Medizinische Genetik最新文献

Radiation therapy is now well tolerated and associated with few side effects. However, people with certain germline genetic variants may be more sensitive to radiation, increasing their risk of experiencing adverse effects from treatment. Increased sensitivity to radiation can be tested in various ways; chromosomal aberrations, which are mutations, are particularly useful for this purpose. Many genetic variants only cause a slight increase in radiation sensitivity such as heterozygous pathogenic variants in the breast cancer risk genes BRCA1 and BRCA2. Variants of tumour suppressor genes, such as TP53, neurofibromatosis (NF1, PTCH1) and retinoblastoma (RB1), cause a slightly higher increase in radiation sensitivity. However, these also carry a high risk of secondary cancers for only a slightly increased level of risk for therapy-related side effects. Some patients with variants have significantly higher levels of radiation sensitivity - up to double the normal level - while others are even more sensitive. Nevertheless, significant variations exist within each specific genetic disorder. This means that radiosensitivity testing should be considered for all patients with a genetic disorder suspected to markedly increase their radiosensitivity, before they undergo radiotherapy. It implies that patients at risk of germline variants, such as children, young people and others at risk with a tumour, should be carefully evaluated and testing for genetic variants should be performed.

Significant progress in comprehensive molecular diagnostics and targeted therapies for advanced malignancies has, in part, led to substantial improvements in patient outcomes. Nevertheless, comprehensive genomic profiling necessitates interdisciplinary discussion of potential clinical recommendations within interdisciplinary molecular tumor boards. (Likely) pathogenic germline variants (PGVs) typically warrant genetic counseling for patients and, where appropriate, their relatives. Concurrently, the rapidly expanding availability of targeted therapies introduces new therapeutic implications based on germline alterations that must be integrated into clinical decision-making. Moreover, the identification of PGVs may not only inform therapy in patients with manifest malignancy but also offer opportunities for targeted chemoprevention.

Almost 70 years ago, the World Health Organization (WHO) decided to propose a "Classification of Tumours". Since then, a systematic and extensive classification system for tumours has been continuously developed in successive editions and nowadays closely interlinks with coding systems for cancer registries like the International Classification of Diseases for Oncology (ICD-O). Whereas past editions had their focus on histopathological aspects of tumour classification in different organ systems and topologies, to which (somatic) genetic alterations increasingly contributed, the current fifth edition of the WHO Classification for the first time includes a separate "Blue Book" volume on "Genetic Tumour Syndromes". Along with chapters dedicated to tumour predisposition inferred by constitutional (germline) genetic pathogenic variants in the different organ-specific volumes of the classification, this new addition to the WHO classification highlights the increasing importance of constitutional genetic alterations for the diagnosis and clinical management of patients with such tumours. The WHO classification of Genetic Tumour Syndromes applies a hierarchical system based on four levels: the major (cellular) mechanism affected, the molecular pathway involved, the (clinical) syndrome, and the specific gene(s) affected. It provides - in part novel or modified - names to the genetic tumour syndromes as well as definitions and descriptions of clinical, epidemiologic, etiologic, pathogenetic and pathological aspects. Essential and desirable diagnostic criteria are given as well as rules for reporting, thus paving the way to international standardization. While the final version of the WHO Classification of Genetic Tumour Syndromes is in proof-stage, the present article, which is based on its beta-version, aims to provide an overview of the concepts underpinning the classification.

Genomic variants affecting an individual's response to drug therapies are common in populations worldwide. For clinical use, information on pharmacogenomic variation is translated into genotype-based therapy recommendations in evidence-based clinical practice guidelines for an increasing number of drugs. While clinical pharmacogenetic testing is currently still frequently performed at the level of individual genes, recent evidence highlighted the potential of a panel-based testing approach to substantially reduce the incidence of adverse drug reactions. This review provides background on pharmacogenetics, nomenclature used for reporting pharmacogenetic test results, as well as an overview of available resources for pharmacogenetic test interpretation.