Identification of Germline FOXE1 and Somatic MAPK Pathway Gene Alterations in Patients with Malignant Struma Ovarii, Cleft Palate and Thyroid Cancer

• Published in: International journal of molecular sciences Vol. 25; no. 4; p. 1966
• Main Authors: Pires, Carolina, Saramago, Ana, Moura, Margarida M, Li, Jing, Donato, Sara, Marques, Inês J, Belo, Hélio, Machado, Ana C, Cabrera, Rafael, Grünewald, Thomas G P, Leite, Valeriano, Cavaco, Branca M
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.02.2024
• Subjects: Animals; Birth defects; cleft palate; Cleft Palate - genetics; Dermoid Cyst; Female; Forkhead Transcription Factors - genetics; Gene expression; genomics; Humans; Hypothyroidism; malignant struma ovarii; molecular tumour pathology; Mutation; Ovarian Neoplasms - metabolism; Patients; Protein expression; Proteins; Rats; Struma Ovarii - diagnosis; Struma Ovarii - metabolism; Struma Ovarii - pathology; Thyroid cancer; thyroid ectopy; Thyroid Neoplasms - pathology; Tumors; molecular tumour pathology; FOXE1; next-generation sequencing; thyroid ectopy; AXIN1; cleft palate; genomics; BRAF; malignant struma ovarii; thyroid cancer
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25041966

Germline variants in the FOXE1 transcription factor have been associated with thyroid ectopy, cleft palate (CP) and thyroid cancer (TC). Here, we aimed to clarify the role of in Portuguese families (F1 and F2) with members diagnosed with malignant struma ovarii (MSO), an ovarian teratoma with ectopic malignant thyroid tissue, papillary TC (PTC) and CP. Two rare germline heterozygous variants in the promoter were identified: F1) c.-522G>C, in the proband (MSO) and her mother (asymptomatic); F2) c.9C>T, in the proband (PTC), her sister and her mother (CP). Functional studies using rat normal thyroid (PCCL3) and human PTC (TPC-1) cells revealed that c.9C>T decreased promoter transcriptional activity in both cell models, while c.-522G>C led to opposing activities in the two models, when compared to the wild type. Immunohistochemistry and RT-qPCR analyses of patients' thyroid tumours revealed lower FOXE1 expression compared to adjacent normal and hyperplastic thyroid tissues. The patient with MSO also harboured a novel germline variant, presenting a loss of heterozygosity in its benign and malignant teratoma tissues and observable β-catenin cytoplasmic accumulation. The sequencing of the F1 (MSO) and F2 (PTC) probands' tumours unveiled somatic and variants, respectively. Germline and variants might have a role in thyroid ectopy and cleft palate, which, together with MAPK pathway activation, may contribute to tumours' malignant transformation.