstract
Budding yeast, Saccharomyces cerevisiae, is widely used as a model organism to study the genetics underlying eukaryotic cellular processes and growth critical to cancer development, such as cell division and cell cycle progression. The budding yeast cell cycle is also one of the best-studied dynamical systems owing to its thoroughly resolved genetics. However, the dynamics underlying the crucial cell cycle decision point called the START transition, at which the cell commits to a new round of DNA replication and cell division, are under-studied. The START machinery involves a central cyclin-dependent kinase; cyclins responsible for starting the transition, bud formation, and initiating DNA synthesis; and their transcriptional regulators. However, evidence has shown that the mechanism is more complicated than a simple irreversible transition switch. Activating a key transcription regulator SBF requires the phosphorylation of its inhibitor, Whi5, or an SBF/MBF monomeric component, Swi6, but not necessarily both. Also, the timing and mechanism of the inhibitor Whi5's nuclear export, while important, are not critical for the timing and execution of START. Therefore, there is a need for a consolidated model for the budding yeast START transition, reconciling regulatory and spatial dynamics. We built a detailed mathematical model (START-BYCC) for the START transition in the budding yeast cell cycle based on established molecular interactions and experimental phenotypes. START-BYCC recapitulates the underlying dynamics and correctly emulates key phenotypic traits of ~150 known START mutants, including regulation of size control, localization of inhibitor/transcription factor complexes, and the nutritional effects on size control. Such a detailed mechanistic understanding of the underlying dynamics gets us closer towards deconvoluting the aberrant cellular development in cancer.
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Affiliation(s)
- Janani Ravi
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Kewalin Samart
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
- Computational Bioscience program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Jason Zwolak
- InSilica Labs, Asheville, North Carolina, United States of America
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Berry JL, Pike S, Shah R, Reid MW, Peng CC, Wang Y, Yellapantula V, Biegel J, Kuhn P, Hicks J, Xu L. Aqueous Humor Liquid Biopsy as a Companion Diagnostic for Retinoblastoma: Implications for Diagnosis, Prognosis, and Therapeutic Options: Five Years of Progress. Am J Ophthalmol 2024; 263:188-205. [PMID: 38040321 PMCID: PMC11148850 DOI: 10.1016/j.ajo.2023.11.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 11/22/2023] [Accepted: 11/22/2023] [Indexed: 12/03/2023]
Abstract
PURPOSE To define the prospective use of the aqueous humor (AH) as a molecular diagnostic and prognostic liquid biopsy for retinoblastoma (RB). METHODS This is a prospective, observational study wherein an AH liquid biopsy is performed at diagnosis and longitudinally through therapy for patients with RB. Tumor-derived cell-free DNA is isolated and sequenced for single nucleotide variant analysis of the RB1 gene and detection of somatic copy number alterations (SCNAs). The SCNAs are used to determine tumor fraction (TFx). Specific SCNAs, including 6p gain and focal MycN gain, along with TFx, are prospectively correlated with intraocular tumor relapse, response to therapy, and globe salvage. RESULTS A total of 26 eyes of 21 patients were included with AH taken at diagnosis. Successful ocular salvage was achieved in 19 of 26 (73.1%) eyes. Mutational analysis of 26 AH samples identified 23 pathogenic RB1 variants and 2 focal RB1 deletions; variant allele fraction ranged from 30.5% to 100% (median 93.2%). At diagnosis, SCNAs were detectable in 17 of 26 (65.4%) AH samples. Eyes with 6p gain and/or focal MycN gain had significantly greater odds of poor therapeutic outcomes (odds ratio = 6.75, 95% CI = 1.06-42.84, P = .04). Higher AH TFx was observed in eyes with vitreal progression (TFx = 46.0% ± 40.4) than regression (22.0 ± 29.1; difference: -24.0; P = .049). CONCLUSIONS Establishing an AH liquid biopsy for RB is aimed at addressing (1) our inability to biopsy tumor tissue and (2) the lack of molecular biomarkers for intraocular prognosis. Current management decisions for RB are made based solely on clinical features without objective molecular testing. This prognostic study shows great promise for using AH as a companion diagnostic. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
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Affiliation(s)
- Jesse L Berry
- From the Vision Center, Children's Hospital Los Angeles (J.L.B., S.P., M.W.R., C.-C.P., L.X.); USC Roski Eye Institute, Keck School of Medicine of the University of Southern California (J.L.B., S.P., M.W.R., C.-C.P., L.X.); the Saban Research Institute, Children's Hospital Los Angeles (J.L.B., V.Y., J.B., L.X.); Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California (J.L.B., P.K., J.H.).
| | - Sarah Pike
- From the Vision Center, Children's Hospital Los Angeles (J.L.B., S.P., M.W.R., C.-C.P., L.X.); USC Roski Eye Institute, Keck School of Medicine of the University of Southern California (J.L.B., S.P., M.W.R., C.-C.P., L.X.)
| | - Rachana Shah
- Cancer and Blood Disease Institute, Children's Hospital Los Angeles (R.S.)
| | - Mark W Reid
- From the Vision Center, Children's Hospital Los Angeles (J.L.B., S.P., M.W.R., C.-C.P., L.X.); USC Roski Eye Institute, Keck School of Medicine of the University of Southern California (J.L.B., S.P., M.W.R., C.-C.P., L.X.)
| | - Chen-Ching Peng
- From the Vision Center, Children's Hospital Los Angeles (J.L.B., S.P., M.W.R., C.-C.P., L.X.); USC Roski Eye Institute, Keck School of Medicine of the University of Southern California (J.L.B., S.P., M.W.R., C.-C.P., L.X.)
| | - Yingfei Wang
- Cancer and Blood Disease Institute, Children's Hospital Los Angeles (R.S.); Department of Quantitative and Computational Biology, University of Southern California (Y.W.)
| | - Venkata Yellapantula
- the Saban Research Institute, Children's Hospital Los Angeles (J.L.B., V.Y., J.B., L.X.); Center for Personalized Medicine, Children's Hospital Los Angeles (V.Y., J.B.)
| | - Jaclyn Biegel
- the Saban Research Institute, Children's Hospital Los Angeles (J.L.B., V.Y., J.B., L.X.)
| | - Peter Kuhn
- Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California (J.L.B., P.K., J.H.); USC Michelson Center for Convergent Biosciences and Department of Biological Sciences (P.K., J.H.), Los Angeles, California, USA
| | - James Hicks
- Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California (J.L.B., P.K., J.H.); USC Michelson Center for Convergent Biosciences and Department of Biological Sciences (P.K., J.H.), Los Angeles, California, USA
| | - Liya Xu
- From the Vision Center, Children's Hospital Los Angeles (J.L.B., S.P., M.W.R., C.-C.P., L.X.); USC Roski Eye Institute, Keck School of Medicine of the University of Southern California (J.L.B., S.P., M.W.R., C.-C.P., L.X.); the Saban Research Institute, Children's Hospital Los Angeles (J.L.B., V.Y., J.B., L.X.)
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Cobrinik D. Retinoblastoma Origins and Destinations. N Engl J Med 2024; 390:1408-1419. [PMID: 38631004 DOI: 10.1056/nejmra1803083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/19/2024]
Affiliation(s)
- David Cobrinik
- From the Vision Center, Department of Surgery, and Saban Research Institute, Children's Hospital Los Angeles, and the Departments of Ophthalmology and Biochemistry and Molecular Medicine, Roski Eye Institute, and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California - both in Los Angeles
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Zhou BW, Wu QQ, Mauki DH, Wang X, Zhang SR, Yin TT, Chen FL, Li C, Liu YH, Wang GD, Zhang YP. Germline gene fusions across species reveal the chromosomal instability regions and cancer susceptibility. iScience 2023; 26:108431. [PMID: 38205119 PMCID: PMC10777377 DOI: 10.1016/j.isci.2023.108431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 06/24/2023] [Accepted: 11/08/2023] [Indexed: 01/12/2024] Open
Abstract
The canine transmissible venereal tumor (CTVT) is a clonal cell-mediated cancer with a long evolutionary history and extensive karyotype rearrangements in its genome. However, little is known about its genetic similarity to human tumors. Here, using multi-omics data we identified 11 germline gene fusions (GGFs) in CTVT, which showed higher genetic susceptibility than others. Additionally, we illustrate a mechanism of a complex gene fusion of three gene segments (HSD17B4-DMXL1-TNFAIP8) that we refer to "greedy fusion". Our findings also provided evidence that expressions of GGFs are downregulated during the tumor regressive phase, which is associated with DNA methylation level. This study presents a comprehensive landscape of gene fusions (GFs) in CTVT, which offers a valuable genetic resource for exploring potential genetic mechanisms underlying the development of cancers in both dogs and humans.
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Affiliation(s)
- Bo-Wen Zhou
- State Key Laboratory of Genetic Resources and Evolution & Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Qing-Qin Wu
- School of Ecology and Environmental Sciences, Yunnan University, Kunming, Yunnan 650500, China
| | - David H. Mauki
- Institute of Neurological Disease, National-Local Joint Engineering Research Center of Translational Medicine, State Key Lab of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xuan Wang
- State Key Laboratory of Genetic Resources and Evolution & Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Shu-Run Zhang
- State Key Laboratory of Genetic Resources and Evolution & Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
| | - Ting-Ting Yin
- State Key Laboratory of Genetic Resources and Evolution & Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
| | - Fang-Liang Chen
- Kunming Police Dog Base of the Ministry of Public Security, Kunming, Yunnan 650204, China
| | - Chao Li
- State Key Laboratory for Conservation and Utilization of Bio-Resource, Yunnan University, Kunming, Yunnan 650500, China
| | - Yan-Hu Liu
- State Key Laboratory of Genetic Resources and Evolution & Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
| | - Guo-Dong Wang
- State Key Laboratory of Genetic Resources and Evolution & Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Ya-Ping Zhang
- State Key Laboratory of Genetic Resources and Evolution & Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
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Marković L, Bukovac A, Varošanec AM, Šlaus N, Pećina-Šlaus N. Genetics in ophthalmology: molecular blueprints of retinoblastoma. Hum Genomics 2023; 17:82. [PMID: 37658463 PMCID: PMC10474694 DOI: 10.1186/s40246-023-00529-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 08/25/2023] [Indexed: 09/03/2023] Open
Abstract
This review presents current knowledge on the molecular biology of retinoblastoma (RB). Retinoblastoma is an intraocular tumor with hereditary and sporadic forms. 8,000 new cases of this ocular malignancy of the developing retina are diagnosed each year worldwide. The major gene responsible for retinoblastoma is RB1, and it harbors a large spectrum of pathogenic variants. Tumorigenesis begins with mutations that cause RB1 biallelic inactivation preventing the production of functional pRB proteins. Depending on the type of mutation the penetrance of RB is different. However, in small percent of tumors additional genes may be required, such as MYCN, BCOR and CREBBP. Additionally, epigenetic changes contribute to the progression of retinoblastoma as well. Besides its role in the cell cycle, pRB plays many additional roles, it regulates the nucleosome structure, participates in apoptosis, DNA replication, cellular senescence, differentiation, DNA repair and angiogenesis. Notably, pRB has an important role as a modulator of chromatin remodeling. In recent years high-throughput techniques are becoming essential for credible biomarker identification and patient management improvement. In spite of remarkable advances in retinoblastoma therapy, primarily in high-income countries, our understanding of retinoblastoma and its specific genetics still needs further clarification in order to predict the course of this disease and improve therapy. One such approach is the tumor free DNA that can be obtained from the anterior segment of the eye and be useful in diagnostics and prognostics.
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Affiliation(s)
- Leon Marković
- Department of Ophthalmology, Reference Center of the Ministry of Health of the Republic of Croatia for Pediatric Ophthalmology and Strabismus, University Hospital "Sveti Duh", Zagreb, Croatia
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Anja Bukovac
- Department of Biology, School of Medicine, University of Zagreb, Šalata 3, 10000, Zagreb, Croatia
- Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, 10000, Zagreb, Croatia
| | - Ana Maria Varošanec
- Department of Ophthalmology, Reference Center of the Ministry of Health of the Republic of Croatia for Pediatric Ophthalmology and Strabismus, University Hospital "Sveti Duh", Zagreb, Croatia
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Nika Šlaus
- Department of Biology, School of Medicine, University of Zagreb, Šalata 3, 10000, Zagreb, Croatia
| | - Nives Pećina-Šlaus
- Department of Biology, School of Medicine, University of Zagreb, Šalata 3, 10000, Zagreb, Croatia.
- Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, 10000, Zagreb, Croatia.
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Venkadakrishnan VB, Yamada Y, Weng K, Idahor O, Beltran H. Significance of RB Loss in Unlocking Phenotypic Plasticity in Advanced Cancers. Mol Cancer Res 2023; 21:497-510. [PMID: 37052520 PMCID: PMC10239360 DOI: 10.1158/1541-7786.mcr-23-0045] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/27/2023] [Accepted: 03/09/2023] [Indexed: 04/14/2023]
Abstract
Cancer cells can undergo plasticity in response to environmental stimuli or under selective therapeutic pressures that result in changes in phenotype. This complex phenomenon of phenotypic plasticity is now recognized as a hallmark of cancer. Lineage plasticity is often associated with loss of dependence on the original oncogenic driver and is facilitated, in part, by underlying genomic and epigenetic alterations. Understanding the molecular drivers of cancer plasticity is critical for the development of novel therapeutic strategies. The retinoblastoma gene RB1 (encoding RB) is the first tumor suppressor gene to be discovered and has a well-described role in cell-cycle regulation. RB is also involved in diverse cellular functions beyond cell cycle including differentiation. Here, we describe the emerging role of RB loss in unlocking cancer phenotypic plasticity and driving therapy resistance across cancer types. We highlight parallels in cancer with the noncanonical role of RB that is critical for normal development and lineage specification, and the downstream consequences of RB loss including epigenetic reprogramming and chromatin reorganization that can lead to changes in lineage program. Finally, we discuss potential therapeutic approaches geared toward RB loss cancers undergoing lineage reprogramming.
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Affiliation(s)
| | - Yasutaka Yamada
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Kenny Weng
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Boston College, Chestnut Hill, Massachusetts, USA
| | - Osasenaga Idahor
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Harvard University, Cambridge, Massachusetts, USA
| | - Himisha Beltran
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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12
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Ramos-Dávila EM, Garza-Garza LA, Villafuerte-de la Cruz R, Aguilar-Y-Mendez D, Morales-Garza HJ, Garza-Leon M, Ruiz-Lozano RE, Ancona-Lezama D. Novel RB1 germline mutation in a healthy man. Ophthalmic Genet 2022; 43:561-566. [PMID: 35410579 DOI: 10.1080/13816810.2022.2062390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND Retinoblastoma (Rb) most frequently presents as a unilateral sporadic disease up to 40% of cases, however, arise from a monoallelic germline pathogenic variant. Only 10% of the germline mutations are inherited, and high penetrance is seen in up to 90% of these cases. As an effort to optimize counseling and screening, mutations are classified according to inheritance patterns. However, RB1 spectrum is highly heterogeneous, and information for unaffected carriers remains scarce. MATERIALS AND METHODS The Mexican family of a 5-month-old patient diagnosed with Rb was studied. The family consisted of five individuals (father, mother, and three siblings). Genetic testing using a next-generation sequencing assay targeting RB1 with oligonucleotide baits designed to capture its exons and 20 bases flanking intronic sequences was performed in every family member. Clinical history and a complete ophthalmological examination (best-corrected visual acuity, slit-lamp biomicroscopy, macular optical coherence tomography, fundus autofluorescence, optical coherence tomography angiography, and electrophysiological studies) were performed in members testing positive to RB1 mutation. RESULTS The father and her five-month-old daughter tested positive for a non-synonymous RB1 mutation c.459del (p.Lys154Serfs*21). The girl presented with bilateral retinoblastoma, successfully treated with cryotherapy and intravenous chemotherapy. The father had no relevant findings on imaging studies or ophthalmologic evaluation. CONCLUSIONS This report describes a rare case of a novel low-penetrance RB1 germline mutation. Long-term follow-up of the father will include periodic evaluation of the eyes and orbits, and surveillance for systemic sarcoma and secondary malignancies. Implications for unaffected individuals need to be further studied.
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Affiliation(s)
- Eugenia M Ramos-Dávila
- Ocular Oncology Service, Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico
| | - Lucas A Garza-Garza
- Ocular Oncology Service, Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico
| | - Rocío Villafuerte-de la Cruz
- Ocular Oncology Service, Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico
| | - Dione Aguilar-Y-Mendez
- Ocular Oncology Service, Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico
| | - Héctor J Morales-Garza
- Ocular Oncology Service, Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico
| | - Manuel Garza-Leon
- Departamento de Ciencias Clínicas de la División de Ciencias de la Salud, Universidad de Monterrey, San Pedro Garza García, México
| | - Raul E Ruiz-Lozano
- Ocular Oncology Service, Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico
| | - David Ancona-Lezama
- Ocular Oncology Service, Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico
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13
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Wong KM, King DA, Schwartz EK, Herrera RE, Morrison AJ. Retinoblastoma protein regulates carcinogen susceptibility at heterochromatic cancer driver loci. Life Sci Alliance 2022; 5:e202101134. [PMID: 34983823 PMCID: PMC8739494 DOI: 10.26508/lsa.202101134] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 12/11/2022] Open
Abstract
Carcinogenic insult, such as UV light exposure, creates DNA lesions that evolve into mutations if left unrepaired. These resulting mutations can contribute to carcinogenesis and drive malignant phenotypes. Susceptibility to carcinogens (i.e., the propensity to form a carcinogen-induced DNA lesion) is regulated by both genetic and epigenetic factors. Importantly, carcinogen susceptibility is a critical contributor to cancer mutagenesis. It is known that mutations can be prevented by tumor suppressor regulation of DNA damage response pathways; however, their roles carcinogen susceptibility have not yet been reported. In this study, we reveal that the retinoblastoma (RB1) tumor suppressor regulates UV susceptibility across broad regions of the genome. In particular, centromere and telomere-proximal regions exhibit significant increases in UV lesion susceptibility when RB1 is deleted. Several cancer-related genes are located within genomic regions of increased susceptibility, including telomerase reverse transcriptase, TERT, thereby accelerating mutagenic potential in cancers with RB1 pathway alterations. These findings reveal novel genome stability mechanisms of a tumor suppressor and uncover new pathways to accumulate mutations during cancer evolution.
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Affiliation(s)
- Ka Man Wong
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Devin A King
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Erin K Schwartz
- Department of Biology, Stanford University, Stanford, CA, USA
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14
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Flores M, Goodrich DW. Retinoblastoma Protein Paralogs and Tumor Suppression. Front Genet 2022; 13:818719. [PMID: 35368709 PMCID: PMC8971665 DOI: 10.3389/fgene.2022.818719] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/25/2022] [Indexed: 01/01/2023] Open
Abstract
The retinoblastoma susceptibility gene (RB1) is the first tumor suppressor gene discovered and a prototype for understanding regulatory networks that function in opposition to oncogenic stimuli. More than 3 decades of research has firmly established a widespread and prominent role for RB1 in human cancer. Yet, this gene encodes but one of three structurally and functionally related proteins that comprise the pocket protein family. A central question in the field is whether the additional genes in this family, RBL1 and RBL2, are important tumor suppressor genes. If so, how does their tumor suppressor activity overlap or differ from RB1. Here we revisit these questions by reviewing relevant data from human cancer genome sequencing studies that have been rapidly accumulating in recent years as well as pertinent functional studies in genetically engineered mice. We conclude that RBL1 and RBL2 do have important tumor suppressor activity in some contexts, but RB1 remains the dominant tumor suppressor in the family. Given their similarities, we speculate on why RB1 tumor suppressor activity is unique.
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Affiliation(s)
| | - David W. Goodrich
- Roswell Park Comprehensive Cancer Center, Department of Pharmacology and Therapeutics, Buffalo, NY, United States
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15
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Leite Rocha D, Ashton-Prolla P, Rosset C. Reviewing the occurrence of large genomic rearrangements in patients with inherited cancer predisposing syndromes: importance of a comprehensive molecular diagnosis. Expert Rev Mol Diagn 2022; 22:319-346. [PMID: 35234551 DOI: 10.1080/14737159.2022.2049247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Hereditary cancer predisposition syndromes are caused by germline pathogenic or likely pathogenic variants in cancer predisposition genes (CPG). The majority of pathogenic variants in CPGs are point mutations, but large gene rearrangements (LGRs) are present in several CPGs. LGRs can be much more difficult to characterize and perhaps they may have been neglected in molecular diagnoses. AREAS COVERED We aimed to evaluate the frequencies of germline LGRs in studies conducted in different populations worldwide through a qualitative systematic review based on an online literature research in PubMed. Two reviewers independently extracted data from published studies between 2009 and 2020. In total, 126 studies from 37 countries and 5 continents were included in the analysis. The number of studies in different continents ranged from 3 to 48 and for several countries there was an absolute lack of information. Asia and Europe represented most of the studies, and LGR frequencies varied from 3.04 to 15.06% in different continents. MLPA was one of the methods of choice in most studies (93%). EXPERT OPINION The LGR frequencies found in this review reinforce the need for comprehensive molecular testing regardless of the population of origin and should be considered by genetic counseling providers.
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Affiliation(s)
- Débora Leite Rocha
- Laboratório de Medicina Genômica, Serviço de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos, 2350, CEP: 90035-930, Porto Alegre, Rio Grande do Sul, Brazil
| | - Patrícia Ashton-Prolla
- Laboratório de Medicina Genômica, Serviço de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos, 2350, CEP: 90035-930, Porto Alegre, Rio Grande do Sul, Brazil.,Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil. Av. Bento Gonçalves, 9500 - Prédio 43312 M, CEP: 91501-970, Caixa Postal 1505, Porto Alegre, Rio Grande do Sul, Brazil.,Serviço de Genética Médica, HCPA, Rio Grande do Sul, Brazil. Rua Ramiro Barcelos, 2350, CEP: 90035-930, Porto Alegre, Rio Grande do Sul, Brazil
| | - Clévia Rosset
- Laboratório de Medicina Genômica, Serviço de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos, 2350, CEP: 90035-930, Porto Alegre, Rio Grande do Sul, Brazil
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16
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Jiang Y, Yam JC, Chu WK. Poly ADP Ribose Polymerase Inhibitor Olaparib Targeting Microhomology End Joining in Retinoblastoma Protein Defective Cancer: Analysis of the Retinoblastoma Cell-Killing Effects by Olaparib after Inducing Double-Strand Breaks. Int J Mol Sci 2021; 22:10687. [PMID: 34639028 PMCID: PMC8508856 DOI: 10.3390/ijms221910687] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/23/2021] [Accepted: 09/28/2021] [Indexed: 11/16/2022] Open
Abstract
Retinoblastoma is the most common intraocular cancer in childhood. Loss of function in both copies of the RB1 gene is the causal mutation of retinoblastoma. Current treatment for retinoblastoma includes the use of chemotherapeutic agents, such as the DNA damaging agent etoposide, which is a topoisomerase II poison that mainly generates DNA double-strand breaks (DSBs) and genome instability. Unfaithful repairing of DSBs could lead to secondary cancers and serious side effects. Previously, we found that RB knocked-down mammalian cells depend on a highly mutagenic pathway, the micro-homology mediated end joining (MMEJ) pathway, to repair DSBs. Poly ADP ribose polymerase 1 (PARP1) is a major protein in promoting the MMEJ pathway. In this study, we explored the effects of olaparib, a PARP inhibitor, in killing retinoblastoma cells. Retinoblastoma cell line Y79 and primary retinoblastoma cells expressed the cone-rod homeobox protein (CRX), a photoreceptor-specific marker. No detectable RB expression was found in these cells. The co-treatment of olaparib and etoposide led to enhanced cell death in both the Y79 cells and the primary retinoblastoma cells. Our results demonstrated the killing effects in retinoblastoma cells by PARP inhibitor olaparib after inducing DNA double-strand breaks. The use of olaparib in combination with etoposide could improve the cell-killing effects. Thus, lower dosages of etoposide can be used to treat retinoblastoma, which would potentially lead to a lower level of DSBs and a relatively more stable genome.
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Affiliation(s)
- Yuning Jiang
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China; (Y.J.); (J.C.Y.)
- Department of Radiation Oncology, University of Virginia, Charlottesville, VA 22908, USA
| | - Jason C. Yam
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China; (Y.J.); (J.C.Y.)
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Wai Kit Chu
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China; (Y.J.); (J.C.Y.)
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong 999077, China
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17
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Antonarakis SE. History of the methodology of disease gene identification. Am J Med Genet A 2021; 185:3266-3275. [PMID: 34159713 PMCID: PMC8596769 DOI: 10.1002/ajmg.a.62400] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 11/06/2022]
Abstract
The past 45 years have witnessed a triumph in the discovery of genes and genetic variation that cause Mendelian disorders due to high impact variants. Important discoveries and organized projects have provided the necessary tools and infrastructure for the identification of gene defects leading to thousands of monogenic phenotypes. This endeavor can be divided in three phases in which different laboratory strategies were employed for the discovery of disease-related genes: (i) the biochemical phase, (ii) the genetic linkage followed by positional cloning phase, and (iii) the sequence identification phase. However, much more work is needed to identify all the high impact genomic variation that substantially contributes to the phenotypic variation.
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Affiliation(s)
- Stylianos E Antonarakis
- University of Geneva Medical School, Geneva, Switzerland.,Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland
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18
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Martínez-Sánchez M, Hernandez-Monge J, Rangel M, Olivares-Illana V. Retinoblastoma: from discovery to clinical management. FEBS J 2021; 289:4371-4382. [PMID: 34042282 DOI: 10.1111/febs.16035] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/13/2021] [Accepted: 05/24/2021] [Indexed: 01/02/2023]
Abstract
The retinoblastoma gene (RB1) was the first tumour suppressor cloned; the role of its protein product (RB) as the principal driver of the G1 checkpoint in cell cycle control has been extensively studied. However, many other RB functions are continuously reported. Its role in senescence, DNA repair and apoptosis, among others, is indications of the significance of RB in a vast network of cellular interactions, explaining why RB loss or its malfunction is one of the leading causes of a large number of paediatric and adult cancers. RB was first reported in retinoblastoma, a common intraocular malignancy in the paediatric population worldwide. Currently, its diagnosis is clinical, and in nondeveloped countries, where the incidence is higher, it is performed in advanced stages of the disease, compromising the integrity of the eye and the patient's life. Even though new treatments are being continuously developed, enucleation is still a major choice due to the late disease stage diagnosis and treatments costs. Research into biomarkers is our best option to improve the chances of good results in the treatment and hopes of patients' good quality of life. Here, we recapitulated the history of the disease and the first treatments to put the advances in its clinical management into perspective. We also review the different functions of the protein and the progress in the search for biomarkers. It is clear that there is still a long way to go, but we should offer these children and their families a better way to deal with the disease with the community's effort.
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Affiliation(s)
- Mayra Martínez-Sánchez
- Laboratorio de Interacciones Biomoleculares y Cancer, Instituto de Física, Universidad Autónoma de San Luis Potosí, Mexico
| | - Jesús Hernandez-Monge
- Catedra CONACyT - Laboratorio de Biomarcadores Moleculares, Instituto de Física, Universidad Autónoma de San Luis Potosí, Mexico
| | - Martha Rangel
- Departamento de Oftalmología. Hospital Central "Ignacio Morones Prieto", San Luis Potosí, Mexico
| | - Vanesa Olivares-Illana
- Laboratorio de Interacciones Biomoleculares y Cancer, Instituto de Física, Universidad Autónoma de San Luis Potosí, Mexico
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19
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Cao D, Jia Z, Wu Y, Su T, Zhao D, Wu M, Tsukamoto T, Oshima M, Jiang J, Cao X. Demethylation of the RB1 promoter concomitant with reactivation of TET2 and TET3 impairs gastric carcinogenesis in K19-Wnt1/C2mE transgenic mice. Life Sci 2020; 263:118580. [PMID: 33058920 DOI: 10.1016/j.lfs.2020.118580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 09/24/2020] [Accepted: 10/03/2020] [Indexed: 02/07/2023]
Abstract
Aberrant methylation of promoter CpG islands (CGIs) can inactivate the expression of many tumor suppressor genes and play an important role in the carcinogenesis of gastric cancer. The tumor suppressor gene RB1, which encodes a cell cycle regulator, is hypermethylated and downregulated in multiple kinds of cancer. Activation of RB1 expression through DNA demethylation is a potential strategy for the treatment of gastric cancer. Herein, we found that the methylation status of the RB1 promoter was negatively related to the development of gastric tumors, while its expression was positively correlated with TET2 and TET3 expression. Further reactivation of RB1 expression by curcumin could inhibit gastric cell viability and carcinogenesis both in vitro and in vivo. Molecular docking and other studies confirmed that curcumin could bind to and upregulate the expression of TET2 and TET3 with hydrogen bonds and arene-H bonds, suggesting that demethylation of RB1 was attributed to reactivation of the demethylation enzymes TET2 and TET3 after curcumin treatment. Thus, our findings reveal a promising therapeutic strategy for gastric cancer prevention and treatment through RB1 demethylation and reactivation.
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Affiliation(s)
- Donghui Cao
- Division of Clinical Research, The First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Zhifang Jia
- Division of Clinical Research, The First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Yanhua Wu
- Division of Clinical Research, The First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Tongrong Su
- Department of Gastric and Colorectal Surgery, First Hospital of Jilin University, Changchun 130021, China
| | - Dan Zhao
- Division of Clinical Research, The First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Menghui Wu
- Department of Gastric and Colorectal Surgery, First Hospital of Jilin University, Changchun 130021, China
| | - Tetsuya Tsukamoto
- Department of Diagnostic Pathology I, School of Medicine, Fujita Health University, Toyoake 470-1192, Japan
| | - Masanobu Oshima
- Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan
| | - Jing Jiang
- Division of Clinical Research, The First Hospital of Jilin University, Changchun 130021, Jilin, China.
| | - Xueyuan Cao
- Department of Gastric and Colorectal Surgery, First Hospital of Jilin University, Changchun 130021, China.
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20
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Pruteanu DP, Olteanu DE, Cosnarovici R, Mihut E, Nagy V. Genetic predisposition in pediatric oncology. Med Pharm Rep 2020; 93:323-334. [PMID: 33225257 PMCID: PMC7664724 DOI: 10.15386/mpr-1576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 03/10/2020] [Accepted: 07/25/2020] [Indexed: 11/23/2022] Open
Abstract
Identifying patients with a genetic predisposition for developing malignant tumors has a significant impact on both the patient and family. Recognition of genetic predisposition, before diagnosing a malignant pathology, may lead to early diagnosis of a neoplasia. Recognition of a genetic predisposition syndrome after the diagnosis of neoplasia can result in a change of treatment plan, a specific follow-up of adverse treatment effects and, of course, a long-term follow-up focusing on the early detection of a second neoplasia. Responsible for genetic syndromes that predispose individuals to malignant pathology are germline mutations. These mutations are present in all cells of conception, they can be inherited or can occur de novo. Several mechanisms of inheritance are described: Mendelian autosomal dominant, Mendelian autosomal recessive, X-linked patterns, constitutional chromosomal abnormality and non-Mendelian inheritance. In the following review we will present the most important genetic syndromes in pediatric oncology.
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Affiliation(s)
- Doina Paula Pruteanu
- Department of Pediatric Oncology, "Prof. Dr. Ion Chiricuta" Oncology Institute, Cluj-Napoca, Romania.,Department of Radiation Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Diana Elena Olteanu
- Department of Pediatric Oncology, "Prof. Dr. Ion Chiricuta" Oncology Institute, Cluj-Napoca, Romania
| | - Rodica Cosnarovici
- Department of Pediatric Oncology, "Prof. Dr. Ion Chiricuta" Oncology Institute, Cluj-Napoca, Romania
| | - Emilia Mihut
- Department of Pediatric Oncology, "Prof. Dr. Ion Chiricuta" Oncology Institute, Cluj-Napoca, Romania
| | - Viorica Nagy
- Department of Pediatric Oncology, "Prof. Dr. Ion Chiricuta" Oncology Institute, Cluj-Napoca, Romania.,Department of Radiation Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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21
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Lyu J, Yang EJ, Zhang B, Wu C, Pardeshi L, Shi C, Mou PK, Liu Y, Tan K, Shim JS. Synthetic lethality of RB1 and aurora A is driven by stathmin-mediated disruption of microtubule dynamics. Nat Commun 2020; 11:5105. [PMID: 33037191 PMCID: PMC7547687 DOI: 10.1038/s41467-020-18872-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 09/16/2020] [Indexed: 11/13/2022] Open
Abstract
RB1 mutational inactivation is a cancer driver in various types of cancer including lung cancer, making it an important target for therapeutic exploitation. We performed chemical and genetic vulnerability screens in RB1-isogenic lung cancer pair and herein report that aurora kinase A (AURKA) inhibition is synthetic lethal in RB1-deficient lung cancer. Mechanistically, RB1-/- cells show unbalanced microtubule dynamics through E2F-mediated upregulation of the microtubule destabilizer stathmin and are hypersensitive to agents targeting microtubule stability. Inhibition of AURKA activity activates stathmin function via reduced phosphorylation and facilitates microtubule destabilization in RB1-/- cells, heavily impacting the bipolar spindle formation and inducing mitotic cell death selectively in RB1-/- cells. This study shows that stathmin-mediated disruption of microtubule dynamics is critical to induce synthetic lethality in RB1-deficient cancer and suggests that upstream factors regulating microtubule dynamics, such as AURKA, can be potential therapeutic targets in RB1-deficient cancer.
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Affiliation(s)
- Junfang Lyu
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Eun Ju Yang
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Baoyuan Zhang
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Changjie Wu
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Lakhansing Pardeshi
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Changxiang Shi
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Pui Kei Mou
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Yifan Liu
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Kaeling Tan
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China
| | - Joong Sup Shim
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China.
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22
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Desvoyes B, Gutierrez C. Roles of plant retinoblastoma protein: cell cycle and beyond. EMBO J 2020; 39:e105802. [PMID: 32865261 PMCID: PMC7527812 DOI: 10.15252/embj.2020105802] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/16/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022] Open
Abstract
The human retinoblastoma (RB1) protein is a tumor suppressor that negatively regulates cell cycle progression through its interaction with members of the E2F/DP family of transcription factors. However, RB-related (RBR) proteins are an early acquisition during eukaryote evolution present in plant lineages, including unicellular algae, ancient plants (ferns, lycophytes, liverworts, mosses), gymnosperms, and angiosperms. The main RBR protein domains and interactions with E2Fs are conserved in all eukaryotes and not only regulate the G1/S transition but also the G2/M transition, as part of DREAM complexes. RBR proteins are also important for asymmetric cell division, stem cell maintenance, and the DNA damage response (DDR). RBR proteins play crucial roles at every developmental phase transition, in association with chromatin factors, as well as during the reproductive phase during female and male gametes production and embryo development. Here, we review the processes where plant RBR proteins play a role and discuss possible avenues of research to obtain a full picture of the multifunctional roles of RBR for plant life.
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23
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Baker SJ, Vogelstein B. p53: a tumor suppressor hiding in plain sight. J Mol Cell Biol 2020; 11:536-538. [PMID: 31276589 PMCID: PMC6736432 DOI: 10.1093/jmcb/mjz068] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022] Open
Affiliation(s)
- Suzanne J Baker
- St Jude Children's Research Hospital, Department of Developmental Neurobiology, 262 Danny Thomas Place, Memphis, TN 38105, USA
| | - Bert Vogelstein
- Ludwig Center & Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, 1650 Orleans Street St, Baltimore, MD 21205, USA
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24
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Lan X, Xu W, Tang X, Ye H, Song X, Lin L, Ren X, Yu G, Zhang H, Wu S. Spectrum of RB1 Germline Mutations and Clinical Features in Unrelated Chinese Patients With Retinoblastoma. Front Genet 2020; 11:142. [PMID: 32218800 PMCID: PMC7080181 DOI: 10.3389/fgene.2020.00142] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 02/06/2020] [Indexed: 11/13/2022] Open
Abstract
Retinoblastoma (Rb) is a primary intraocular malignant tumor that occurs primarily in children, and results from loss-of-function mutations in the RB transcriptional corepressor 1 (RB1) gene. Genetic testing forms the basis of genetic counseling for affected families, as well as for clinical management of this disease. The aim of this study was to identify germline RB1 mutations and correlate the identified mutations with the clinical features of Rb patients. Genomic DNA was isolated from peripheral blood of 180 unrelated Rb patients and their parents (118 unilaterally and 62 bilaterally affected probands). Mutations in the RB1 gene, including the promoter region and exons 1-27 with flanking intronic sequences, were identified by Sanger sequencing. The samples with negative sequencing results were further subjected to methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to detect gross deletions or duplications. Sixty-three distinct mutations were identified in 75 of the 180 (41.7%) probands. Of the 75 patients carrying RB1 mutations, 56 developed bilateral Rb, while 19 developed unilateral Rb. The total detection rates for bilateral and unilateral Rb were 90.3% (56/62) and 16.1% (19/118), respectively. Among the 75 patients, the spectrum of mutation types comprised 29.3% (22/75) nonsense mutations, 22.7% (17/75) splicing mutations, 17.3% (13/75) small insertions/deletions, 16.0% (12/75) large deletions/duplications, and 13.3% (10/75) missense mutations, while only 1% (1/75) of the mutations were in the promoter region of the RB1 gene. Age at diagnosis was significantly different (p < 0.01) between patients with positive and negative test results for germline RB1 mutations. A c.2359C > T mutation (p.R787X) was identified in identical twins, but one child was affected bilaterally and the other unilaterally. Of the five patients with deletion of the entire RB1 gene, the deletion of two patients was inherited from unaffected parents. In conclusion, in this study, we provide a comprehensive spectrum of RB1 germline mutations in Chinese Rb patients, and describe the correlations among RB1 mutations, age at diagnosis, and laterality; moreover, we report that the clinical features of individuals carrying an identical mutation in the RB1 gene were highly variable, indicating that the pathogenesis of Rb is more complicated than currently believed.
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Affiliation(s)
- Xiaoping Lan
- Molecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Wuhen Xu
- Molecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaojun Tang
- Molecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Haiyun Ye
- Department of Ophthalmology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaozhen Song
- Molecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Longlong Lin
- Department of Neurology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiang Ren
- Department of Radiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Guangjun Yu
- Molecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hong Zhang
- Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Shengnan Wu
- Molecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
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25
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Kattner P, Strobel H, Khoshnevis N, Grunert M, Bartholomae S, Pruss M, Fitzel R, Halatsch ME, Schilberg K, Siegelin MD, Peraud A, Karpel-Massler G, Westhoff MA, Debatin KM. Compare and contrast: pediatric cancer versus adult malignancies. Cancer Metastasis Rev 2020; 38:673-682. [PMID: 31832830 DOI: 10.1007/s10555-019-09836-y] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Cancer is a leading cause of death in both adults and children, but in terms of absolute numbers, pediatric cancer is a relatively rare disease. The rarity of pediatric cancer is consistent with our current understanding of how adult malignancies form, emphasizing the view of cancer as a genetic disease caused by the accumulation and selection of unrepaired mutations over time. However, considering those children who develop cancer merely as stochastically "unlucky" does not fully explain the underlying aetiology, which is distinct from that observed in adults. Here, we discuss the differences in cancer genetics, distribution, and microenvironment between adult and pediatric cancers and argue that pediatric tumours need to be seen as a distinct subset with their own distinct therapeutic challenges. While in adults, the benefit of any treatment should outweigh mostly short-term complications, potential long-term effects have a much stronger impact in children. In addition, clinical trials must cope with low participant numbers when evaluating novel treatment strategies, which need to address the specific requirements of children.
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Affiliation(s)
- Patricia Kattner
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstrasse 24, 89075, Ulm, Germany
| | - Hannah Strobel
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstrasse 24, 89075, Ulm, Germany
| | - Nika Khoshnevis
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstrasse 24, 89075, Ulm, Germany
| | - Michael Grunert
- Department of Radiology, German Armed Forces Hospital of Ulm, Ulm, Germany
| | - Stephan Bartholomae
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstrasse 24, 89075, Ulm, Germany
| | - Maximilian Pruss
- Department of Neurosurgery, University Medical Center Ulm, Ulm, Germany
| | - Rahel Fitzel
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstrasse 24, 89075, Ulm, Germany
| | | | | | - Markus D Siegelin
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Aurelia Peraud
- Pediatric Neurosurgery Section, Department of Neurosurgery, University Medical Center Ulm, Ulm, Germany
| | | | - Mike-Andrew Westhoff
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstrasse 24, 89075, Ulm, Germany.
| | - Klaus-Michael Debatin
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstrasse 24, 89075, Ulm, Germany
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26
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Abstract
The transition between proliferating and quiescent states must be carefully regulated to ensure that cells divide to create the cells an organism needs only at the appropriate time and place. Cyclin-dependent kinases (CDKs) are critical for both transitioning cells from one cell cycle state to the next, and for regulating whether cells are proliferating or quiescent. CDKs are regulated by association with cognate cyclins, activating and inhibitory phosphorylation events, and proteins that bind to them and inhibit their activity. The substrates of these kinases, including the retinoblastoma protein, enforce the changes in cell cycle status. Single cell analysis has clarified that competition among factors that activate and inhibit CDK activity leads to the cell's decision to enter the cell cycle, a decision the cell makes before S phase. Signaling pathways that control the activity of CDKs regulate the transition between quiescence and proliferation in stem cells, including stem cells that generate muscle and neurons. © 2020 American Physiological Society. Compr Physiol 10:317-344, 2020.
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Affiliation(s)
- Hilary A Coller
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California, USA.,Department of Biological Chemistry, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California, USA.,Molecular Biology Institute, University of California, Los Angeles, California, USA
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27
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Gudiseva HV, Berry JL, Polski A, Tummina SJ, O’Brien JM. Next-Generation Technologies and Strategies for the Management of Retinoblastoma. Genes (Basel) 2019; 10:E1032. [PMID: 31835688 PMCID: PMC6947430 DOI: 10.3390/genes10121032] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 11/26/2019] [Accepted: 12/09/2019] [Indexed: 12/27/2022] Open
Abstract
Retinoblastoma (RB) is an inherited retinal disorder (IRD) caused by the mutation in the RB1 gene or, rarely, by alterations in the MYCN gene. In recent years, new treatment advances have increased ocular and visual preservation in the developed world. The management of RB has improved significantly in recent decades, from the use of external beam radiation to recently, more localized treatments. Determining the underlying genetic cause of RB is critical for timely management decisions. The advent of next-generation sequencing technologies have assisted in understanding the molecular pathology of RB. Liquid biopsy of the aqueous humor has also had significant potential implications for tumor management. Currently, patients' genotypic information, along with RB phenotypic presentation, are considered carefully when making treatment decisions aimed at globe preservation. Advances in molecular testing that improve our understanding of the molecular pathology of RB, together with multiple directed treatment options, are critical for developing precision medicine strategies to treat this disease.
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Affiliation(s)
- Harini V. Gudiseva
- Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA;
| | - Jesse L. Berry
- The Vision Center at Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (J.L.B.); (A.P.)
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Ashley Polski
- The Vision Center at Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (J.L.B.); (A.P.)
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Santa J. Tummina
- Office of the Director, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Joan M. O’Brien
- Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA;
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28
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Berry JL, Polski A, Cavenee WK, Dryja TP, Murphree AL, Gallie BL. The RB1 Story: Characterization and Cloning of the First Tumor Suppressor Gene. Genes (Basel) 2019; 10:genes10110879. [PMID: 31683923 PMCID: PMC6895859 DOI: 10.3390/genes10110879] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 10/24/2019] [Accepted: 10/30/2019] [Indexed: 12/26/2022] Open
Abstract
The RB1 gene is the first described human tumor suppressor gene and plays an integral role in the development of retinoblastoma, a pediatric malignancy of the eye. Since its discovery, the stepwise characterization and cloning of RB1 have laid the foundation for numerous advances in the understanding of tumor suppressor genes, retinoblastoma tumorigenesis, and inheritance. Knowledge of RB1 led to a paradigm shift in the field of cancer genetics, including widespread acceptance of the concept of tumor suppressor genes, and has provided crucial diagnostic and prognostic information through genetic testing for patients affected by retinoblastoma. This article reviews the long history of RB1 gene research, characterization, and cloning, and also discusses recent advances in retinoblastoma genetics that have grown out of this foundational work.
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Affiliation(s)
- Jesse L Berry
- USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
- The Vision Center at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
| | - Ashley Polski
- USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
- The Vision Center at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
| | - Webster K Cavenee
- Ludwig Institute for Cancer Research, University of California, San Diego, CA 92093, USA.
- Department of Medicine, UCSD School of Medicine, San Diego, CA 92093, USA.
- Moores Cancer Center, UCSD School of Medicine, San Diego, CA 92093, USA.
| | - Thaddeus P Dryja
- Cogan Eye Pathology Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.
| | - A Linn Murphree
- USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
- The Vision Center at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
| | - Brenda L Gallie
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5T 3A9, Canada.
- Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, ON M5T 3A9, Canada.
- Departments of Molecular Genetics and Medical Biophysics, University of Toronto, Toronto, ON M5T 3A9, Canada.
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29
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Blond F, Léveillard T. Functional Genomics of the Retina to Elucidate its Construction and Deconstruction. Int J Mol Sci 2019; 20:E4922. [PMID: 31590277 PMCID: PMC6801968 DOI: 10.3390/ijms20194922] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 10/01/2019] [Indexed: 12/20/2022] Open
Abstract
The retina is the light sensitive part of the eye and nervous tissue that have been used extensively to characterize the function of the central nervous system. The retina has a central position both in fundamental biology and in the physiopathology of neurodegenerative diseases. We address the contribution of functional genomics to the understanding of retinal biology by reviewing key events in their historical perspective as an introduction to major findings that were obtained through the study of the retina using genomics, transcriptomics and proteomics. We illustrate our purpose by showing that most of the genes of interest for retinal development and those involved in inherited retinal degenerations have a restricted expression to the retina and most particularly to photoreceptors cells. We show that the exponential growth of data generated by functional genomics is a future challenge not only in terms of storage but also in terms of accessibility to the scientific community of retinal biologists in the future. Finally, we emphasize on novel perspectives that emerge from the development of redox-proteomics, the new frontier in retinal biology.
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Affiliation(s)
- Frédéric Blond
- Department of Genetics, Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France.
| | - Thierry Léveillard
- Department of Genetics, Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France.
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30
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Munier FL, Beck-Popovic M, Chantada GL, Cobrinik D, Kivelä TT, Lohmann D, Maeder P, Moll AC, Carcaboso AM, Moulin A, Schaiquevich P, Bergin C, Dyson PJ, Houghton S, Puccinelli F, Vial Y, Gaillard MC, Stathopoulos C. Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. "Alive, with good vision and no comorbidity". Prog Retin Eye Res 2019; 73:100764. [PMID: 31173880 DOI: 10.1016/j.preteyeres.2019.05.005] [Citation(s) in RCA: 134] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 05/25/2019] [Accepted: 05/29/2019] [Indexed: 12/21/2022]
Abstract
Retinoblastoma is lethal by metastasis if left untreated, so the primary goal of therapy is to preserve life, with ocular survival, visual preservation and quality of life as secondary aims. Historically, enucleation was the first successful therapeutic approach to decrease mortality, followed over 100 years ago by the first eye salvage attempts with radiotherapy. This led to the empiric delineation of a window for conservative management subject to a "state of metastatic grace" never to be violated. Over the last two decades, conservative management of retinoblastoma witnessed an impressive acceleration of improvements, culminating in two major paradigm shifts in therapeutic strategy. Firstly, the introduction of systemic chemotherapy and focal treatments in the late 1990s enabled radiotherapy to be progressively abandoned. Around 10 years later, the advent of chemotherapy in situ, with the capitalization of new routes of targeted drug delivery, namely intra-arterial, intravitreal and now intracameral injections, allowed significant increase in eye preservation rate, definitive eradication of radiotherapy and reduction of systemic chemotherapy. Here we intend to review the relevant knowledge susceptible to improve the conservative management of retinoblastoma in compliance with the "state of metastatic grace", with particular attention to (i) reviewing how new imaging modalities impact the frontiers of conservative management, (ii) dissecting retinoblastoma genesis, growth patterns, and intraocular routes of tumor propagation, (iii) assessing major therapeutic changes and trends, (iv) proposing a classification of relapsing retinoblastoma, (v) examining treatable/preventable disease-related or treatment-induced complications, and (vi) appraising new therapeutic targets and concepts, as well as liquid biopsy potentiality.
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Affiliation(s)
- Francis L Munier
- Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland.
| | - Maja Beck-Popovic
- Unit of Pediatric Hematology-Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Guillermo L Chantada
- Hemato-Oncology Service, Hospital JP Garrahan, Buenos Aires, Argentina; Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Barcelona, Spain; Institut de Recerca Sant Joan de Deu, Barcelona, Spain
| | - David Cobrinik
- The Vision Center and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA; USC Roski Eye Institute, Department of Biochemistry & Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Tero T Kivelä
- Department of Ophthalmology, Ocular Oncology and Pediatric Ophthalmology Services, Helsinki University Hospital, Helsinki, Finland
| | - Dietmar Lohmann
- Eye Oncogenetics Research Group, Institute of Human Genetics, University Hospital Essen, Essen, Germany
| | - Philippe Maeder
- Unit of Neuroradiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Annette C Moll
- UMC, Vrije Universiteit Amsterdam, Department of Ophthalmology, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Angel Montero Carcaboso
- Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Barcelona, Spain; Institut de Recerca Sant Joan de Deu, Barcelona, Spain
| | - Alexandre Moulin
- Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland
| | - Paula Schaiquevich
- Unit of Clinical Pharmacokinetics, Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina; National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Ciara Bergin
- Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland
| | - Paul J Dyson
- Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland
| | - Susan Houghton
- Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland
| | - Francesco Puccinelli
- Interventional Neuroradiology Unit, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Yvan Vial
- Materno-Fetal Medicine Unit, Woman-Mother-Child Department, University Hospital of Lausanne, Switzerland
| | - Marie-Claire Gaillard
- Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland
| | - Christina Stathopoulos
- Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland
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31
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Abstract
Cancer is a common non-communicable disease worldwide, although it exhibits differential population trends in incidence and mortality rates. The differences relate to population structure, environmental risk factors as well as health system organization. This article discusses the potential impact of genetic testing on population health, focusing in particular on the mutational spectrum of breast cancer susceptibility genes in diverse populations. We identify the need for improved access to, and increased investment in, comprehensive cancer risk assessment and genetic testing as well as cancer control measures that take into account lifestyle, environmental, and social factors in understudied minority groups.
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32
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Dimaras H, Corson TW. Retinoblastoma, the visible CNS tumor: A review. J Neurosci Res 2019; 97:29-44. [PMID: 29314142 PMCID: PMC6034991 DOI: 10.1002/jnr.24213] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 12/02/2017] [Accepted: 12/11/2017] [Indexed: 12/11/2022]
Abstract
The pediatric ocular cancer retinoblastoma is the only central nervous system (CNS) tumor readily observed without specialized equipment: it can be seen by, and in, the naked eye. This accessibility enables unique imaging modalities. Here, we review this cancer for a neuroscience audience, highlighting these clinical and research imaging options, including fundus imaging, optical coherence tomography, ultrasound, and magnetic resonance imaging. We also discuss the subtype of retinoblastoma driven by the MYCN oncogene more commonly associated with neuroblastoma, and consider trilateral retinoblastoma, in which an intracranial tumor arises along with ocular tumors in patients with germline RB1 gene mutations. Retinoblastoma research and clinical care can offer insights applicable to CNS malignancies, and also benefit from approaches developed elsewhere in the CNS.
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Affiliation(s)
- Helen Dimaras
- Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada
- Division of Clinical Public Health, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, M5S 1A8, Canada
- Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada
- Child Health Evaluative Sciences Program, SickKids Research Institute, Toronto, ON, M5G 1X8, Canada
- Department of Human Pathology, College of Health Sciences, University of Nairobi, Nairobi, Kenya
| | - Timothy W. Corson
- Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 46202, USA
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33
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Abstract
Osteosarcoma (OS) is the most common primary bone tumor affecting predominantly adolescents and young adults. It accounts for about 5% of all childhood cancers. Although the majority of OSs are sporadic, a small percentage occur as a component of hereditary cancer syndromes. Early onset, bilateral, multifocal, and metachronous tumors suggest genetic predisposition. The inheritance patterns can be autosomal dominant or recessive. These syndromes predispose to a wide variety of mesenchymal and epithelial cancers with propensity for certain mutations being prevalent in specific cancer subtypes. Li-Fraumeni syndrome, retinoblastoma, Rothmund-Thompson syndrome (type 2), Werner syndrome, and Bloom syndrome, constitute the majority of the tumor syndromes predisposing to OS and will be the focus for this review.
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34
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Abstract
The analysis of the molecular mechanisms governing multistep carcinogenesis became experimentally approachable since the identification and characterization in tumor cells of altered or activated versions of cellular genes (oncogenes) that normally control cell growth and differentiation. The activating mutations confer new properties to the oncogene products and should therefore be considered as gain of function mutations. In addition, the oncogenes appear to act as dominant genetic traits since they act also in the presence of the homologous wild-type allele. However, the concept of a dominance of the transformed phenotype has been challenged by early experiments with somatic cell hybrids which showed that the fusion of normal and malignant cells may suppress the tumorigenic phenotype. The suppression or reversion of the malignant phenotype by the introduction of a normal chromosome into a tumor cell line has lent support to the idea that a family of cellular genes are coding for factors capable to interact with the cell-growth control machinery. These genes seem to reconstitute the normal control of cell growth even in the presence of an activated oncogene. In addition, a two-mutation model has been proposed to explain the epidemiological and clinical features of childhood cancers. According to the model, the development of these malignancies can be caused by the loss or inactivation of both alleles of cellular genes, as suggested by the somatic cell hybrid experiments where the function of the inactivated genes is restored by the contribution of those derived from the normal parental cells. This family of genes is designated as onco-suppressor genes since their product is necessary for the normal regulated cell growth and is lacking or inactivated in malignant cells. At gene level they should be considered as recessive genetic traits, since the tumor phenotype appears when both alleles of an oncosuppressor gene are inactivated. The mutations affecting their normal functions belong to the type « loss of function ». The molecular analysis of retinoblastoma has led to the cloning and sequencing of the related onco-suppressor gene (RB gene) whose product displays the features of a gene-regulatory protein. In addition, a binding between the RB product and various viral onco-proteins (E1A, large T, E7) has been demonstrated, thus suggesting a mechanism of RB inactivation by which some DNA viruses can transform the host cell. Finally, the increasing availability of DNA markers, defining restriction fragment length polymorphisms, has led to the mapping of the loci of inherited predisposition for familial cancer syndromes such as MEN-1, VHL and NF-2 and to the extension to common cancers of the allele losses analysis that can reveal onco-suppressor gene inactivation. This indirect approach has suggested the occurrence of different onco-suppressor genes for sporadic breast, colonic and lung cancers, bladder carcinoma, germinal tumors of the testis and malignant melanoma. In particular, colonic cancer provides a significant example of a possible multistep scenario for carcinogenesis in humans in which activated oncogenes (e.g. ras) and inactivated putative onco-suppressor genes (on chromosome 17 and 18) coexist in the same cell.
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Affiliation(s)
- G Della Porta
- Division of Experimental Oncology A, Istituto Nazionale Tumori, Milan, Italy
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35
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Parma D, Ferrer M, Luce L, Giliberto F, Szijan I. RB1 gene mutations in Argentine retinoblastoma patients. Implications for genetic counseling. PLoS One 2017; 12:e0189736. [PMID: 29261756 PMCID: PMC5738096 DOI: 10.1371/journal.pone.0189736] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 11/30/2017] [Indexed: 11/21/2022] Open
Abstract
Retinoblastoma (RB) is an inherited childhood ocular cancer caused by mutations in the tumor suppressor RB1 gene. Identification of RB1 mutations is essential to assess the risk of developing retinoblastoma in the patients´ relatives. Retinoblastoma is a potentially curable cancer and an early diagnosis is critical for survival and eye preservation. Unilateral retinoblastoma is mostly non-heritable and results from two somatic mutations whereas bilateral retinoblastoma is heritable and results from one germline and one somatic mutation, both have high penetrance, 90%. The purpose of this study was to identify causative RB1 mutations in RB patients with different clinical presentations. A comprehensive approach was used to study a cohort of 34 patients with unilateral, bilateral and trilateral retinoblastoma. Blood and tumor DNA was analyzed by sequencing and multiplex ligation-dependent probe amplification (MLPA) assay. Validation of an insertion mutation was performed by cloning the PCR product. Most of the patients in our cohort had unilateral RB, eight patients had bilateral RB and one patient had a trilateral tumor with ocular and suprasellar/sellar locations. Other tumors in addition to retinoblastoma were also found in the affected families. One patient had two syndromes, retinoblastoma and schwannomatosis, and another RB patient had a father with a retinoma. Five out of the 25 unilateral RB patients carried germinal mutations (20%), which were mostly missense mutations. The bilateral and trilateral patients carried splice-site, nonsense and frameshift mutations as well as a whole RB1 gene deletion. Missense mutations were associated with mild phenotype: unilateral retinoblastoma, retinoma or no tumor. In this study we identified causative RB1 mutations in most bilateral RB patients and in some unilateral RB patients, including five novel mutations. These data are crucial for genetic counseling and confirm the need to perform complete genetic screening for RB1 mutations in both constitutional and tumor tissues.
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Affiliation(s)
- Diana Parma
- Cátedra de Genética, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires. Buenos Aires. Argentina
| | - Marcela Ferrer
- Division de Neurocirugia, Hospital de Clinicas “Jose de San Martin”, Universidad de Buenos Aires. Buenos Aires. Argentina
| | - Leonela Luce
- Cátedra de Genética, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires. Buenos Aires. Argentina
| | - Florencia Giliberto
- Cátedra de Genética, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires. Buenos Aires. Argentina
| | - Irene Szijan
- Cátedra de Genética, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires. Buenos Aires. Argentina
- * E-mail:
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36
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Modernizing Human Cancer Risk Assessment of Therapeutics. Trends Pharmacol Sci 2017; 39:232-247. [PMID: 29242029 DOI: 10.1016/j.tips.2017.11.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 11/17/2017] [Accepted: 11/17/2017] [Indexed: 12/14/2022]
Abstract
Cancer risk assessment of therapeutics is plagued by poor translatability of rodent models of carcinogenesis. In order to overcome this fundamental limitation, new approaches are needed that enable us to evaluate cancer risk directly in humans and human-based cellular models. Our enhanced understanding of the mechanisms of carcinogenesis and the influence of human genome sequence variation on cancer risk motivates us to re-evaluate how we assess the carcinogenic risk of therapeutics. This review will highlight new opportunities for applying this knowledge to the development of a battery of human-based in vitro models and biomarkers for assessing cancer risk of novel therapeutics.
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Berry JL, Xu L, Murphree AL, Krishnan S, Stachelek K, Zolfaghari E, McGovern K, Lee TC, Carlsson A, Kuhn P, Kim JW, Cobrinik D, Hicks J. Potential of Aqueous Humor as a Surrogate Tumor Biopsy for Retinoblastoma. JAMA Ophthalmol 2017; 135:1221-1230. [PMID: 29049475 DOI: 10.1001/jamaophthalmol.2017.4097] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Importance Retinoblastoma (Rb) is one of the first tumors to have a known genetic etiology. However, because biopsy of this tumor is contraindicated, it has not been possible to define the effects of secondary genetic changes on the disease course. Objective To investigate whether the aqueous humor (AH) of Rb eyes has sufficient tumor-derived DNA to perform genetic analysis of the tumor, including DNA copy number alterations. Design, Setting, and Participants This investigation was a case series study at a tertiary care hospital (Children's Hospital Los Angeles) with a large Rb treatment center. Cell-free DNA (cfDNA) was isolated from 6 AH samples from 3 children with Rb, including 2 after primary enucleation and 1 undergoing multiple intravitreous injections of melphalan for vitreous seeding. Samples were taken between December 2014 and September 2015. Main Outcomes and Measures Measurable levels of nucleic acids in the AH and identification of tumor-derived DNA copy number variation in the AH. The AH was analyzed for DNA, RNA, and micro-RNA using Qubit high-sensitivity kits. Cell-free DNA was isolated from the AH, and sequencing library protocols were optimized. Shallow whole-genome sequencing was performed on an Illumina platform, followed by genome-wide chromosomal copy number variation profiling to assess the presence of tumor DNA fractions in the AH cfDNA of the 3 patients. One child's cfDNA from the AH and tumor DNA were subjected to Sanger sequencing to isolate the RB1 mutation. Results Six AH samples were obtained from 3 Rb eyes in 3 children (2 male and 1 female; diagnosed at ages 7, 20, and 28 months). A corroborative pattern between the chromosomal copy number variation profiles of the AH cfDNA and tumor-derived DNA from the enucleated samples was identified. In addition, a nonsense RB1 mutation (Lys→STOP) from 1 child was also identified from the AH samples obtained during intravitreous injection of melphalan, which matched the tumor sample postsecondary enucleation. Sanger sequencing of the AH cfDNA and tumor DNA with polymerase chain reaction primers targeting RB1 gene c.1075A demonstrated this same RB1 mutation. Conclusions and Relevance In this study evaluating nucleic acids in the AH from Rb eyes undergoing salvage therapy with intravitreous injection of melphalan, the results suggest that the AH can serve as a surrogate tumor biopsy when Rb tumor tissue is not available. This novel method will allow for analyses of tumor-derived DNA in Rb eyes undergoing salvage therapy that have not been enucleated.
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Affiliation(s)
- Jesse L Berry
- The Vision Center at Children's Hospital Los Angeles, Los Angeles, California.,USC Roski Eye Institute, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles
| | - Liya Xu
- Department of Biological Sciences, USC Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles
| | - A Linn Murphree
- The Vision Center at Children's Hospital Los Angeles, Los Angeles, California.,USC Roski Eye Institute, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles
| | | | - Kevin Stachelek
- The Vision Center at Children's Hospital Los Angeles, Los Angeles, California
| | - Emily Zolfaghari
- The Vision Center at Children's Hospital Los Angeles, Los Angeles, California.,USC Roski Eye Institute, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles
| | - Kathleen McGovern
- The Vision Center at Children's Hospital Los Angeles, Los Angeles, California
| | - Thomas C Lee
- The Vision Center at Children's Hospital Los Angeles, Los Angeles, California.,USC Roski Eye Institute, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles
| | - Anders Carlsson
- Department of Biological Sciences, USC Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles
| | - Peter Kuhn
- Department of Biological Sciences, USC Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles.,Norris Comprehensive Cancer Center, Keck School of Medicine of USC, University of Southern California, Los Angeles.,Department of Aerospace and Mechanical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles.,Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles
| | - Jonathan W Kim
- The Vision Center at Children's Hospital Los Angeles, Los Angeles, California.,USC Roski Eye Institute, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles
| | - David Cobrinik
- The Vision Center at Children's Hospital Los Angeles, Los Angeles, California.,USC Roski Eye Institute, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles.,Norris Comprehensive Cancer Center, Keck School of Medicine of USC, University of Southern California, Los Angeles.,Department of Biochemistry and Molecular Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
| | - James Hicks
- Department of Biological Sciences, USC Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles.,Norris Comprehensive Cancer Center, Keck School of Medicine of USC, University of Southern California, Los Angeles
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Abstract
In this review, Dyson summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients? The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?
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Heidenreich B, Kumar R. Altered TERT promoter and other genomic regulatory elements: occurrence and impact. Int J Cancer 2017; 141:867-876. [PMID: 28407294 DOI: 10.1002/ijc.30735] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 03/28/2017] [Accepted: 03/31/2017] [Indexed: 12/19/2022]
Abstract
Study of genetic alterations, inherited or acquired, that increase the risk or drive cancers and many other diseases had remained mostly confined to coding sequences of the human genome. Data from genome wide associations studies, development of the Encyclopedia of DNA Elements (ENCODE), and a spurt in detection of driver somatic mutations have shifted focus towards noncoding regions of the human genome. The majority of genetic variants robustly associated with cancers and other syndromes identified through genome wide studies are located within noncoding regulatory regions of the genome. Genome wide techniques have put an emphasis on the role of three-dimensional chromosomal structures and cis-acting elements in regulations of different genes. The variants within noncoding genomic regions can potentially alter a number of regulatory elements including promoters, enhancers, insulators, noncoding long RNAs and others that affect cancers and various diseases through altered expression of critical genes. With effect of genetic alterations within regulatory elements dependent on other partner molecules like transcription factors and histone marks, an understanding of such modifications can potentially identify extended therapeutic targets. That concept has been augmented by the detection of driver somatic noncoding mutations within the promoter region of the telomerase reverse transcriptase (TERT) gene in different cancers. The acquired somatic noncoding mutations within different regulatory elements are now being reported in different cancers with an increased regularity. In this review we discuss the occurrence and impact of germline and somatic alterations within the TERT promoter and other genomic regulatory elements.
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Affiliation(s)
- Barbara Heidenreich
- Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Rajiv Kumar
- Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.,German Consortium for Translational Research (DKTK), German Cancer Research Center, Heidelberg, Germany
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40
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Zainuddin A, Chua KH, Tan JK, Jaafar F, Makpol S. γ-Tocotrienol prevents cell cycle arrest in aged human fibroblast cells through p16INK4a pathway. J Physiol Biochem 2016; 73:59-65. [DOI: 10.1007/s13105-016-0524-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Accepted: 09/27/2016] [Indexed: 11/28/2022]
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Li WL, Buckley J, Sanchez-Lara PA, Maglinte DT, Viduetsky L, Tatarinova TV, Aparicio JG, Kim JW, Au M, Ostrow D, Lee TC, O'Gorman M, Judkins A, Cobrinik D, Triche TJ. A Rapid and Sensitive Next-Generation Sequencing Method to Detect RB1 Mutations Improves Care for Retinoblastoma Patients and Their Families. J Mol Diagn 2016; 18:480-93. [PMID: 27155049 DOI: 10.1016/j.jmoldx.2016.02.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 01/14/2016] [Accepted: 02/01/2016] [Indexed: 01/26/2023] Open
Abstract
Retinoblastoma is a childhood eye malignancy that can lead to the loss of vision, eye(s), and sometimes life. The tumors are initiated by inactivating mutations in both alleles of the tumor-suppressor gene, RB1, or, rarely, by MYCN amplification. Timely identification of a germline RB1 mutation in blood samples or either somatic RB1 mutation or MYCN amplification in tumors is important for effective care and management of retinoblastoma patients and their families. However, current procedures to thoroughly test RB1 mutations are complicated and lengthy. Herein, we report a next-generation sequencing-based method capable of detecting point mutations, small indels, and large deletions or duplications across the entire RB1 gene and amplification of MYCN gene on a single platform. From DNA extraction to clinical interpretation requires only 3 days, enabling early molecular diagnosis of retinoblastoma and optimal treatment outcomes. This method can also detect low-level mosaic mutations in blood samples that can be missed by routine Sanger sequencing. In addition, it can differentiate between RB1 mutation- and MYCN amplification-driven retinoblastomas. This rapid, comprehensive, and sensitive method for detecting RB1 mutations and MYCN amplification can readily identify RB1 mutation carriers and thus improve the management and genetic counseling for retinoblastoma patients and their families.
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Affiliation(s)
- Wenhui L Li
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Department of Pathology, USC Roski Eye Institute, University of Southern California, Los Angeles, California.
| | - Jonathan Buckley
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Department of Pathology, USC Roski Eye Institute, University of Southern California, Los Angeles, California
| | - Pedro A Sanchez-Lara
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Department of Pathology, USC Roski Eye Institute, University of Southern California, Los Angeles, California; Department of Pediatrics, USC Roski Eye Institute, University of Southern California, Los Angeles, California
| | - Dennis T Maglinte
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California
| | - Lucy Viduetsky
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California
| | - Tatiana V Tatarinova
- Department of Pediatrics, USC Roski Eye Institute, University of Southern California, Los Angeles, California; Spatial Sciences Institute, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | | | - Jonathan W Kim
- Vision Center, Children's Hospital Los Angeles, Los Angeles, California; Department of Opthalmology, USC Roski Eye Institute, University of Southern California, Los Angeles, California
| | - Margaret Au
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California
| | - Dejerianne Ostrow
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California
| | - Thomas C Lee
- Vision Center, Children's Hospital Los Angeles, Los Angeles, California; Department of Opthalmology, USC Roski Eye Institute, University of Southern California, Los Angeles, California
| | - Maurice O'Gorman
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Department of Pathology, USC Roski Eye Institute, University of Southern California, Los Angeles, California
| | - Alexander Judkins
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Department of Pathology, USC Roski Eye Institute, University of Southern California, Los Angeles, California
| | - David Cobrinik
- Vision Center, Children's Hospital Los Angeles, Los Angeles, California; Department of Opthalmology, USC Roski Eye Institute, University of Southern California, Los Angeles, California; Division of Ophthalmology and Department of Surgery, and Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Biochemistry & Molecular Biology, USC Roski Eye Institute, University of Southern California, Los Angeles, California; Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Timothy J Triche
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Department of Pathology, USC Roski Eye Institute, University of Southern California, Los Angeles, California.
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Akizawa Y, Miyashita T, Sasaki R, Nagata R, Aoki R, Ishitani K, Nagashima Y, Matsui H, Saito K. Gorlin syndrome with an ovarian leiomyoma associated with a PTCH1 second hit. Am J Med Genet A 2016; 170A:1029-34. [PMID: 26782978 DOI: 10.1002/ajmg.a.37517] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 12/06/2015] [Indexed: 11/08/2022]
Abstract
We describe a Gorlin syndrome (GS) case with two different second hit mutations of PTCH1, one in a keratocystic odontogenic tumor (KCOT) and the other in an ovarian leiomyoma. GS is a rare genetic condition manifesting as multiple basal cell nevi associated with other features such as medulloblastomas, skeletal abnormalities, and ovarian fibromas. A 21-year-old Japanese woman with a history of two KCOTs was diagnosed with GS according to clinical criteria. A PTCH1 mutation, c.1427del T, was detected in peripheral blood. A novel PTCH1 mutation, c.264_265insAATA, had been found in the maxillary KCOT as a second hit mutation. More recently, the ovarian tumor was detected during a gynecological examination. Laparoscopic adnexectomy was performed, and the pathological diagnosis of the ovarian tumor was leiomyoma. Interestingly, another novel mutation, loss of heterozygosity spanning from 9q22.32 to 9q31.2, including PTCH1 and 89 other genes, was detected in this ovarian tumor, providing evidence of a second hit mutation. This is the first report describing a GS-associated ovarian tumor carrying a second hit in the PTCH1 region. We anticipate that accumulation of more cases will clarify the importance of second hit mutations in ovarian tumor formation in GS.
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Affiliation(s)
- Yoshika Akizawa
- Department of Obstetrics and Gynecology, Tokyo Women's Medical University, Tokyo, Japan.,Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan
| | - Toshiyuki Miyashita
- Department of Molecular Genetics, Kitasato University School of Medicine, Kanagawa, Japan
| | - Ryo Sasaki
- Department of Oral and Maxillofacial Surgery, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Reiko Nagata
- Department of Obstetrics and Gynecology, Tokyo Women's Medical University, Tokyo, Japan
| | - Ryoko Aoki
- Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan
| | - Ken Ishitani
- Department of Obstetrics and Gynecology, Tokyo Women's Medical University, Tokyo, Japan
| | - Yoji Nagashima
- Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan
| | - Hideo Matsui
- Department of Obstetrics and Gynecology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kayoko Saito
- Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan
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Stranneheim H, Wedell A. Exome and genome sequencing: a revolution for the discovery and diagnosis of monogenic disorders. J Intern Med 2016; 279:3-15. [PMID: 26250718 DOI: 10.1111/joim.12399] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Massively parallel DNA sequencing has revolutionized analyses of human genetic variation. From having been out of reach for individual research groups and even more so for clinical diagnostic laboratories until recently, it is now possible to analyse complete human genomes within reasonable time frames and at a reasonable cost using technologies that are becoming increasingly available. This represents a huge advance in our ability to provide correct diagnoses for patients with rare inherited disorders and their families. This paradigm shift is especially dramatic within the area of monogenic disorders. Not only can rapid and safe diagnostics of virtually all known single-gene defects now be established, but novel causes of disease in previously unsolved cases can also be identified, illuminating novel pathways important for normal physiology. This greatly increases the capability not only to improve management of rare disorders, but also to improve understanding of pathogenetic mechanisms relevant for common, complex diseases.
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Affiliation(s)
- H Stranneheim
- Department of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet and the Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - A Wedell
- Department of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet and the Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden
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44
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Abstract
Approximately 50% of all congenital anomalies cannot be linked to any specific genetic etiology, but in recent years cost effective high throughput sequencing has emerged as an efficient strategy for identifying single nucleotide polymorphisms (SNPs) associated with disease. However, in many cases there is not enough evidence to determine if these SNPs underlie disease. To bridge this gap in our understanding advances in functional analyses are warranted. Several preclinical model systems are currently being utilized to provide such evidence, including the advantageous zebrafish embryo. While every system exhibits disadvantages and caveats, a new era of multidisciplinary research has evolved, which uses a broad spectrum of functional analysis tools. This approach will make it possible to identify potential therapeutic targets for both common and rare human disorders.
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Affiliation(s)
- Anita M Quintana
- Department of Biological Sciences, The University of Texas at El Paso, 500 West University Avenue, El Paso TX 79934
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45
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Dimaras H, Corson TW, Cobrinik D, White A, Zhao J, Munier FL, Abramson DH, Shields CL, Chantada GL, Njuguna F, Gallie BL. Retinoblastoma. Nat Rev Dis Primers 2015; 1:15021. [PMID: 27189421 PMCID: PMC5744255 DOI: 10.1038/nrdp.2015.21] [Citation(s) in RCA: 368] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Retinoblastoma is a rare cancer of the infant retina that is diagnosed in approximately 8,000 children each year worldwide. It forms when both retinoblastoma gene (RB1) alleles are mutated in a susceptible retinal cell, probably a cone photoreceptor precursor. Loss of the tumour-suppressive functions of the retinoblastoma protein (pRB) leads to uncontrolled cell division and recurrent genomic changes during tumour progression. Although pRB is expressed in almost all tissues, cone precursors have biochemical and molecular features that may sensitize them to RB1 loss and enable tumorigenesis. Patient survival is >95% in high-income countries but <30% globally. However, outcomes are improving owing to increased disease awareness for earlier diagnosis, application of new guidelines and sharing of expertise. Intra-arterial and intravitreal chemotherapy have emerged as promising methods to salvage eyes that with conventional treatment might have been lost. Ongoing international collaborations will replace the multiple different classifications of eye involvement with standardized definitions to consistently assess the eligibility, efficacy and safety of treatment options. Life-long follow-up is warranted, as survivors of heritable retinoblastoma are at risk for developing second cancers. Defining the molecular consequences of RB1 loss in diverse tissues may open new avenues for treatment and prevention of retinoblastoma, as well as second cancers, in patients with germline RB1 mutations.
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Affiliation(s)
- Helen Dimaras
- Department of Ophthalmology & Vision Sciences, The Hospital for Sick Children & University of Toronto, Toronto, Canada
| | - Timothy W. Corson
- Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - David Cobrinik
- The Vision Center, Children’s Hospital Los Angeles & USC Eye Institute, University of Southern California, Los Angeles, CA USA
| | | | - Junyang Zhao
- Department of Ophthalmology, Beijing Children’s Hospital, Capital Medial University, Beijing, China
| | - Francis L. Munier
- Department of Ophthalmology, Jules-Gonin Eye Hospital, Lausanne, Switzerland
| | - David H. Abramson
- Department of Ophthalmology, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Carol L. Shields
- Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, USA
| | | | - Festus Njuguna
- Department of Department of Child Health and Paediatrics, Moi University, Eldoret, Kenya
| | - Brenda L. Gallie
- Department of Ophthalmology & Vision Sciences, The Hospital for Sick Children & University of Toronto, 555 University Ave, Toronto, Ontario M5G1X8, Canada
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The expression of tumour suppressors and proto-oncogenes in tissues susceptible to their hereditary cancers. Br J Cancer 2015; 113:345-53. [PMID: 26079304 PMCID: PMC4506389 DOI: 10.1038/bjc.2015.205] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 03/05/2014] [Accepted: 05/15/2015] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Studies of familial cancers have found that only a small subset of tissues are affected by inherited mutations in a given tumour suppressor gene (TSG) or proto-oncogene (POG), even though the mutation is present in all tissues. Previous tests have shown that tissue specificity is not due to the presence vs absence of gene expression, as TSGs and POGs are expressed in nearly every type of normal human tissue. Using published microarray expression data we tested the related hypothesis that tissue-specific expression of a TSG or POG is highest in tissue where it is of oncogenic importance. METHODS We tested this hypothesis by examining whether individual TSGs and POGs had higher expression in the normal (noncancerous) tissues where they are implicated in familial cancers relative to those tissues where they are not. We examined data for 15 TSGs and 8 POGs implicated in familial cancer across 12 human tissue types. RESULTS We found a significant difference between expression levels in susceptible vs nonsusceptible tissues. It was found that 9 (60%, P<0.001) of the TSGs and 5 (63%, P<0.001) of the POGs had their highest expression level in the tissue type susceptible to their oncogenic effect. CONCLUSIONS This highly significant association supports the hypothesis that mutation of a specific TSG or POG is likely to be most oncogenic in the tissue where the gene has its highest level of expression. This suggests that high expression in normal tissues is a potential marker for linking cancer-related genes with their susceptible tissues.
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Engel BE, Cress WD, Santiago-Cardona PG. THE RETINOBLASTOMA PROTEIN: A MASTER TUMOR SUPPRESSOR ACTS AS A LINK BETWEEN CELL CYCLE AND CELL ADHESION. ACTA ACUST UNITED AC 2014; 7:1-10. [PMID: 28090172 DOI: 10.2147/chc.s28079] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
RB1 was the first tumor suppressor gene discovered. Over four decades of work have revealed that the Rb protein (pRb) is a master regulator of biological pathways influencing virtually every aspect of intrinsic cell fate including cell growth, cell-cycle checkpoints, differentiation, senescence, self-renewal, replication, genomic stability and apoptosis. While these many processes may account for a significant portion of RB1's potency as a tumor suppressor, a small, but growing stream of evidence suggests that RB1 also significantly influences how a cell interacts with its environment, including cell-to-cell and cell-to-extracellular matrix interactions. This review will highlight pRb's role in the control of cell adhesion and how alterations in the adhesive properties of tumor cells may drive the deadly process of metastasis.
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Affiliation(s)
- B E Engel
- Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - W D Cress
- Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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48
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Choe JY, Yun JY, Jeon YK, Kim SH, Choung HK, Oh S, Park M, Kim JE. Sonic hedgehog signalling proteins are frequently expressed in retinoblastoma and are associated with aggressive clinicopathological features. J Clin Pathol 2014; 68:6-11. [PMID: 25296932 DOI: 10.1136/jclinpath-2014-202434] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
AIMS This study aimed to examine the expression of Sonic hedgehog (SHH) signalling proteins in retinoblastoma and to evaluate its clinical significance. METHODS Seventy-nine enucleated retinoblastoma tumours were investigated immunohistochemically using antibodies against SHH pathway proteins, such as SHH, glioma-associated oncogene homologue (GLI) 1, GLI2, GLI3 and ABC binding cassette G2 (ABCG2). Western blotting of SHH signalling proteins was performed in two retinoblastoma cell lines. RESULTS SHH was expressed in most retinoblastoma cases (78 of 79, 98.7%), with 21 cases (26.6%) showing strong expression. GLI1 and GLI2 were also frequently expressed: 67 of 78 cases (85.9%) and 71 of 77 cases (92.2%), respectively. GLI3, a transcriptional repressor, was expressed at low levels in 23 of the 78 cases (29.5%). High ABCG2 expression was found in 23 of the 78 cases (29.5%). High expression levels of these proteins in retinoblastoma cell lines were confirmed by western blotting. The expression of SHH was associated with advanced stages, local invasion and metastasis (all p<0.05). CONCLUSIONS SHH signalling molecules were frequently expressed in retinoblastoma tumour cells, and high SHH expression was closely related to an advanced disease status. Our results suggest that the SHH signalling pathway may play a role in the progression of retinoblastoma.
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Affiliation(s)
- Ji-Young Choe
- Department of Pathology, Seoul National University, College of Medicine, Seoul, Korea Department of Pathology, Seoul National University Bundang Hospital, Gyeonggi-Do, Korea
| | - Ji Yun Yun
- Department of Pathology, Seoul National University, College of Medicine, Seoul, Korea Department of Pathology, Seoul National University Bundang Hospital, Gyeonggi-Do, Korea
| | - Yoon Kyung Jeon
- Department of Pathology, Seoul National University, College of Medicine, Seoul, Korea Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Se Hoon Kim
- Department of Pathology, Yonsei Unversity, College of Medicine, Seoul, Korea
| | - Ho-Kyung Choung
- Department of Ophthalmology, Seoul National University Boramae Hospital, Seoul, Korea
| | - Sohee Oh
- Department of Biostatistics, Seoul National University Boramae Hospital, Seoul, Korea
| | - Mira Park
- Department of Pathology, Seoul National University Boramae Hospital, Seoul, Korea
| | - Ji Eun Kim
- Department of Pathology, Seoul National University, College of Medicine, Seoul, Korea Department of Pathology, Seoul National University Boramae Hospital, Seoul, Korea
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Desvoyes B, de Mendoza A, Ruiz-Trillo I, Gutierrez C. Novel roles of plant RETINOBLASTOMA-RELATED (RBR) protein in cell proliferation and asymmetric cell division. JOURNAL OF EXPERIMENTAL BOTANY 2014; 65:2657-66. [PMID: 24323507 PMCID: PMC4557542 DOI: 10.1093/jxb/ert411] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
The retinoblastoma (Rb) protein was identified as a human tumour suppressor protein that controls various stages of cell proliferation through the interaction with members of the E2F family of transcription factors. It was originally thought to be specific to animals but plants contain homologues of Rb, called RETINOBLASTOMA-RELATED (RBR). In fact, the Rb-E2F module seems to be a very early acquisition of eukaryotes. The activity of RBR depends on phosphorylation of certain amino acid residues, which in most cases are well conserved between plant and animal proteins. In addition to its role in cell-cycle progression, RBR has been shown to participate in various cellular processes such as endoreplication, transcriptional regulation, chromatin remodelling, cell growth, stem cell biology, and differentiation. Here, we discuss the most recent advances to define the role of RBR in cell proliferation and asymmetric cell division. These and other reports clearly support the idea that RBR is used as a landing platform of a plethora of cellular proteins and complexes to control various aspects of cell physiology and plant development.
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Affiliation(s)
- Bénédicte Desvoyes
- Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, Cantoblanco, Nicolas Cabrera 1, 28049 Madrid, Spain
| | - Alex de Mendoza
- Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Passeig Marítim de la Barceloneta 37-49, 08003 Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Catalonia, Spain
| | - Iñaki Ruiz-Trillo
- Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Passeig Marítim de la Barceloneta 37-49, 08003 Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Catalonia, Spain
| | - Crisanto Gutierrez
- Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, Cantoblanco, Nicolas Cabrera 1, 28049 Madrid, Spain
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Realizing the promise of cancer predisposition genes. Nature 2014; 505:302-8. [PMID: 24429628 DOI: 10.1038/nature12981] [Citation(s) in RCA: 445] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 11/21/2013] [Indexed: 12/14/2022]
Abstract
Genes in which germline mutations confer highly or moderately increased risks of cancer are called cancer predisposition genes. More than 100 of these genes have been identified, providing important scientific insights in many areas, particularly the mechanisms of cancer causation. Moreover, clinical utilization of cancer predisposition genes has had a substantial impact on diagnosis, optimized management and prevention of cancer. The recent transformative advances in DNA sequencing hold the promise of many more cancer predisposition gene discoveries, and greater and broader clinical applications. However, there is also considerable potential for incorrect inferences and inappropriate clinical applications. Realizing the promise of cancer predisposition genes for science and medicine will thus require careful navigation.
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