Over-representation of a germline variant in the gene encoding RET co-receptor GFRα-1 but not GFRα-2 or GFRα-3 in cases with sporadic medullary thyroid carcinoma

Gimm, Oliver; Dziema, Heather; Brown, Jay C.; Hoang‐Vu, Cuong; Hinze, Raoul; Dralle, Henning; Mulligan, Lois M.; Eng, Charis

doi:10.1038/sj.onc.1204289

Cited by 29 publications

(21 citation statements)

References 34 publications

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“…With regard to germline sequence variant in intron 14 (IVS14–24G→A), it has been found to be both associated [69] and unassociated [81] with sporadic MTC. Although GFRα1–193, a polymorphism of the GFR α 1 gene, was found to be associated with sporadic MTC in a small case-control study [82], this result was not confirmed in 2 larger studies [77,83]. …”

Section: Molecular Biology Of Mtc and The Ret Proto-oncogenementioning

confidence: 64%

Medullary Thyroid Cancer: Molecular Biology and Novel Molecular Therapies

Çakır¹,

Grossman²

2009

Neuroendocrinology

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Medullary thyroid cancer (MTC) arises from neural-crest-derived parafollicular C cells of the thyroid gland and accounts for approximately 4% of all thyroid cancers. Up to 25–30% of MTC cases occur as inherited disorders while the remaining cases represent the sporadic form of the disease. In this review, the structure and signalling properties of the RET proto-oncogene in its wild-type and mutant forms, and its role in hereditary and sporadic MTC, are discussed. A full data search was performed through PubMed over the years 2000–2008 with the key words ‘medullary thyroid cancer, treatment, molecular biology, RET, molecular mechanism’, and all relevant publications have been included, together with selected publications prior to that date. We also review novel therapies for metastatic MTC, especially the tyrosine kinase inhibitors which have activity at multiple receptor subtypes, and summarize the current ongoing trials in this area. While such tyrosine kinase inhibitors, particularly those affecting RET activity such as vandetanib, sorafenib and sunitinib, are promising, the low rate of partial responses and absence of complete responses in all of the various trials of monotherapy emphasize the need for new and more effective single agents or combinations of therapeutic agents with acceptable toxicity.

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Section: Molecular Biology Of Mtc and The Ret Proto-oncogenementioning

confidence: 64%

Medullary Thyroid Cancer: Molecular Biology and Novel Molecular Therapies

Çakır¹,

Grossman²

2009

Neuroendocrinology

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“…Association studies in sMTC reported negative results, apart from for several RET SNPs (Fugazzola et al 2008, Fernandez et al 2009, for variants in GFRA2 (Gimm et al 2001b, Borrego et al 2002, Cebrian et al 2005, GFRA3 (Gimm et al 2001b, Borrego et al 2002, Cebrian et al 2005, Ruiz-Llorente et al 2007, GFRA4 (Cebrian et al 2005), NTRK2 (Gimm et al 2001a), and NTRK3 (Gimm et al 2001a), among many others, assessed in the study by Ruiz-Llorente et al (2007). Some of these genes should not be completely discarded, however, due to the limited power of some of the studies.…”

Section: Negative Resultsmentioning

confidence: 99%

“…One of them is the GDNF family receptor a 1, which acts as a co-receptor of RET, and is encoded by the GFRA1 gene. The promoter variant rs45568534 (c.K193COG) was first associated with sMTC development in a small group of patients, who also showed a tendency toward a higher expression of tumoral GFRA1 at both the mRNA and the protein levels when carrying the risk alleles (Gimm et al 2001b). This association was not reproduced in larger casecontrol studies (Borrego et al 2002, Cebrian et al 2005, although another variant in the 3 0 UTR (rs1061413, c.*946COG) was significantly associated (Cebrian et al 2005).…”

Section: Ret Polymorphisms In Smtcmentioning

confidence: 99%

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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“…32 Recently, it has been reported that a -193C to G sequence variant in the 5Ј-untranslated region of GFRA1 was found in 15% of cases with sporadic medullary thyroid cancer, suggesting an association of this variant with carcinogenesis. 33 Despite the limitations of a cross-sectional study, our analyses showed a prominent effect of 3 gene polymorphisms on the risk of developing HCC. Because most HCV-related HCCs arise from a background of cirrhosis, these 3 SNPs might have association with cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

Large-Scale Search of Single Nucleotide Polymorphisms for Hepatocellular Carcinoma Susceptibility Genes in Patients With Hepatitis C *

Kato

Wang

et al. 2005

Hepatology

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Hepatitis C virus (HCV) infection is a major risk factor for developing hepatocellular carcinoma (HCC). The host genetic factors that are involved in the development of HCC in patients with HCV infection remain to be investigated. To search for single nucleotide polymorphisms (SNPs) in HCC susceptibility genes, 393 SNPs in 171 candidate genes were examined in 188 Japanese patients with chronic HCV infection, including 77 patients with HCC. HCC-related SNPs were then examined in another 188 patients (including 93 patients with HCC) with chronic HCV infection. Haplotype analyses of HCC-related genes were performed in a total of 376 patients. Of the 393 SNPs, 31 SNPs in 29 genes were significantly associated with HCC based on an initial screening (P < .05). Of these 31 SNPs, 3 SNPs of 3 genes (SCYB14, GFRA1, and CRHR2) were significantly associated with HCC in a secondary screening. Haplotype analyses of these 3 genes identified 2 haplotype blocks associated with HCC. In conclusion, these SNPs and haplotypes located in the SCBY14, CRHR2, and GFRA1 genes will be used as markers to identify a subgroup of Japanese patients with chronic HCV infection who are at high risk of developing HCC. M ore than 170 million people worldwide are estimated to have chronic hepatitis C virus (HCV) infection (http://www.who.int/inf-fs/ en/fact164.html). The most important sequelae of chronic HCV infection are progressive liver fibrosis leading to cirrhosis, and hepatocellular carcinoma (HCC), which is responsible for significant morbidity and mortality throughout the world. 1-4 Many factors, such as alcohol intake, older age at time of infection, male sex, and coinfection with hepatitis B virus, are reported to accelerate disease progression in HCV infection. [5][6][7][8] In addition, host genetic factors have been reported to affect the risk of developing HCC. [9][10][11][12][13][14][15] Recently, we reported that genetic polymorphisms in interleukin-1␤ 11 and uridine 5Ј-diphosphate-glucuronosyltransferase 1A7 12 are associated with the development of HCC in Japanese patients with chronic HCV infection. Genetic polymorphisms in CYP enzymes, 13 the microsomal epoxide hydrolase gene, 14 and the aldehyde dehydrogenase 2 gene 15 also have been reported to be associated with HCC and the severity of HCV-related liver disease. The number of candidate genes that have been examined is, however, rather limited.We performed a large-scale candidate-gene-based search of single-nucleotide polymorphisms (SNPs) to look for SNPs in genes associated with HCC susceptibility. A total of 393 SNPs in 171 candidate genes were examined in Japanese patients with chronic HCV infection.

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Over-representation of a germline variant in the gene encoding RET co-receptor GFRα-1 but not GFRα-2 or GFRα-3 in cases with sporadic medullary thyroid carcinoma

Cited by 29 publications

References 34 publications

Medullary Thyroid Cancer: Molecular Biology and Novel Molecular Therapies

Medullary Thyroid Cancer: Molecular Biology and Novel Molecular Therapies

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

Large-Scale Search of Single Nucleotide Polymorphisms for Hepatocellular Carcinoma Susceptibility Genes in Patients With Hepatitis C *

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