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Genetic Syndromes with an Increased Risk of Developing Cancer As an Example of the Use of New Technologies

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Genetic Syndromes with an Increased Risk of Developing Cancer As an Example of the Use of New Technologies Genetics and Molecular Biology, 37, 1 (suppl), 241-249 (2014) Copyright © 2014, Sociedade Brasileira de Genética. Printed in Brazil www.sbg.org.br Review Article Impact of NGS in the medical sciences: Genetic syndromes with an increased risk of developing cancer as an example of the use of new technologies Pablo Lapunzina1,2, Rocío Ortiz López3,4, Lara Rodríguez-Laguna2, Purificación García-Miguel5, Augusto Rojas Martínez3,4 and Víctor Martínez-Glez1,2 1Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain. 2Instituto de Genética Médica y Molecular, Hospital Universitario la Paz, Madrid, Spain. 3Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León. Monterrey, Nuevo León, México. 4Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México. 5Unidad de Oncología Pediátrica, Hospital Infantil La Paz, Madrid, Spain. Abstract The increased speed and decreasing cost of sequencing, along with an understanding of the clinical relevance of emerging information for patient management, has led to an explosion of potential applications in healthcare. Cur- rently, SNP arrays and Next-Generation Sequencing (NGS) technologies are relatively new techniques used to scan genomes for gains and losses, losses of heterozygosity (LOH), SNPs, and indel variants as well as to perform com- plete sequencing of a panel of candidate genes, the entire exome (whole exome sequencing) or even the whole ge- nome. As a result, these new high-throughput technologies have facilitated progress in the understanding and diagnosis of genetic syndromes and cancers, two disorders traditionally considered to be separate diseases but that can share causal genetic alterations in a group of developmental disorders associated with congenital malformations and cancer risk. The purpose of this work is to review these syndromes as an example of a group of disorders that has been included in a panel of genes for NGS analysis. We also highlight the relationship between development and cancer and underline the connections between these syndromes. Keywords: NGS, new technologies, developmental syndrome, cancer predisposition. Introduction The impact of genetics and genomics in health Genetic testing using new technologies, such as During the last two decades, developments in genet- Next-Generation Sequencing (NGS), is transitioning from ics and enormous advances in genomic technologies have the research to the diagnostic phase. Methodologies for altered the capability of understanding diseases, making di- translating new technologies to the clinical setting are not agnoses and providing effective clinical management. well established and are currently in the difficult process of From a mechanistic point of view, genetic disorders may be transitioning from a primarily research environment and roughly subdivided in three main subtypes: genomic, ge- culture to a more quality controlled diagnostic environ- netic and epigenetic. Genomic disorders encompass those ment. This significant change is having an enormous im- diseases in which there is either a gain or loss (sometimes pact on health, but it is also creating diagnostic dilemmas. both) of genomic material. They usually include very large The rapid development of NGS has radically reduced both gains and losses, such as those that are observed in triso- the cost and time required for exome or genome analysis mies and monosomies, as well as smaller, cryptic, me- and has allowed for the implementation of panels of genes dium-size aberrations, such as those that are observed in for diagnosis and research in both genetic syndromes and microduplication and microdeletion syndromes. Although cancer. there is no absolute consensus, the term genomic disorders applies to rearrangements of between 5 kb and several Send correspondence to Víctor Martínez-Glez. Instituto de Gené- tica Médica y Molecular, Hospital Universitario la Paz, Instituto de megabases. Genetic disorders refer to small gains and Salud Carlos III, Paseo de la Castellana 261, 28046 Madrid, Spain. losses, usually of 1-5000 bp. Epigenetic disorders are those E-mail: [email protected]. without gains and losses that have chemical changes (often 242 Lapunzina et al. methylation defects but also acetylation as well as others). quence, through WGS, or the portion of the genome that en- Considering these disorders together (~8000), genomic dis- codes proteins, through WES, will become a part of main- orders account for ~8-12% of the cases, genetic disorders stream healthcare practices. Genomics is having an impact ~85-87% and epigenetic disorders ~2-3%. The current vi- in many areas of clinical medicine, but it is not so much a sion of genomics in healthcare and public health represents revolution as it is an evolution. Clinical research leaders are a confluence of the development of three important strands: slowly gaining knowledge and experience with these ap- genetic technologies, clinical genetics and genomic proaches, and the process of embedding new practices in healthcare. Genetic technologies encompass the whole high quality care pathways throughout our country is grad- range of laboratory technologies that provide detailed se- ual and difficult. quence and other genomic information, whether related to New technologies and clinical knowledge have facili- an individual’s germ-line or somatic cells, that is, the al- tated significant progress in the capability of clinicians to tered genome within cancer cells. diagnose and manage genetic and heritable disorders aris- The explosion of potential applications in healthcare ing in a wide range of clinical areas. It is believed that this has arisen from the increased speed and decreasing cost of will be rapidly followed rapidly a burgeoning of “genomic sequencing, along with an increased understanding of the medicine” in which a wider analysis of genomic informa- clinical relevance of emerging information for patient man- tion will be used to predict, prevent, diagnose and treat agement. Currently, SNP arrays and NGS technologies are many common chronic and rare disorders. It is important relatively new techniques used to scan the genome for gains that the development and configuration of clinical and lab- and losses and losses of heterozygosity (LOH), SNPs and oratory genetics and other specialties is optimized to meet indel variants. SNP arrays are proving to be useful tools in the expected future capacity and range of needs. Such opti- the detection of chromosomal imbalances and LOH in a mization should build on the strengths of existing structures wide range of disorders (Miller et al., 2010), and NGS pro- and processes and should aim to incorporate genomics into vides a rapid and complete sequencing of a set of candidate existing clinical pathways. It has been recommended that genes, the entire exome (whole exome sequencing, WES) relationships between specialty genetic services and a and even the whole genome (WGS) (Tucker et al., 2009; range of other clinical specialties should be formed as a key Ng et al., 2010). foundation for the development of genomic medicine. Clinical genetics is a specialty that provides services The rapid development of NGS has radically reduced for individuals and families affected by or at risk of a ge- both the cost and the time required for WES and WGS. The netic disorder or congenital abnormality. It includes diag- Human Genome Project took approximately 13 years to se- nostic assessment, counseling and support, genetic testing quence the first human genome and cost several billion dol- and provision of advice to patients and their extended fam- lars; today, the same process can be completed within ily. Traditionally, clinical genetics has encompassed chro- weeks for a few thousand dollars using NGS. Soon it may mosomal disorders, dysmorphic syndromes, teratogenic be easier and cheaper to sequence an entire genome than to disorders and single gene disorders, which may be evident sequence a single gene or genotype a series of known muta- in childhood or later in life. The challenge that arises for tions. Furthermore, using the same technologies, gene ex- clinical genetics is that many inherited disorders, including pression profiling and epigenetic analyses are becoming a large number of single gene disorders, manifest with a simpler and cheaper. WES and WGS together with our wide range of clinical symptoms; as a result, clinicians in evolving knowledge of genes and disease are likely to some specialties need to be skilled in recognizing, diagnos- change the current practice of medicine and public health ing and managing these genetic conditions. Genomic by facilitating more accurate, sophisticated and cost- healthcare widens the range of applications of genomic effective genetic testing. WES and WGS have several im- technologies to include instances where they may be used portant clinical applications in the short to medium term: to recognize a precise molecular sub-type of disease and improved diagnosis and management of diseases with a hence fine-tune treatment or determine disease susceptibil- strong heritable component as well as personalized diagno- ity. sis and stratified treatment of cancer through tumor profil- ing. Over the long term, these technologies may also have The impact of new technologies in genomic many other applications, including tissue matching, risk medicine prediction and pharmacogenetics.
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