Multiple endocrine neoplasia type 2A in two families with the familial medullary thyroid carcinoma associated G533C mutation of the RET proto-oncogene

Abstract

Introduction: Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant hereditary disorder, associated with a cluster of germline gain-of-function mutations of the RET proto-oncogene (RET), mainly in exons 10-15. The G533C mutation in exon 8 of the RET is rare and has been mainly related to the familial medullary thyroid carcinoma. Patients-methods: We describe the RET G533C mutation in exon 8 of the RET in two unrelated female index patients, with MEN2A phenotype, consisting of pheochromocytoma which was the presenting feature and medullary thyroid carcinoma. In addition, 12 family members were also studied. DNA extraction, PCR, and sequencing of RET was performed in exons 7-19 and 21, following standard procedures. Results: The mutation was found in both index patients and in 6 out of 12 family members (50%). Three of them were biochemically affected with histologically proven medullary thyroid carcinoma in two of them while there are no certain clues regarding the other three members as they declined further evaluation. Conclusion: Patients with MEN2A should be also searched in exon 8 while positive carriers of this mutation should be screened annually for pheochromocytoma or other components of the syndrome.

Prevalence by Age and Predictors of Medullary Thyroid Cancer in Patients with Lower Risk GermlineRETProto-Oncogene Mutations

“…Codon 533 is located in exon 8 of the RET proto-oncogene, a region that is not routinely sequenced in most commercial laboratories in the United States offering RET analysis; therefore, patients with this mutation could easily be missed, which might account for its apparent rarity. Even though the majority of the 71 codon 533 patients came from a single large Brazilian family or from one of 5 different families of Greek ancestry (10,16,33,47), our data argue in favor of routinely sequencing exon 8, given that it is now a well-characterized and clearly deleterious mutation.…”

Four novel RET germline variants in exons 8 and 11 display an oncogenic potential in vitro

“…FMTC (OMIM*155240) is associated with mutations either in the extracellular or in the intracellular domain of RET, mostly affecting exons 10, 11, 13, 14 and 15 and never involving exon 16. Mutations in exons 5 and 8 have been reported respectively in one Czech family (8) and in five families originating from Brazil (9), Italy (10) and Greece (11)(12)(13). Nevertheless, the genetic analysis of these exons is routinely performed only in few centres, consistent with the very recent ATA guidelines for the management of MTCs (14), which include among the relevant exons of RET to be screened only exons 10 …”

“…It is also tempting to speculate that the high in vitro transforming potential found for this variant could be responsible for the aggressive behaviour of MTC with lung metastases found in patient 2. It is worth noting that another non-cysteine variant in RET exon 8 (Gly533Cys) has been described previously, but not functionally characterized, in five Greek families, three with MEN2A (11,13) and two with FMTC (12), and in one large Brazilian multigenerational family with FMTC (9). On the basis of all these data, exon 8 appears to be an underestimated hotspot of RET variants with an oncogenic potential.…”

Medullary Thyroid Carcinoma Associated with RET Mutations Located in Exon 8

“…Furthermore, the MTC was least aggressive as it was not clinically apparent, while none of the family members died from MTC-related causes. (Peppa 2008) Moreover, Kamakari et al, have identified the same G533C mutation in 11 unrelated families with FMTC and 4 with MEN2A, explaining the 'RET-negative' FMTC/MEN2A patients. .…”

“…(Schuffenecker 1998, Karga 1998 In addition, the same mutations are associated with significantly earlier progression from C-cell hyperplasia to MTC and earlier lymph node involvement than patients with most other mutations related to MEN2A and FMTC. (Peppa 2008, Hofstra 1994 According to the International RET Exon 10 Consortium, codon-associated penetrance by age 50, ranged from 60% (codon 611) to 86% (620) while more advanced stage and increasing risk of metastases correlated with mutation in codon position (609→620) near the juxtamembrane domain. 50%) family members.…”