Completeness of  RET  testing in patients with medullary thyroid carcinoma in Denmark 1997–2013: a nationwide study

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Abstract

Background

The completeness of REarranged during Transfection ( RET) testing in patients with medullary thyroid carcinoma (MTC) was recently reported as 60%. However, the completeness on a population level is unknown. Similarly, it is unknown if the first Danish guidelines from 2002, recommending RET testing in all MTC patients, improved completeness in Denmark. We conducted a nationwide retrospective cohort study aiming to evaluate the completeness of RET testing in the Danish MTC cohort. Additionally, we aimed to assess the completeness before and after publication of the first Danish guidelines and characterize MTC patients who had not been tested.

Methods

The study included 200 patients identified from the nationwide Danish MTC cohort 1997–2013. To identify RET tested MTC patients before December 31, 2014, the MTC cohort was cross-checked with the nationwide Danish RET cohort 1994–2014. To characterize MTC patients who had not been RET tested, we reviewed their medical records and compared them with MTC patients who had been tested.

Results

Completeness of RET testing in the overall MTC cohort was 87% (95% CI: 0.81–0.91; 173/200). In the adjusted MTC cohort, after excluding patients diagnosed with hereditary MTC by screening, completeness was 83% (95% CI: 0.76–0.88; 131/158). Completeness was 88% (95% CI: 0.75–0.95; 42/48) and 81% (95% CI: 0.72–0.88) (89/110) before and after publication of the first Danish guidelines, respectively. Patients not RET tested had a higher median age at diagnosis compared to those RET tested. Median time to death was shorter in those not tested relative to those tested.

Conclusion

The completeness of RET testing in MTC patients in Denmark seems to be higher than reported in other cohorts. No improvement in completeness was detected after publication of the first Danish guidelines. In addition, data indicate that advanced age and low life expectancy at MTC diagnosis may serve as prognostic indicators to identify patients having a higher likelihood of missing the compulsory RET test.

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Most cited references 30

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Guidelines for diagnosis and therapy of MEN type 1 and type 2.

M. Brandi, R F Gagel, A. Angeli … (2001)

This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

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Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.

L M Mulligan, J B Kwok, C S Healey … (1993)

Multiple endocrine neoplasia type 2A (MEN 2A) is a dominantly inherited cancer syndrome that affects tissues derived from neural ectoderm. It is characterized by medullary thyroid carcinoma (MTC) and phaeochromocytoma. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10q11.2 (refs 2,3). The DNA segment encompasses the RET proto-oncogene, a receptor tyrosine kinase gene expressed in MTC and phaeochromocytoma and at lower levels in normal human thyroid. This suggested RET as a candidate for the MEN2A gene. We have identified missense mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls. Further, 19 of these 20 mutations affect the same conserved cysteine residue at the boundary of the RET extracellular and transmembrane domains.

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Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

P. S. Wells, P N Goodfellow, S Dou … (1993)

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.

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Author and article information

Journal

Journal ID (nlm-ta): Clin Epidemiol

Journal ID (iso-abbrev): Clin Epidemiol

Journal ID (publisher-id): Clinical Epidemiology

Title: Clinical Epidemiology

Publisher: Dove Medical Press

ISSN (Electronic): 1179-1349

Publication date Collection: 2019

Publication date (Electronic): 10 January 2019

Volume: 11

Pages: 93-99

Affiliations

[1 ]Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark, jes_mathiesen@ 123456yahoo.dk

[2 ]Department of Clinical Research, University of Southern Denmark, Odense, Denmark, jes_mathiesen@ 123456yahoo.dk

[3 ]Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark

[4 ]Steno Diabetes Center North Jutland, Aalborg, Denmark

[5 ]Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark

[6 ]Center for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark

[7 ]Department of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark

[8 ]Department of ORL Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark

[9 ]Department of ORL Head & Neck Surgery, Aalborg University Hospital, Aalborg, Denmark

[10 ]Department of ORL Head & Neck Surgery, Copenhagen University Hospital, Copenhagen, Denmark

[11 ]Department of Oncology, Herlev Hospital, Herlev, Denmark

[12 ]Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark

[13 ]Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark

[14 ]Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark

[15 ]Department of Clinical Genetics, Odense University Hospital, Odense, Denmark

Author notes

Correspondence: Jes Sloth Mathiesen, Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, J. B. Winsløws Vej 4, DK-5000 Odense, Denmark, Email jes_mathiesen@ 123456yahoo.dk

Article

Publisher ID: clep-11-093

DOI: 10.2147/CLEP.S183268

PMC ID: 6330966

PubMed ID: 30666164

SO-VID: 42b746fd-f494-4730-9b19-2721225c51af

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The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

Completeness of RET testing in patients with medullary thyroid carcinoma in Denmark 1997–2013: a nationwide study

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Most cited references 30

Guidelines for diagnosis and therapy of MEN type 1 and type 2.

Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.

Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

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