Distribution of RET Mutations and Evaluation of Treatment Approaches in Hereditary Medullary Thyroid Carcinoma in Turkey

Abstract

Objective:This retrospective multicenter study, centrally conducted and supported by the Society of Endocrinology and Metabolism of Turkey, aimed to evaluate the impact of free RET proto-oncogene testing in medullary thyroid carcinoma (MTC) patients. Surgical timing, adequacy of the treatment, and frequency of prophylactic thyroidectomy (PTx) in mutation carriers were also assessed.Methods:Genetic testing for MTC and pheochromocytoma was conducted between July 2008 and January 2012 in 512 patients. Application forms and RET mutation analyses of these patients whose blood samples were sent from various centers around Turkey were assessed retrospectively. An evaluation form was sent to the physicians of the eligible 319 patients who had confirmed sporadic MTC, familial MTC (FMTC), multiple endocrine neoplasia type 2 (MEN2), or who were mutation carriers. Physicians were asked to give information about the surgical history, latest calcitonin levels, morbidity, mortality, genetic screening, and PTx among family members. Twenty-five centers responded by filling in the forms of 192 patients.Results:Among the 319 patients, RET mutation was detected in 71 (22.3%). Cys634Arg mutation was the most prevalent mutation (43.7%), followed by Val804Met in 18 patients (25.4%), and Cys634Tyr in 6 patients (8.5%). Among 192 MTC patients, the diagnosis was sporadic MTC in 146 (76.4%), FMTC in 14 (7.3%), MEN2A in 15 patients (7.9%), and MEN2B in one patient. The number of mutation carriers among 154 apparently sporadic MTC patients was 8 (5.2%). Ten patients were submitted to PTx out of twenty-four mutation carriers at a mean age of 35±19 years.Conclusion:Turkish people have a similar RET proto-oncogene mutation distribution when compared to other Mediterranean countries. Despite free RET gene testing, the number of the PTx in Turkey is limited and relatively late in the life span of the carriers. This is mainly due to patient and family incompliance and incomplete family counselling.

Case report of adrenocortical carcinoma associated with double germline mutations in MSH2 and RET

“…The p.Val804Met mutation is one of the most common mutations in the RET gene; the American Thyroid Association (ATA) classifies this mutation as moderate risk in the guidelines for the management of MTC (Loveday et al, 2008; Møller et al, 2017; Romei et al, 2016). This variant has received significant attention because of its variable age‐related penetrance and clinical heterogeneity (Feldman et al, 2000; Frohnauer & Decker, 2000; İmge Aydoğan et al, 2016; Learoyd et al, 2005; Rich et al, 2014; Wells et al, 2015). The manifestation of disease from carriers of the p.Val804Met mutation ranges from metastatic MTC at an early age to no evidence of disease by age 80 (Feldman et al, 2000; Wells et al, 2015) and includes several reports of pheochromocytoma (Høie et al, 2000; Nilsson et al, 1999), papillary thyroid carcinoma (Brauckhoff et al, 2002; Gibelin et al, 2004), and concomitant papillary and medullary carcinoma (Shifrin et al, 2009).…”

Role of tissue and circulating microRNAs and DNA as biomarkers in medullary thyroid cancer

“…Abraham, et al, 2011). A later study on a Turkish cohort reported the possible limitations of late prophylactic thyroidectomy in the lifespan (Aydoğan, et al, 2016). Investigations were carried out to identify activating mutations in genes other than RET and the most commonly mutated gene was RAS. In a series of RET-wild type and RET-mutant sMTCs, somatic mutations of HRAS and KRAS were detected in 56% and 12% of cases respectively.…”

“…DNA was isolated from peripheral blood leukocytes by MagNA Pure LC 2.0 with automation (Roche Applied Science) (Aydoğan, et al, 2016), using the QIAMP blood kit (QIAGEN) (Romei, et al, 2016;Schilling, et al, 2001) or using the standard salting out/proteinase K method, dissolved in TE buffer (Yeganeh, et al, 2015).…”

“…M. Moura, et al, 2011;Patocs, et al, 2006;Qari, 2013;Romei, et al, 2016). Three studies performed Sanger sequencing (Aydoğan, et al, 2016;Cho, et al, 2014;Simbolo, et al, 2014).…”

Primary hyperparathyroidism as first manifestation in multiple endocrine neoplasia type 2A: an international multicenter study

“…Data were drawn from the registry of each center. Some of the patients have been reported on previous occasions and updated data were obtained (17,18,19,20,21,22,23,24,25,26).…”