Clinical and molecular analysis of a MEN2A kindred harboring the rare RET variant p.ser904phe

Scapineli Jessica Oliboni; Guerra Giulia Limana; Camelier Marli Viapiana; Ferreira Carla Vaz; Ribeiro Goncalves Iracema Cunha; Maia Ana Luiza

doi:10.1530/endoabs.101.PS2-13-01

PS2-13-01

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Endocrine Abstracts (2024) 101 PS2-13-01 | DOI: 10.1530/endoabs.101.PS2-13-01

ETA2024 Poster Presentations Medullary thyroid cancer-2 (10 abstracts)

Clinical and molecular analysis of a MEN2A kindred harboring the rare RET variant p.ser904phe

Jessica Oliboni Scapineli ¹ , Giulia Limana Guerra ² , Marli Viapiana Camelier ³ , Carla Vaz Ferreira ³ , Iracema Cunha Ribeiro Gonçalves ² & Ana Luiza Maia ³

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¹Hospital de Clínicas de Porto Alegre, Thyroid Section, Endocrinology Division, Porto Alegre, Brazil; ²Hospital Nossa Senhora Da Conceição, Brazil; ³Hospital de Clínicas de Porto Alegre, Brazil

Introduction: Medullary thyroid carcinoma (MTC) is a rare malignant tumor that originates from the thyroid C cells. MTC may occur sporadically (75%) or as part of cancer syndrome (hMTC). hMTC is associated with germline mutations in the RET proto-oncogene. The pathogenic variants at codon 634 were the most prevalent (30-50%). Other pathogenic variants were found in less than 10% of MEN2A subjects. The rare RET variant p. Ser904Phe has been reported in only 3 kindreds worldwide and is currently classified as likely pathogenic. Objectives: To characterize the clinical and molecular features of the MEN 2A kindred with a variant at codon 904 and investigate its penetrance and risk of progression.

Methods: Ascending, collateral, and descending relatives of subjects with p. Ser904Phe variant were invited to participate in this study. Molecular analysis was performed by Sanger sequencing of RET exon 15.

Results: Of the 48 individuals screened, 31 (64.5%) harbored the mutation: 17 (54%) were women, and the median age was 34.4 ± 15.7 years. Thyroid ultrasound was performed on 24 subjects, revealing a nodule in 12 of them (0.8 ± 0.46 cm). All participants with thyroid nodules had high calcitonin levels (reference value up to 5ng/l). Twelve patients underwent total thyroidectomy (7 women and 5 men): 10 presented MTC (mean 1.06 cm), 1 had mixed MTC and papillary carcinoma carcinoma (1.2 cm), and 1 had C cell hyperplasia with amyloid deposits (0.1 cm). Gene carriers without any evidence of clinical disease are being monitored. Twelve relatives are awaiting sample collection for molecular screening. Conclusions: This large hereditary MTC kindred with rare RET variant p. Ser904Phe indicate that this variant is associate with low aggressive tumor. Furthermore, the strong genotype-phenotype association indicate that it must be reclassified as pathogenic variant rather than likely pathogenic. Follow-up of these subjects will be necessary for a better understanding of the long-term behavior of the disease in carriers of this rare variant.