CDKN1B V109G polymorphism a new prognostic factor in sporadic medullary thyroid carcinoma

Pasquali, Daniela; Circelli, Luisa; Faggiano, Antongiulio; Pancione, Massimo; Renzullo, Andrea; Elisei, Rossella; Romei, Cristina; Accardo, Giacomo; Coppola, Viviana Raffaella; Palma, Maurizio De; Ferollà, Piero; Grimaldi, Franco; Colao, Annamaria; Colantuoni, Vittorio

doi:10.1530/eje-10-0929

Cited by 31 publications

(34 citation statements)

References 30 publications

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“…In contrast, rs2066827 was not associated either with sporadic counterpart of MEN2-component neoplasias or with MTC or pheochromocytoma groups (PO0.05 in all models tested). To our knowledge, this is the first study that investigated p27 polymorphisms in pheochromocytoma, while two independent reports that were recently published analyzed the role of p27 variants in European MTC cohorts (Landa et al 2010, Pasquali et al 2011. In accordance to our results for Brazilian MTC patients, no association of p27-V109G with increased risk of sporadic MTC was observed in a large cohort of Spanish MTC cases, while a borderline significance was observed in the analysis of tumor risk of Italian MTC patients (Landa et al 2010, Pasquali et al 2011).…”

Section: Discussionsupporting

confidence: 89%

“…Furthermore, the coding 326TOG (V109G) allelic variant has been associated with cancer risk and progression of different tumors including prostate cancer (Kibel et al 2003), oral squamous cell carcinoma (Li et al 2004), invasive epithelial ovarian cancer (Gayther et al 2007), highgrade breast tumors (Tigli et al 2005), and pancreatic carcinoma (Chen et al 2010). A recent study has shown that the variant G allele at position 326 protects against thyroid cancer development (Pasquali et al 2011), so that the role of the V109G polymorphism in increasing/ decreasing tumor risk remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

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p27 variant and corticotropinoma susceptibility: a genetic and in vitro study

Sekiya

Bronstein

Benfini

et al. 2014

Endocrine-Related Cancer

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Germline mutations in p27 kip1 are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms of this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, nZ252; pheochromocytomas, nZ125; medullary thyroid carcinoma, nZ51; and parathyroid adenomas, nZ19) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (PZ0.01), particularly for those with ACTH-secreting pituitary adenomas (PZ0.005). In contrast, no association was found with GH-secreting pituitary tumors alone or with the sporadic counterpart of MEN2-component neoplasias. Our in vitro analyses revealed increased colony formation and cell growth rate for an AtT20 corticotropin mouse cell line overexpressing the p27-V109G variant compared with cells transfected with the WT p27. However, the genotypic effects in genetic and in vitro approaches were divergent. In accordance with our genetic data showing specificity for ACTH-secreting pituitary tissues, the overexpression of p27-V109G in a GH3 somatotropin rat cell line resulted in no difference compared with the WT. Pituitary tumors are one of the major clinical components of syndromes associated with the p27 pathogenic mutations MENX and MEN4. Our genetic and in vitro data indicate that the common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus far.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

p27 variant and corticotropinoma susceptibility: a genetic and in vitro study

Sekiya

Bronstein

Benfini

et al. 2014

Endocrine-Related Cancer

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“…The CDKN1B V109G polymorphism was reported to influence the clinical course of patients presenting sporadic MTC (15). In addition, cell cycle and apoptosis regulators have long been recognized as critical in the initiation of malignant cell proliferation and this study has recently demonstrated the influence of the presence of a C homozygous allele for the TP53 gene on the susceptibility to s-MTC (17).…”

Section: Introductionmentioning

confidence: 67%

“…Nine polymorphisms were genotyped: CDKN1A (rs1801270 and rs1059234), CDKN1B (rs2066827 and rs34330), CDKN2A (rs11515), CDKN2B (rs2069426, rs3731239, and rs1063192), and CDKN2C (rs12885) using the TaqMan system (Applied Biosystems), as described previously (17). These SNPs were chosen because they have previously been associated with thyroid carcinoma or other tumor risks as described in Table 1 (13,15,16,20,21,22).…”

Section: Genotypingmentioning

confidence: 99%

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Polymorphisms of cell cycle control genes influence the development of sporadic medullary thyroid carcinoma

Barbieri

Bufalo

Secolin

et al. 2014

European Journal of Endocrinology

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Background: The role of key cell cycle regulation genes such as, CDKN1B, CDKN2A, CDKN2B, and CDKN2C in sporadic medullary thyroid carcinoma (s-MTC) is still largely unknown. Methods: In order to evaluate the influence of inherited polymorphisms of these genes on the pathogenesis of s-MTC, we used TaqMan SNP genotyping to examine 45 s-MTC patients carefully matched with 98 controls. Results: A multivariate logistic regression analysis demonstrated that CDKN1B and CDKN2A genes were related to s-MTC susceptibility. The rs2066827*GTCGG CDKN1B genotype was more frequent in s-MTC patients (62.22%) than in controls (40.21%), increasing the susceptibility to s-MTC (ORZ2.47; 95% CIZ1.048-5.833; PZ0.038). By contrast, the rs11515*CGCGG of CDKN2A gene was more frequent in the controls (32.65%) than in patients (15.56%), reducing the risk for s-MTC (ORZ0.174; 95% CIZ0.048-0.627; PZ0.0075). A stepwise regression analysis indicated that two genotypes together could explain 11% of the total s-MTC risk. In addition, a relationship was found between disease progression and the presence of alterations in the CDKN1A (rs1801270), CDKN2C (rs12885), and CDKN2B (rs1063192) genes. WTrs1801270 CDKN1A patients presented extrathyroidal tumor extension more frequently (92%) than polymorphic CDKN1A rs1801270 patients (50%; PZ0.0376). Patients with the WT CDKN2C gene (rs12885) presented larger tumors (2.9G1.8 cm) than polymorphic patients (1.5G0.7 cm; PZ0.0324). On the other hand, patients with the polymorphic CDKN2B gene (rs1063192) presented distant metastases (36.3%; PZ0.0261). Conclusion: In summary, we demonstrated that CDKN1B and CDKN2A genes are associated with susceptibility, whereas the inherited genetic profile of CDKN1A, CDKN2B, and CDKN2C is associated with aggressive features of tumors. This study suggests that profiling cell cycle genes may help define the risk and characterize s-MTC aggressiveness.

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Genetic risk association of CDKN1A and RET gene SNPs with medullary thyroid carcinoma: Results from the largest MTC cohort and meta‐analysis

et al. 2019

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Background Medullary thyroid carcinoma (MTC) is a rare subtype of thyroid cancer. Other than gain‐of‐function RET mutations, no other genetic, lifestyle or environmental risk associations have been established for MTC. Several case‐control studies and meta‐analysis have examined the risk association of different SNPs with MTC in different populations but with contradictory or inconclusive results. Methods In a large cohort of 438 Indian MTC cases and 489 gender and ethnicity matched healthy controls from 1000 genome project, a comprehensive risk association of 13 SNPs of three pathways—detoxification, cell cycle regulation and RET was performed along with meta‐analysis of RET SNPs. Results Multivariate logistic regression analysis identified a protective risk association of CDKN1ASer31Arg SNP with both hereditary (OR 0.26; 95% confidence interval [CI] 0.13‐0.55; P < .001) and sporadic MTC (OR 0.53; 95% CI 0.36‐0.78; P = .001). An increased risk association was identified for NAT2Y94Y SNP (OR 1.62, 95% CI 1.17‐2.25, P = .004) and CDKN2A3′UTR SNP (OR 1.89, 95% CI 1.19‐2.98, P = .006) with sporadic MTC and RET S904S with hereditary MTC (OR 2.82, 95% CI 1.64‐4.86, P < .001). Meta‐analysis of RET SNPs including our cohort identified increased risk association of all four RET SNPs with MTC. Conclusion In this largest SNP risk association study for MTC and the only risk association study of the 13 most commonly studied MTC associated SNPs in a single cohort of this rare cancer, a significant protective risk association of CDKN1ASer31Arg SNP with MTC was shown for the first time. Meta‐analysis identified significant risk association of all four RET SNPs, not observed in previous meta‐analysis.

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CDKN1B V109G polymorphism a new prognostic factor in sporadic medullary thyroid carcinoma

Cited by 31 publications

References 30 publications

p27 variant and corticotropinoma susceptibility: a genetic and in vitro study

p27 variant and corticotropinoma susceptibility: a genetic and in vitro study

Polymorphisms of cell cycle control genes influence the development of sporadic medullary thyroid carcinoma

Genetic risk association of CDKN1A and RET gene SNPs with medullary thyroid carcinoma: Results from the largest MTC cohort and meta‐analysis

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