Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

Familial medullary thyroid cancer (MTC) and its precursor, C cell hyperplasia (CCH), is associated with germline RET mutations causing multiple endocrine neoplasia type 2. However, some rare families with apparent MTC/CCH predisposition do not have a detectable RET mutation. To identify novel MTC/CCH predisposition genes we undertook exome resequencing studies in a family with apparent predisposition to MTC/CCH and no identifiable RET mutation. We identified a novel ESR2 frameshift mutation, c.948delT, which segregated with histological diagnosis following thyroid surgery in family members and demonstrated loss of ESR2-encoded ERβ expression in the MTC tumour. ERα and ERβ form heterodimers binding DNA at specific oestrogen-responsive elements (EREs) to regulate gene transcription. ERβ represses ERα-mediated activation of the ERE and the RET promoter contains three EREs. In vitro, we showed that ESR2 c.948delT results in unopposed ERα mediated increased cellular proliferation, activation of the ERE and increased RET expression. In vivo, immunostaining of CCH and MTC using an anti-RET antibody demonstrated increased RET expression. Together these findings identify germline ESR2 mutation as a novel cause of familial MTC/CCH and provide important insights into a novel mechanism causing increased RET expression in tumourigenesis.

Multiple primary malignant tumours (MPMT) are frequently taken as an indicator of potential inherited cancer susceptibility and occur at appreciable frequency both among unselected cancer patients and, particularly, among referrals to cancer genetics services. However, there is a paucity of information on the clinical genetic evaluation of cohorts of MPMT patients representing a variety of tumour types. We ascertained a referral-based series of MPMT cases and describe the patterns of tumours observed. Service-based molecular genetic testing had demonstrated a pathogenic germline variant in an inherited cancer gene in fewer than one in four unselected referrals. To assess for evidence of thus far unidentified variants in those who tested negative, comparisons were made with those who tested positive. This revealed considerable overlap between the two groups with respect to clinical characteristics indicative of an inherited cancer syndrome. We therefore proceeded to test a subset of unexplained MPMT cases (n ¼ 62) for pathogenic germline variants in TP53 and PTEN but none were detected. Individuals with MPMT may receive negative genetic test results for a number of reasons, which are discussed. Many of these may be addressed by the increasing application of next generation sequencing techniques such as inherited cancer gene panels.

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease. When fully expressed, it is characterized by inflammatory soft tissue changes, exophthalmos, ocular dysmotility causing diplopia, and, rarely, sight-threatening dysthyroid optic neuropathy (DON). The prevalence of GO among Graves' patients seems lately declining, probably due to early diagnosis, early intervention on risk factors associated with its occurrence or progression (smoking, uncontrolled thyroid dysfunction), early correction of hyper and hypothyroidism. Only about 25-30% of newly diagnosed Graves' hyperthyroids are affected with GO, which is usually mild and rarely progressive. Assessment of activity and severity of GO according to standardized criteria is fundamental to plan management. The European Thyroid Association and the European Group on Graves' Orbitopathy (EUGOGO) have recently published the first guideline on management of GO. Mild GO usually requires only a watchful strategy, in addition to local measures (eye drops, ointments) and removal of risk factors. Intravenous glucocorticoids (ivGCs) are the first-line treatment for moderate-to-severe and active GO, as demonstrated by randomized clinical trials. When ivGCs fail or GO recurs after treatment withdrawal, options include a second course of ivGCs, oral GCs combined with orbital radiotherapy or cyclosporine, rituximab. Evidence that the any of the above treatment be effective in the context of a poor response to a first course of ivGCs is limited and should be investigated in larger studies. In addition to rituximab, ongoing investigations are exploring the role of other biologics targeting, e.g., the IGF-1 receptor or the IL-6 receptor, and results will probably available in 1-2 years. When GO has been treated medically and is inactive, rehabilitative surgery (orbital decompression, squint surgery, eyelid surgery) is often needed. S2Role of T3 and TRH in the hypothalamic regulation of energy metabolism Eric Fliers (e.fliers@amc.uva.nl) Department of Endocrinology and Metabolism at the Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands Thyroid Research 2017, 10(Suppl 1):S2The relation between thyrotoxicosis, the clinical syndrome resulting from exposure to excessive thyroid hormone, and the autonomic nervous system remains enigmatic. Recent experiments from our lab and others have shown that T3 may act within several hypothalamic nuclei to modulate hepatic glucose metabolism and brown adipose tissue (BAT) activity. These effects are mediated via pre-autonomic neurons connecting the paraventricular and ventromedial nuclei (PVN and VMH) with these peripheral organs via neural pathways. Intrahypothalamic effects of T3 on glucose metabolism in the liver could be modulated by selective hepatic sympathetic and parasympathetic denervation. Thyroid hormone appeared to stimulate hepatic glucose production via a sympathetic pathway, representing a novel central route for thyroid hormone action. As most of the experiments were performed in a ...

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