Suh I, Filetti S, Vriens MR, Guerrero MA, Tumino S, Wong M et al.. Distinct loci on chromosome 1q21 and 6q22 predispose to familial nonmedullary thyroid cancer: a SNP array-based linkage analysis of 38 families. Surgery 146: 1073-1080
Familial nonmedullary thyroid cancer (FNMTC) is associated with earlier onset and more aggressive behavior than its sporadic counterpart. Although candidate chromosomal loci have been proposed for isolated families with variants of FNMTC, the etiology of most cases is unknown. We aimed to identify loci linked to FNMTC susceptibility using single-nucleotide polymorphism (SNP) array-based linkage analysis in a broad sampling of affected families.
We enrolled and pedigreed 38 FNMTC families. Genomic DNA was extracted from the peripheral blood of 110 relatives, and hybridized to Affymetrix SNP arrays. We performed genotyping and linkage analysis, calculating exponential logarithm-of-the-odds (LOD) scores to identify chromosomal loci with a significant likelihood of linkage.
Forty-nine affected and 61 unaffected members of FNMTC families were genotyped. In pooled linkage analysis of all families, 2 distinct loci with significant linkage were detected at 6q22 and 1q21 (LOD=3.3 and 3.04, respectively).
We have identified 2 loci on chromosomes 1 and 6 that demonstrate linkage in a broad sampling of FNMTC families. Our findings suggest the presence of germline mutations in heretofore-undiscovered genes at these loci, which may potentially lead to accurate genetic tests. Future studies will consist of technical validation and subset analyses of higher-risk pedigrees.
"Usually the familial NMTC pedigrees are small with 3 or fewer affected individuals; autosomal dominant inheritance with reduced penetrance is usually suggested in these families. In the past these findings provided the rationale for linkage studies in NMTC families, which identified at least 7 different genomic regions on chromosomes 1q21 , 2q21 , 6q22 , 8p23 , 8q24 , 14q31 , and 19p32  showing linkage peaks presumably harboring predisposing genes. In most cases no predisposing gene mutation has been described. "
[Show abstract][Hide abstract] ABSTRACT: Thyroid cancer shows high heritability but causative genes remain largely unknown. According to a common hypothesis the genetic predisposition to thyroid cancer is highly heterogeneous; being in part due to many different rare alleles. Here we used linkage analysis and targeted deep sequencing to detect a novel single-nucleotide mutation in chromosome 4q32 (4q32A>C) in a large pedigree displaying non-medullary thyroid carcinoma (NMTC). This mutation is generally ultra-rare; it was not found in 38 NMTC families, in 2676 sporadic NMTC cases or 2470 controls. The mutation is located in a long-range enhancer element whose ability to bind the transcription factors POU2F and YY1 is significantly impaired, with decreased activity in the presence of the C- allele compared with the wild type A-allele. An enhancer RNA (eRNA) is transcribed in thyroid tissue from this region and is greatly downregulated in NMTC tumors. We suggest that this is an example of an ultra-rare mutation predisposing to thyroid cancer with high penetrance.
PLoS ONE 09/2013; 8(5):e61920. DOI:10.1371/journal.pone.0061920 · 3.23 Impact Factor
"In linkage studies, several groups have identified chromosomal loci associated with FNMTC: 1q21, 2q21, 6q22, 8p23.1-p22, and 19p13.2 ,, ,, , ,. Mutation analysis has shown that kindreds with FNMTC do not have germ line mutations in BRAF, RAS, and RET/PTC genes that are commonly mutated somatically in thyroid cancers of follicular cell origin . Furthermore, analysis of somatic mutations (BRAF, RAS, and RET/PTC) in sporadic and familial papillary thyroid cancer tumor samples showed no difference in the rate and type of mutations in these histologies , , . "
[Show abstract][Hide abstract] ABSTRACT: The molecular basis and characteristics of familial non-medullary thyroid cancer are poorly understood. In this study, we performed microRNA (miRNA) profiling of familial and sporadic papillary thyroid cancer tumor samples.
Genome wide miRNA profiling of sporadic and familial papillary thyroid cancer was performed. Differentially expressed miRNAs were validated by quantitative RT-PCR. Ectopic expression of miR-886-3p in thyroid cancer lines was performed to identify pathways targeted by the miRNA, as well as, to determine its effect on tumor cell biology. We found four differentially expressed miRNAs between familial and sporadic papillary thyroid cancer tumor samples. MiR-886-3p and miR-20a were validated to be differentially expressed by 3- and 4-fold, respectively. Pathway analysis of genome-wide expression data on cells overexpressing miR-886-3p and target prediction analysis showed genes involved in DNA replication and focal adhesion pathways were regulated by miR-886-3p. Overexpression of miR-886-3p in thyroid cancer cell lines significantly inhibited cellular proliferation, the number and size of spheroids and cellular migration. Additionally, overexpression of miR-886-3p increased the number of cells in S phase.
Our findings for the first time suggest that miR-886-3p plays an important role in thyroid cancer tumor cell biology and regulates genes involved in DNA replication and focal adhesion. Thus, miR-886-3p may play a role in the initiation and or progression of papillary thyroid cancer.
PLoS ONE 10/2011; 6(10):e24717. DOI:10.1371/journal.pone.0024717 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Approximately 5% of differentiated thyroid cancers are hereditary. Hereditary non-medullary thyroid cancer may occur as a minor component of familial cancer syndromes (e.g. familial adenomatous polyposis) or as a primary feature (familial non-medullary thyroid cancer [FNMTC]). Among FNMTC, PTC is the most common. Although a hereditary predisposition to non-medullary thyroid cancer is well established, the susceptibility genes are poorly known. Up to now, by linkage analysis using microsatellite markers, several putative loci have been described - 1q21, 6q22, 8p23.1-p22, and 8q24; however, validation studies have been unsuccessful. In the present review we discuss the results of linkage analysis and the most recent results of genome wide association studies (GWAS) with high resolution SNP (single nucleotide polymorphism) arrays.
Endokrynologia Polska 61(5):486-9. · 0.99 Impact Factor
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