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      RB1 gene mutations in Argentine retinoblastoma patients. Implications for genetic counseling

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          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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          Most cited references 28

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          Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion.

          Consistent gene mutation nomenclature is essential for efficient and accurate reporting, testing, and curation of the growing number of disease mutations and useful polymorphisms being discovered in the human genome. While a codified mutation nomenclature system for simple DNA lesions has now been adopted broadly by the medical genetics community, it is inherently difficult to represent complex mutations in a unified manner. In this article, suggestions are presented for reporting just such complex mutations. Copyright 2000 Wiley-Liss, Inc.
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            Promoter proximal splice sites enhance transcription.

            Reconstruction of a gene with its introns removed results in reduced levels of cytoplasmic mRNA. This is partly explained by introns promoting the export of mRNA through coupling splicing to nuclear export processes. However, we show here that splicing signals can have a direct role in enhancing gene transcription. Removal of promoter proximal splice signals from a mammalian gene or the excision of introns from two different yeast genes results in a marked reduction in levels of nascent transcription, based on both nuclear run-on and direct image analysis. This further establishes that mRNA processing and transcription are tightly coupled mechanisms.
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              Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk.

              There is a substantial risk of a second cancer for persons with hereditary retinoblastoma, which is enhanced by radiotherapy. To examine long-term risk of new primary cancers in survivors of childhood retinoblastoma and quantify the role of radiotherapy in sarcoma development. Cohort incidence study of patients with retinoblastoma followed for a median of 20 years, and nested case-control study of a radiation dose-response relationship for bone and soft tissue sarcomas. A total of 1604 patients with retinoblastoma who survived at least 1 year after diagnosis, identified from hospital records in Massachusetts and New York during 1914 to 1984. Incidence of subsequent cancers was statistically significantly elevated only in the 961 patients with hereditary retinoblastoma, in whom 190 cancers were diagnosed, vs 6.3 expected in the general population (relative risk [RR], 30 [95% confidence interval, 26-47]). Cumulative incidence (+/-SE) of a second cancer at 50 years after diagnosis was 51.0% (+/-6.2%) for hereditary retinoblastoma, and 5.0% (+/-3.0%) for nonhereditary retinoblastoma. All 114 sarcomas of diverse histologic types occurred in patients with hereditary retinoblastoma. For soft tissue sarcomas, the RRs showed a stepwise increase at all dose categories, and were statistically significant at 10 to 29.9 Gy and 30 to 59.9 Gy. A radiation risk for all sarcomas combined was evident at doses above 5 Gy, rising to 10.7-fold at doses of 60 Gy or greater (P<.05). Genetic predisposition has a substantial impact on risk of subsequent cancers in retinoblastoma patients, which is further increased by radiation treatment. A radiation dose-response relationship is demonstrated for all sarcomas and, for the first time in humans, for soft tissue sarcomas. Retinoblastoma patients should be examined for new cancers and followed into later life to determine whether their extraordinary cancer risk extends to common cancers of adulthood.
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                Author and article information

                Contributors
                Role: Data curation
                Role: Validation
                Role: ConceptualizationRole: Software
                Role: Funding acquisition
                Role: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                20 December 2017
                2017
                : 12
                : 12
                Affiliations
                [1 ] Cátedra de Genética, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires. Buenos Aires. Argentina
                [2 ] Division de Neurocirugia, Hospital de Clinicas “Jose de San Martin”, Universidad de Buenos Aires. Buenos Aires. Argentina
                Odense University Hospital, DENMARK
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-17-24494
                10.1371/journal.pone.0189736
                5738096
                29261756
                © 2017 Parma et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 3, Tables: 1, Pages: 12
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100005363, Universidad de Buenos Aires;
                Award ID: 20020090200492
                Award Recipient :
                The funder of this work is the Buenos Aires University, the Grant number is: UBACYT 2010-2012 GEF, Nº 20020090200492. The web site is the Universidad de Buenos Aires.
                Categories
                Research Article
                Biology and Life Sciences
                Genetics
                Mutation
                Frameshift Mutation
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Biology and Life Sciences
                Genetics
                Mutation
                Insertion Mutation
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Blastomas
                Retinoblastoma
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Ophthalmologic Tumors
                Retinoblastoma
                Biology and Life Sciences
                Genetics
                Mutation
                Nonsense Mutation
                Biology and Life Sciences
                Genetics
                Mutation
                Deletion Mutation
                Biology and Life Sciences
                Genetics
                Mutation
                Research and Analysis Methods
                Database and Informatics Methods
                Biological Databases
                Mutation Databases
                Biology and Life Sciences
                Genetics
                Mutation
                Mutation Databases
                Custom metadata
                All relevant data are within the paper and held at the public repository rb1-lsdb at the following link: http://rb1-lovd.d-lohmann.de.

                Uncategorized

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