Single nucleotide polymorphisms act as modifiers and correlate with the development of medullary and simultaneous medullary/papillary thyroid carcinomas in 2 large, non-related families with the RET V804M proto-oncogene mutation

Shifrin, Alexander; Ogilvie, Jennifer B.; Stang, Michael T.; Fay, Aaron; Kuo, Yen-Hong; Matulewicz, Theodore J.; Xenachis, Cristina; Vernick, Jerome

doi:10.1016/j.surg.2010.09.004

Cited by 23 publications

(17 citation statements)

References 23 publications

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“…Moreover, because polymorphisms are relatively common in the population, they may present a much higher attributable risk in the general population than rare mutations in high-penetrance cancer susceptibility genes such as RET (de Groot et al 2006). Several RET SNPs have been postulated as modifiers of phenotype in the familial forms of the disease (Gil et al 2002, Robledo et al 2003, Lesueur et al 2006, Tamanaha et al 2009, Shifrin et al 2010. This modifier effect on familial forms has already been reviewed (Weber & Eng 2005) and will not be further commented on here.…”

Section: Ret Polymorphisms In Smtcmentioning

confidence: 95%

Association studies in thyroid cancer susceptibility: are we on the right track?

Landa¹,

Robledo²

2011

Journal of Molecular Endocrinology

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It is widely accepted that thyroid cancer is strongly determined by the individual genetic background. In this regard, it is expected that sporadic thyroid cancer is the result of multiple low-to moderate-penetrance genes interacting with each other and with the environment, thus modulating individual susceptibility. In the last years, an important number of association studies on thyroid cancer have been published, trying to determine this genetic contribution. The aim of this review is to provide a comprehensive and critical evaluation of the associations reported so far in thyroid cancer susceptibility in case-control studies performed in both non-medullary (papillary and follicular) and medullary thyroid cancers, including their potential strengths and pitfalls. We summarize the genetic variants reported to date, and stress the importance of validating the results in independent series and assessing the functional role of the associated loci.

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Section: Ret Polymorphisms In Smtcmentioning

confidence: 95%

Association studies in thyroid cancer susceptibility: are we on the right track?

Landa¹,

Robledo²

2011

Journal of Molecular Endocrinology

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“…In the current study, we investigated the exon 15 of BRAF , since several SNPs in the genomic region were reported to contribute to PTC in a Chinese population [8] and the transversions in exon 15 are the common morphotype-specific mutation in adult sporadic PTC. The results were shown in Table 3: the examined BRAF sequences involved these susceptibility loci carried no risk alleles and were the same as common TT at BRAF T1799A and AA at BRAF A1801G .…”

Section: Resultsmentioning

confidence: 99%

“…The RET protooncogene is one of the receptor tyrosine kinases, cell-surface molecules that transduce signals for cell growth and differentiation; rearrangements of the RET are found in about 35% of sporadic PTC [7]. Although somatic mutations of the genes like BRAF and RET exclusively play a causative role in sporadic thyroid cancer development, germline mutations of single nucleotide polymorphisms (SNPs) in these genes were also reported to act as modifiers in the cancer process [8,9], it needs to mention here that in a Chinese population, SNPs of BRAF were shown to be associated with PTC [10], and thus it is intriguing to verify these mutations in fPTC families.…”

Section: Introductionmentioning

confidence: 99%

Familial multinodular goiter syndrome with papillary thyroid carcinomas: mutational analysis of the associated genes in 5 cases from 1 Chinese family

et al. 2013

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BackgroundFamilial papillary thyroid cancer (fPTC) is recognized as a distinct entity only recently and no fPTC predisposing genes have been identified. Several potential regions and susceptibility loci for sporadic PTC have been reported. We aimed to evaluate the role of the reported susceptibility loci and potential risk genomic region in a Chinese familial multinodular goiter (fMNG) with PTC family.MethodsWe sequenced the related risk genomic regions and analyzed the known PTC susceptibility loci in the Chinese family members who consented to join the study. These loci included (1) the point mutations of the BRAF and RET; (2) the possible susceptibility loci to sporadic PTC; and (3) the suggested potential fMNG syndrome with PTC risk region.ResultsThe members showed no mutations in the common susceptible BRAF and RET genomic region, although contained several different heterozygous alleles in the RET introns. All the members were homozygous for PTC risk alleles of rs966423 (C) at chromosome 2q35, rs2910164 (C) at chromosome 5q24 and rs2439302 (G) at chromosome 8p12; while carried no risk allele of rs4733616 (T) at chromosome 8q24, rs965513 (A) or rs1867277 (A) at chromosome 9q22 which were associated with radiation-related PTC. The frequency of the risk allele of rs944289 (T) but not that of rs116909374 (T) at chromosome 14q13 was increased in the MNG or PTC family members.ConclusionsOur work provided additional evidence to the genetic predisposition to a Chinese familial form of MNG with PTC. The family members carried quite a few risk alleles found in sporadic PTC; particularly, homozygous rs944289 (T) at chromosome 14q13 which was previously shown to be linked to a form of fMNG with PTC. Moreover, the genetic determinants of radiation-related PTC were not presented in this family.

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“…SNP G691S and S904S are associated with the development of MTC in patients who carry germline mutations of the RET gene [26][27][28][29] . They appear to influence the onset of HMTC, and the age at diagnosis of MTC in these homozygous pleomorphic patients is 10 years earlier than that for heterozygous MEN 2A or patients with the wild-type haplotype [30,31] . However, linkage analysis in this pedigree showed no linkage of SNP G691S and S904S with MTC, which is contrary to the above reports.…”

Section: Color Version Available Onlinementioning

confidence: 94%

Rare RET Variant p.D707E in a Chinese Pedigree with Hereditary Medullary Thyroid Carcinoma

Zhang

Li²,

Li³

et al. 2016

Pathobiology

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Background: Hereditary medullary thyroid carcinoma (HMTC) is thought to be associated with germline mutations of the RET proto-oncogene. Methods: We detected RET proto-oncogene germline mutations from a pedigree with HMTC in the east of China and investigated the characteristics of these mutations in this pedigree and their correlation with HMTC by direct sequencing of all 21 exons in the RET gene of all 46 subjects. Results and Conclusion: (1) Thirteen types of RET gene variants were detected in this pedigree. Of these, p.F285S in exon 4, c.854_855CA in exon 4, and p.D707E in exon 11 are reported for the first time in our study. (2) Both linkage disequilibrium analysis and logistic regression analysis showed a significant correlation between the p.D707E variant and HMTC (LOD = 3.69, OR = 4.413, p = 0.000167), indicating that this variant is a risk factor for medullary thyroid carcinoma (MTC). (3) The single-nucleotide polymorphisms (SNP) G691S in exon 11 (rs1799939), S904S in exon 15 (rs1800863), and rs2075912 and rs2565200 in the 3′-untranslated region of the RET proto-oncogene are in complete linkage disequilibrium (D' = 1, r² = 1); no correlation of these SNP and MTC was observed in this pedigree. (4) No hot-spot mutation of the RET proto-oncogene was detected in this pedigree. We drew the conclusion that the heterozygous nonsynonymous variant p.D707E in the RET proto-oncogene is rare, but it is a risk factor for hereditary MTC.

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Single nucleotide polymorphisms act as modifiers and correlate with the development of medullary and simultaneous medullary/papillary thyroid carcinomas in 2 large, non-related families with the RET V804M proto-oncogene mutation

Cited by 23 publications

References 23 publications

Association studies in thyroid cancer susceptibility: are we on the right track?

Association studies in thyroid cancer susceptibility: are we on the right track?

Familial multinodular goiter syndrome with papillary thyroid carcinomas: mutational analysis of the associated genes in 5 cases from 1 Chinese family

Rare RET Variant p.D707E in a Chinese Pedigree with Hereditary Medullary Thyroid Carcinoma

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