Surveillance recommendations for DICER1 pathogenic variant carriers: a report from the SIOPE Host Genome Working Group and CanGene-CanVar Clinical Guideline Working Group

Familial Cancer https://doi.org/10.1007/s10689-021-00264-y ORIGINAL ARTICLE Surveillance recommendations for DICER1 pathogenic variant carriers: a report from the SIOPE Host Genome Working Group and CanGene‑CanVar Clinical Guideline Working Group Jette J. Bakhuizen1,2 · Helen Hanson3 · Karin van der Tuin4 · Fiona Lalloo5 · Marc Tischkowitz6 · Karin Wadt7 · Marjolijn C. J. Jongmans1,2 · SIOPE Host Genome Working Group · CanGene-CanVar Clinical Guideline Working Group · Expert Network Members Received: 20 November 2020 / Accepted: 19 May 2021 © The Author(s) 2021 Abstract DICER1 syndrome is a rare genetic disorder that predisposes to a wide spectrum of tumors. Developing surveillance protocols for this syndrome is challenging because uncertainty exists about the clinical efficacy of surveillance, and appraisal of potential benefits and harms vary. In addition, there is increasing evidence that germline DICER1 pathogenic variants are associated with lower penetrance for cancer than previously assumed. To address these issues and to harmonize DICER1 syndrome surveillance programs within Europe, the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) and Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom reviewed current surveillance strategies and evaluated additional relevant literature. Consensus was achieved for a new surveillance protocol and information leaflet that informs patients about potential symptoms of DICER1associated tumors. The surveillance protocol comprises a minimum program and an extended version for consideration. The key recommendations of the minimum program are: annual clinical examination from birth to age 20 years, six-monthly chest X-ray and renal ultrasound from birth to age 6 years, and thyroid ultrasound every 3 years from age 8 to age 40 years. The surveillance program for consideration comprises additional surveillance procedures, and recommendations for DICER1 pathogenic variant carriers outside the ages of the surveillance interval. Patients have to be supported in choosing the surveillance program that best meets their needs. Prospective evaluation of the efficacy and patient perspectives of proposed surveillance recommendations is required to expand the evidence base for DICER1 surveillance protocols. Keywords DICER1 · Surveillance · Hereditary · Cancer predisposition syndrome * Marjolijn C. J. Jongmans 1 Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands 2 Department of Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands 3 Department of Clinical Genetics, St George’s University Hospitals NHS Foundation Trust, London, UK 4 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands 5 Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK 6 Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK 7 Department of Clinical Genetics, Copenhagen University Hospital Righospitalet, Copenhagen, Denmark 13 Vol.:(0123456789) J. J. Bakhuizen et al. Introduction DICER1 syndrome is an autosomal dominant hereditary tumor predisposition syndrome that predisposes individuals to a variety of tumors, both benign and malignant [1, 2]. In 2009, disease-associated variants in the DICER1 gene were first described in families with multiple cases of pleuropulmonary blastoma (PPB) [2]. Over time, numerous other manifestations have been associated with pathogenic germline variants in DICER1, including lung cysts, multinodular goiter, thyroid cancer, ovarian sex-cord stromal tumors, and cystic nephroma [1, 3–5]. Less commonly described manifestations in individuals with DICER1 syndrome include nasal chondromesenchymal hamartoma (NCMH), ciliary body medulloepithelioma (CBME), Wilms tumors, primary brain tumors, mesenchymal hamartoma of the liver, and sarcomas of various sites [1, 6–11]. The majority of tumors occur in infancy, childhood, and adolescence [12]. Macrocephaly is one of the few non-neoplastic features of DICER1 syndrome, which may also include retinal and structural renal abnormalities [10, 13, 14]. Possibly additional tumors or non-neoplastic features will be linked to DICER1 syndrome in the future. In 2018, two independent groups proposed DICER1 syndrome surveillance protocols [15, 16]. Developing surveillance protocols for DICER1 syndrome is challenging, not least due to uncertainty about the efficacy of surveillance for individuals with germline pathogenic DICER1 variants. Proposed surveillance protocols aim to reduce DICER1associated morbidity and mortality through early detection of tumors by imaging of several organs. However, the clinical utility of these protocols remains to be validated [15–18]. The natural history (i.e., rate of malignant transformation) and growth rate of most DICER1-associated tumors has not yet been investigated [1, 19]. Another challenge in developing surveillance protocols is the potential harm associated with surveillance. Potential harms in DICER1 syndrome surveillance protocols include overtreatment (e.g., unnecessary surgery for asymptomatic benign cysts detected on surveillance), need for sedation in young children during imaging procedures, radiation exposure and psychosocial burden of repeated investigations and false-positive findings [20]. Given these potential harms, the question has been raised whether less invasive and less frequent surveillance regimes are reasonable. This issue has grown in importance in light of two recent findings. Firstly, approximately 95% of nonindex case individuals with germline pathogenic DICER1 variants did not develop a tumor by age 10 years [12]. Secondly, germline DICER1 pathogenic variants may be more common in the general population than previously thought, reflecting a lower penetrance than previously assumed [19]. The current incidence of loss-of-function (LOF) variants in 13 the gnomAD data set (71,702 genomes, accessed 23/10/20) is 1:5121 [21]. To address these issues, the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) organized a meeting during which current surveillance protocols for DICER1 syndrome were reviewed and new surveillance recommendations were proposed. In addition, the Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom was invited as a collaborator in the guideline development process to harmonize surveillance programs within Europe. The joint recommendations, which both overlap and incorporate modifications compared to previous protocols, are presented and explained in this report. Methods In January 2020, the SIOPE HGWG met in Hannover, Germany, to reassess current surveillance strategies f (...truncated)