With increasing understanding of the molecular alterations leading to thyroid cancers in recent years we have seen a rapid increase in the number of effective targeted systemic therapies available for patients with advanced thyroid cancer; firstly with the advent of the multi-kinase inhibitors and more recently with more specific RET, BRAF, MEK, ALK and NTRK inhibitors. Although these developments are very welcome, they have resulted in a paradigm shift in the management of advanced thyroid cancer to which thyroid oncologists have had to rapidly adapt, learning how to supervise treatment safely with novel agents, the management of novel toxicities, when and how to arrange molecular genetic testing of cancers and, perhaps most importantly, determining when the optimum time is to start these treatments in what can often be a relatively indolent, if progressive, disease. We hope that these guidelines will support clinicians in making these decisions with their patients, as well as signposting and providing useful supporting information both for patients and clinicians.

The landscape of medical sequencing has rapidly changed with the evolution of next generation sequencing (NGS). These technologies have contributed to the molecular characterization of the myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), through the identification of recurrent gene mutations, which are present in >80% of patients. These mutations contribute to a better classification and risk stratification of the patients. Currently, clinical laboratories include NGS genomic analyses in their routine clinical practice, in an effort to personalize the diagnosis, prognosis and treatment of MDS and CMML. NGS technologies have reduced the cost of large-scale sequencing, but there are additional challenges involving the clinical validation of these technologies, as continuous advances are constantly being made. In this context, it is of major importance to standardize the generation, analysis, clinical interpretation and reporting of NGS data. To that end, the Spanish MDS Group (GESMD) has expanded the present set of guidelines, aiming to establish common quality standards for the adequate implementation of NGS and clinical interpretation of the results, hoping that this effort will ultimately contribute to the benefit of patients with myeloid malignancies.

PurposeThe purpose of this document is to provide guidance for the use of next-generation sequencing (NGS, also known as massively parallel sequencing or MPS) in Canadian clinical genetic laboratories for detection of genetic variants in genomic DNA and mitochondrial DNA for inherited disorders, as well as somatic variants in tumour DNA for acquired cancers. They are intended for Canadian clinical laboratories engaged in developing, validating and using NGS methods. METHODS OF STATEMENT DEVELOPMENT: The document was drafted by the Canadian College of Medical Geneticists (CCMG) Ad Hoc Working Group on NGS Guidelines to make recommendations relevant to NGS. The statement was circulated for comment to the CCMG Laboratory Practice and Clinical Practice committees, and to the CCMG membership. Following incorporation of feedback, the document was approved by the CCMG Board of Directors. DISCLAIMER: The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. The current CCMG Practice Guidelines were developed as a resource for clinical laboratories in Canada and should not be considered to be inclusive of all information laboratories should consider in the validation and use of NGS for a clinical laboratory service.

Clinical testing with chromosomal microarray (CMA) is most commonly undertaken for clinical indications such as intellectual disability, dysmorphic features and/or congenital abnormalities. Identification of a structural aberration (SA) involving a cancer susceptibility gene (CSG) constitutes a type of incidental or secondary finding. Laboratory reporting, risk communication and clinical management of these structural aberrations with secondary implications (SASIs) is currently inconsistent. We undertake meta-analysis of 18 622 instances of CMA performed for unrelated indications in which 106 SASIs are identified involving in total 40 different CSGs. Here we present the recommendations of a joint UK working group representing the British Society of Genomic Medicine, UK Cancer Genetics Group and UK Association for Clinical Genomic Science. SASIs are categorised into four groups, defined by the type of SA and the cancer risk. For each group, recommendations are provided regarding reflex parental testing and cancer risk management.

Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first-degree relatives (and second-degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy-catecholamines and bi-annual rapid whole-body magnetic resonance imaging and clinical examination. Surveillance should start 5 years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre-symptomatic genetic testing. The surveillance of children younger than 15 years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow-up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.

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