Distinct loci on chromosome 1q21 and 6q22 predispose to familial nonmedullary thyroid cancer: a SNP array-based linkage analysis of 38 families.
ABSTRACT 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.
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ABSTRACT: Several genome-wide association studies on thyroid cancer (TC) have reported similar findings of a new susceptibility locus, 14q13.3. After that, a number of studies reported that rs944289 polymorphism at chromosome 14q13.3 has been implicated in TC risk. However, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 12 studies involving a total of 7,598 TC cases, 53,613 controls, and 239 nuclear families for 14q13.3-rs944289 polymorphism to evaluate its effect on genetic susceptibility for TC. An overall random-effect per-allele OR of 1.30 (95 % CI 1.21-1.40, P < 10(-5)) was found for the polymorphism. Significant results were also observed for under dominant and recessive genetic models. In the subgroup analysis by ethnicity, we found similar significant results for both Caucasians (T allele: OR 1.29, 95 % CI 1.17-1.42, P < 10(-5)) and East Asians (T allele: OR 1.33, 95 % CI 1.18-1.49, P < 10(-5)). Further in stratified analyses according to study design and sample size, evidence of gene-disease association was also obtained. In addition, we found that rs944289 confers its risk, for both papillary thyroid carcinoma and follicular thyroid carcinoma when stratified by histological types of TC. Furthermore, our results on stratified analysis according to radiation exposure status showed an increased sporadic TC risk, while no associations were detected among radiation-related TCs for rs944289 polymorphism. Our result demonstrated that rs944289 polymorphism on 14q13.3 is a low penetrant risk factor for developing TC.Molecular Genetics and Genomics 01/2015; DOI:10.1007/s00438-014-0981-7 · 2.83 Impact Factor
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ABSTRACT: Thyroid cancer, the commonest of endocrine malignancies, continues increasing in incidence being the 5th more prevalent cancer among women in the United States in 2012. Familial thyroid cancer has become a well-recognized, unique, clinical entity in patients with thyroid cancer originating from follicular cells, that is, nonmedullary thyroid carcinoma. Hereditary nonmedullary thyroid cancer may occur as a minor component of familial cancer syndromes (familial adenomatous polyposis, Gardner's syndrome, Cowden's disease, Carney's complex type 1, Werner's syndrome, and papillary renal neoplasia) or as a primary feature (familial nonmedullary thyroid cancer [FNMTC]). Although there is some controversy, some epidemiologic and clinical kindred studies have shown that FNMTC is associated with more aggressive disease than sporadic cases, with higher rates of multicentric tumours, lymph node metastasis, extrathyroidal invasion, and shorter disease-free survival. This way, preventing screening will allow earlier detection, more timely intervention, and hopefully improved outcomes for patients and their families. On the other hand, in the last years, an important number of genetic studies on FNMTC have been published, trying to determine its genetic contribution. However, the genetic inheritance of FNMTC remains unclear; but it is believed to be autosomal dominant with incomplete penetrance and variable expressivity. This paper provides an extensive overview of FNMTC from several points of view. Firstly, the impact of early detection on prognosis, secondly, the management and follow-up of FNMTC patients, and finally, the role of susceptibility loci, microRNAs (miRNAs) and telomerases in recently identified isolated cases of FNMTC.Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 09/2014; DOI:10.1016/j.bbcan.2014.09.002 · 7.58 Impact Factor
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ABSTRACT: Thyroid cancer is the most heritable cancer of all those not displaying typical Mendelian inheritance. However, most of the genetic factors that would explain the high heritability remain unknown. Our aim was to identify additional common genetic variants associated with susceptibility to this disease. In order to do so, we performed a genome-wide association study in a series of 398 cases and 502 controls from Spain, followed by a replication in 4 well-defined Southern European case-control collections contributing a total of 1422 cases and 1908 controls. The association between the variation at the 9q22 locus near FOXE1 and thyroid cancer risk was consistent across all series, with several SNPs identified (rs7028661: OR=1.64, P=1.0 x 10(-22) , rs7037324: OR=1.54, P=1.2 x 10(-17) ). Moreover, the rare alleles of 3 SNPs (rs2997312, rs10788123 and rs1254167) at 10q26.12 showed suggestive evidence of association with higher risk of the disease (OR=1.35, P=1.2 x 10(-04) , OR=1.26, P=5.2 x 10(-04) and OR=1.38, P=5.9 x 10(-05) , respectively). Finally, the rare allele of rs4075570 at 6q14.1 conferred protection in the series studied (OR=0.82, P=2.0 x 10(-04) ). This study suggests that heterogeneity in genetic susceptibility between populations is a key feature to take into account when exploring genetic risk factors related to this disease. This article is protected by copyright. All rights reserved. © 2014 Wiley Periodicals, Inc. © 2015 UICC.International Journal of Cancer 04/2015; DOI:10.1002/ijc.29557 · 5.01 Impact Factor