Thyroid Cancer, Nonmedullary, 4

A number sign (#) is used with this entry because of evidence that susceptibility to nonmedullary thyroid cancer-4 (NMTC4) is conferred by heterozygous mutation in the FOXE1 gene (602617) on chromosome 9q22.

Description

Nonmedullary thyroid cancer (NMTC) refers to neoplasms originating from the thyroid follicular cells and represents 80 to 95% of all thyroid cancers. Approximately 5% of NMTC occurs on the background of a familial predisposition. Although papillary thyroid carcinoma (PTC) is usually the most frequent thyroid lesion in NMTC families, multinodular goiter (MNG) and follicular thyroid adenoma also occur (summary by Pereira et al., 2015).

For a general phenotypic description and a discussion of genetic heterogeneity of NMTC, see NMTC1 (188550).

Clinical Features

Pereira et al. (2015) described a large 4-generation Portuguese family (family 25) with familial NMTC. The proband had PTC with nodal metastases at the age of 57 years. A cousin of the proband had a follicular variant of PTC at the age of 72 years, in addition to parathyroid adenoma, lymphoma, basal cell carcinoma, and prostate carcinoma. The proband's sister presented with tall cell PTC at the age of 57 years and 2 years later developed nodal metastases. Another individual, consanguineously married to the affected cousin of the proband, had ovarian carcinoma.

Mapping

In a genomewide association study of 192 Icelandic individuals with thyroid cancer and 37,196 controls, Gudmundsson et al. (2009) identified associations with SNPs on chromosomes 9q22.33 and 14q13.3, respectively. The findings were replicated in 2 cohorts of European descent (342 and 90 thyroid cancer cases, respectively). Overall, the strongest association signals were observed for rs965513 on 9q22.33 (odds ratio of 1.75; p = 1.7 x 10(-27)) and rs944289 on 14q13.3 (odds ratio of 1.37; p = 2.0 x 10(-9)). The gene nearest to the 9q22.33 locus is thyroid transcription factor-2 (FOXE1; 602617), and thyroid transcription factor-1 (NKX2-1; 600635) is among the genes located at the 14q13.3 locus. Both variants contributed to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals were homozygous for both variants, and their estimated risk of thyroid cancer was 5.7-fold greater than that of noncarriers. In a large sample set from the general Icelandic population, both risk alleles were associated with low concentrations of TSH, and the 9q22.33 allele was associated with low concentration of T4 and high concentration of T3.

In an association study of the 9q22 locus and thyroid-related phenotypes identified by electronic selection algorithms of medical records, Denny et al. (2011) found no significant association with thyroid cancer.

Radiation-Related PTC

Takahashi et al. (2010) conducted a genomewide association study employing Belarusian patients with papillary thyroid cancer (PTC) aged 18 years or younger at the time of the Chernobyl accident and age-matched Belarusian control subjects. Two series of genome scans were performed using independent sample sets, and association with radiation-related PTC was evaluated. Metaanalysis combining the 2 studies identified 4 SNPs at chromosome 9q22.33 showing significant associations with the disease. The association was further reinforced by a validation analysis using one of these SNP markers, rs965513, with another set of samples. rs965513 is located 57 kb upstream to FOXE1 (602617), a thyroid-specific transcription factor with pivotal roles in thyroid morphogenesis and was reported as the strongest genetic risk marker of sporadic PTC in European populations. Of interest, no association was obtained between radiation-related PTC and rs944289 at 14q13.3, which showed the second strongest association with sporadic PTC in Europeans. The authors suggested that the complex pathway underlying the pathogenesis may be partly shared by the 2 etiologic forms of PTC, but their genetic components do not completely overlap each other, suggesting the presence of other unknown etiology-specific genetic determinants in radiation-related PTC.

Molecular Genetics

In the proband of a family who presented with PTC and nodal metastases at the age of 57 years, Pereira et al. (2015) identified a heterozygous ala248-to-gly (A248G; 602617.0004) mutation in the FOXE1 gene. The mutation was identified in 3 other members of the family and segregated with disease. Functional studies in rat normal thyroid cells and human PTC cell lines demonstrated that the A248G mutation promoted cell proliferation and migration. Two family members carried the BRAF V600E mutation (164757.0001) as well as the A248G FOXE1 mutation. Pereira et al. (2015) also found the A248G mutation in 1 male patient among 80 unrelated Portuguese individuals with apparently sporadic NMTC. This patient had developed PTC with nodal metastases at the age of 24 years.