Allelic variant at −79 (C&gt;T) in CDKN1B (p27Kip1) confers an increased risk of thyroid cancer and alters mRNA levels

Landa, Iñigo; Montero‐Conde, Cristina; Malanga, Donatella; Gisi, Silvia De; Pita, Guillermo; Leandro-García, Luis-Javier; Inglada-Pérez, Lucía; Letón, Rocío; Marco, Carmela De; Rodríguez‐Antona, Cristina; Viglietto, Giuseppe; Robledo, Mercedes

doi:10.1677/erc-09-0016

Cited by 36 publications

(35 citation statements)

References 40 publications

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“…Within the 1‐kb region surrounding CDKN1B , six SNPs resulted to be nominal significant ( P ≤ 0.05). Interestingly, the T allele of rs34330, which maps to the CDKN1B promoter region (‐79 C/T), has been reported to be associated with other tumours including breast 26, endometrial 27, lung 28 and thyroid cancer and with low gene expression of CDKN1B 29. Together, these data led us to exclude other SNPs from further analyses, and to focus our attention on rs34330 ( P = 0.015; OR = 1.15).…”

Section: Resultsmentioning

confidence: 98%

The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma

Capasso

McDaniel

Cimmino

et al. 2017

J Cellular Molecular Medi

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The genetic aetiology of sporadic neuroblastoma is still largely unknown. We have identified diverse neuroblastoma susceptibility loci by genomewide association studies (GWASs); however, additional SNPs that likely contribute to neuroblastoma susceptibility prompted this investigation for identification of additional variants that are likely hidden among signals discarded by the multiple testing corrections used in the analysis of genomewide data. There is evidence suggesting the CDKN1B, coding for the cycle inhibitor p27Kip1, is involved in neuroblastoma. We thus assess whether genetic variants of CDKN1B are associated with neuroblastoma. We imputed all possible genotypes across CDKN1B locus on a discovery case series of 2101 neuroblastoma patients and 4202 genetically matched controls of European ancestry. The most significantly associated rs34330 was analysed in an independent Italian cohort of 311 cases and 709 controls. In vitro functional analysis was carried out in HEK293T and in neuroblastoma cell line SHEP‐2, both transfected with pGL3‐CDKN1B‐CC or pGL3‐CDKN1B‐TT constructs. We identified an association of the rs34330 T allele (‐79C/T) with the neuroblastoma risk (Pcombined = 0.002; OR = 1.17). The risk allele (T) of this single nucleotide polymorphism led to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27Kip1 promoter (P < 0.05). Three independent sets of neuroblastoma tumours carrying ‐79TT genotype showed a tendency towards lower CDKN1B mRNA levels. Our study shows that a functional variant, associated with a reduced CDKN1B gene transcription, influences neuroblastoma susceptibility.

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Section: Resultsmentioning

confidence: 98%

The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma

Capasso

McDaniel

Cimmino

et al. 2017

J Cellular Molecular Medi

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“…Among these, 11 publications appeared to meet the inclusion criteria and were subjected to a detailed full-text review. [12][13][14][15][16][17][18][19][20][21][22] We further excluded three publications because they did not provide detailed genotype data of cases and controls. 18,20,22 Therefore, our final data pooling consisted of eight publications (Table 1).…”

Section: Meta-analyses Databasementioning

confidence: 99%

“…[12][13][14][15][16][17][18][19][20][21][22] We further excluded three publications because they did not provide detailed genotype data of cases and controls. 18,20,22 Therefore, our final data pooling consisted of eight publications (Table 1). [12][13][14][15][16][17]19,21 Three of the eight case-control studies were conducted in Caucasians, and the remaining five studies were conducted in Asians.…”

Section: Meta-analyses Databasementioning

confidence: 99%

“…between the p27V109G polymorphism and breast cancer risk, [15][16][17][18] pancreatic cancer risk, 19,20 prostate cancer risk, 21 and thyroid cancer risk. 22 To investigate whether the p27V109G variant is indeed associated with cancer susceptibility, we performed a systematic review of the published articles, and conducted a meta-analysis to gain insights into the relationship between the p27V109G polymorphism and cancer risk.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

p27^Kip1 V109G Polymorphism and Cancer Risk: A Systematic Review and Meta-Analysis

Feng

Xu²,

Tang³

et al. 2012

Cancer Biotherapy and Radiopharmaceuticals

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Relationship between the p27Kip1 (here after referred to as p27) V109G polymorphism and cancer risk has been extensively studied; however, results from different studies were not fully consistent. Therefore, we carried out a meta-analysis to comprehensively assess the correlation between the p27V109G polymorphism and the cancer risk. Articles on the relationship of the p27V109G polymorphism with cancer risk were searched from Medline, Pub Med, and Web of science databases. A total of eight eligible studies with 3591 cases and 3799 controls were included in this meta-analysis. Overall, it seemed that the G allele was not associated with the elevated cancer risk (pooled odds ratio [OR] = 0.98, 95% confidence interval [CI]: 0.88-1.09, p = 0.68, fixed effects). Analyses in different populations revealed that no statistically significant associations between the G allele and cancer risk were demonstrated in Caucasians or Asians. When analyzed in different types of cancer that, from two studies, the G allele was found to be associated with a decreased risk of prostate cancer in a dominant genetic model (pooled OR = 0.60, 95% CI = 0.36-0.98, p = 0.04, fixed effects), but did not alter the breast cancer risk from four studies. In conclusion, this meta-analysis indicated that the p27V109G polymorphism did not correlate with the overall cancer risk in the general population.

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“…Indeed, patients with the variant AA genotype at position K823 of CDKN1B present low risk of restenosis following coronary stenting, and the variant K838A allele is associated with augmented gene transcription (González et al 2004), whereas the K79COT allelic variant is related to reduced transcription in in vitro studies (Landa et al 2010). 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).…”

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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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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Allelic variant at −79 (C>T) in CDKN1B (p27Kip1) confers an increased risk of thyroid cancer and alters mRNA levels

Cited by 36 publications

References 40 publications

The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma

The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma

p27^Kip1 V109G Polymorphism and Cancer Risk: A Systematic Review and Meta-Analysis

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

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Allelic variant at −79 (C>T) in CDKN1B (p27Kip1) confers an increased risk of thyroid cancer and alters mRNA levels

Cited by 36 publications

References 40 publications

The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma

The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma

p27Kip1 V109G Polymorphism and Cancer Risk: A Systematic Review and Meta-Analysis

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

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p27^Kip1 V109G Polymorphism and Cancer Risk: A Systematic Review and Meta-Analysis