Jes Sloth Mathiesen

Distribution of RET mutations in multiple endocrine neoplasia 2 in Denmark 1994-2014: a nationwide study

Background: Germline mutations of the REarranged during Transfection (RET) proto-oncogene cause multiple endocrine neoplasia 2 (MEN2). It is unclear whether the distribution of RET mutations varies among populations. The first nationwide study of the distribution of RET mutations was conducted, and the results were compared to those of other populations. Methods: This retrospective cohort study included 1583 patients who underwent RET gene testing in one of three centers covering all of Denmark between September 1994 and December 2014. Primary testing method was Sanger sequencing, which included exons 8–11 and 13–16. Mutations were defined according to the ARUP database July 1, 2016. Results: RET mutations were identified in 163 patients from 36 apparently unrelated families. Among the 36 families 13 (36.1%) carried mutations in codon 611, four (11.1%) in codon 618, three (8.3%) in codon 620, one (2.8%) in codon 631, six (16.7%) in codon 634, one (2.8%) in codon 790, one (2.8%) in codon 804, one (2.8%) in codon 852, one (2.8%) in codon 883, and five (13.9%) in codon 918. Among the 13 families with codon 611 mutations, 12 had the p.C611Y mutation. Conclusions: The distribution of RET mutations in Denmark appears to differ from that of other populations. Mutations in codon 611 were the most prevalent, followed by more frequently reported mutations. This might be due to a possible founder effect for the p.C611Y mutation. However, further studies are needed to find possible explanations for the skewed mutational spectrum in Denmark.

Risk profile of the RET A883F germline mutation: an international collaborative study

Context The A883F germline mutation of the rearranged during transfection (RET) proto-oncogene causes multiple endocrine neoplasia 2B. In the revised American Thyroid Association (ATA) guidelines for the management of medullary thyroid carcinoma (MTC), the A883F mutation has been reclassified from the highest to the high-risk level, although no well-defined risk profile for this mutation exists. Objective To create a risk profile for the A883F mutation for appropriate classification among the ATA risk levels. Design Retrospective analysis. Setting International collaboration. Patients Included were 13 A883F carriers. Intervention The intervention was thyroidectomy. Main Outcome Measures Earliest age of MTC, regional lymph node metastases, distant metastases, age-related penetrance of MTC and pheochromocytoma (PHEO), overall and disease-specific survival, and biochemical cure rate. Results One and three carriers were diagnosed at age 7 to 9 years (median, 7.5 years) with a normal thyroid and C-cell hyperplasia, respectively. Nine carriers were diagnosed with MTC at age 10 to 39 years (median, 19 years). The earliest age of MTC, regional lymph node metastasis, and distant metastasis was 10, 20, and 20 years, respectively. Fifty percent penetrance of MTC and PHEO was achieved by age 19 and 34 years, respectively. Five- and 10-year survival rates (both overall and disease specific) were 88% and 88%, respectively. Biochemical cure for MTC at latest follow-up was achieved in 63% (five of eight carriers) with pertinent data. Conclusions MTC of A883F carriers seems to have a more indolent natural course compared with that of M918T carriers. Our results support the classification of the A883F mutation in the ATA high-risk level.

Completeness and validity in a national clinical thyroid cancer database: DATHYRCA

BACKGROUND Although a prospective national clinical thyroid cancer database (DATHYRCA) has been active in Denmark since January 1, 1996, no assessment of data quality has been performed. The purpose of the study was to evaluate completeness and data validity in the Danish national clinical thyroid cancer database: DATHYRCA. STUDY DESIGN AND SETTING National prospective cohort. Denmark; population 5.5 million. Completeness of case ascertainment was estimated by the independent case ascertainment method using three governmental registries as a reference. The reabstracted record method was used to appraise the validity. For validity assessment 100 cases were randomly selected from the DATHYRCA database; medical records were used as a reference. RESULT The database held 1934 cases of thyroid carcinoma and completeness of case ascertainment was estimated to 90.9%. Completeness of registration was around or above 90% in most instances. Perfect agreement on the diagnosis of thyroid carcinoma was found, both inter- and intra-observer, and κ values of selected variables showed overall good to excellent agreement. CONCLUSION In a setup with public health insurance, personal identity numbers and extended governmental databases, it is possible to establish national clinical cancer databases with a satisfactory completeness and validity. The DATHYRCA database is considered reliable in terms of describing thyroid carcinoma at a national level.

Incidence and prevalence of multiple endocrine neoplasia 2B in Denmark: a nationwide study

Multiple endocrine neoplasia 2B (MEN2B) is an autosomal dominant inherited cancer syndrome associating medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), ganglioneuromatosis of the aerodigestive tract and facial, ophthalmologic and skeletal abnormalities. MEN2B is caused by the M918T and A883F mutation of the REarranged during Transfection (RET) proto-oncogene in approximately 95% and <5% of cases, respectively. Only very few other mutations have been reported to cause MEN2B. In approximately 75% of MEN2B patients, mutations occur as de novo (Wells et al. 2015). The epidemiology of MEN2B is poorly defined. A nationwide study from Northern Ireland reported of three MEN2B patients and 1,824,000 inhabitants alive at April 21, 2012, yielding a point prevalence of 1.65 per million (Znaczko et al. 2014). However, it is unclear if this is representative of larger populations. A German study reported an MEN2B incidence (M918T carriers only) of 1.4 per million live births per year from 1991 to 2000 and estimated that at least half of all German RET carriers were captured (Machens et al. 2013). Meanwhile, the incidence of MEN2B and M918T carriers in a complete population is undisclosed. We conducted a nationwide study of the incidence and prevalence of MEN2B in Denmark from 1941 to 2014. This retrospective cohort study included 12 unique MEN2B patients identified through the following sources:

Novel Somatic RET Mutation Questioning the Causality of the RET I852M Germline Sequence Variant in Multiple Endocrine Neoplasia 2A

Author order, full names, highest earned academic degrees, complete affiliations and contact information: Jes Sloth Mathiesen Department of ORL Head & Neck Surgery, Odense University Hospital, Sdr. Boulevard 29, DK‐5000 Odense, Denmark 2 Institute of Clinical Research, University of Southern Denmark, Winsløwparken 19, DK‐ 5000 Odense, Denmark E‐mail address: jes_mathiesen@yahoo.dk Phone: +45 2252 3083

Founder Effect of the RETC611Y Mutation in Multiple Endocrine Neoplasia 2A in Denmark: A Nationwide Study

BACKGROUND Multiple endocrine neoplasia (MEN) 2A and 2B are caused by REarranged during Transfection (RET) germline mutations. In a recent nationwide study, an unusually high prevalence (33%) of families with the C611Y mutation was reported, and it was hypothesized that this might be due to a founder effect. The first nationwide study of haplotypes in MEN2A families was conducted, with the aim of investigating the relatedness and occurrence of de novo mutations among Danish families carrying similar mutations. METHODS The study included 21 apparently unrelated MEN2A families identified from a nationwide Danish RET cohort from 1994 to 2014. Twelve, two, two, three, and two families carried the C611Y, C618F, C618Y, C620R, and C634R mutations, respectively. Single nucleotide polymorphism chip data and identity by descent analysis were used to assess relatedness. RESULTS A common founder mutation was found among all 12 C611Y families and between both C618Y families. No relatedness was identified in the remaining families. CONCLUSION The data suggest that all families with the C611Y germline mutation in Denmark originate from a recent common ancestor, probably explaining the unusually high prevalence of this mutation. Additionally, the results indicate that the C611Y mutation rarely arises de novo, thus underlining the need for thorough multigenerational genetic work up in carriers of this mutation.

Incidence and prevalence of multiple endocrine neoplasia 2A in Denmark 1901–2014: a nationwide study

Background The incidence and prevalence of multiple endocrine neoplasia 2A (MEN2A) have only been reported once in a nationwide setting. However, it is unclear whether the figures are representative of other populations, as the major component of the syndrome, hereditary medullary thyroid carcinoma (MTC), has been reported as rare in the same country. We conducted a nationwide retrospective cohort study of MEN2A in Denmark from 1901 to 2014, aiming to describe the incidence and prevalence. Methods This study included 250 unique MEN2A patients born or resident in Denmark before December 31, 2014. Patients were identified through the Danish REarranged during Transfection (RET) cohort, linkage of MEN2A pedigrees, the Danish MTC cohort, a nationwide collaboration of MEN2 centers, cross-checking of other relevant cohorts, and a systematic literature search. Results The incidence from 1971 to 2000 was 28 (95% CI: 21–37) per million live births per year. Incidence for the specific mutations or for the overall MEN2A group did not change significantly from 1901 to 2014 (P>0.05). Point prevalence at January 1, 2015, was 24 per million (95% CI: 20–28). Conclusion The incidence and prevalence of MEN2A in Denmark seem higher than those reported in other countries. This is likely explained by the Danish C611Y founder effect. Also, our data indicate no significant change in MEN2A incidence during the last century.