Variants in the <i>ATM‐CHEK2‐BRCA1</i> axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma

Wójcicka, Anna; Czetwertyńska, Małgorzata; Świerniak, Michał; Długosińska, Joanna; Maciąg, Monika; Czajka, Agnieszka; Dymecka, Kinga; Klinke, Anna; Kot, Adam; Płoski, Rafał; Chapelle, Albert de la; Jażdżewski, Krystian

doi:10.1002/gcc.22162

Cited by 54 publications

(40 citation statements)

References 39 publications

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“…The odds ratio for breast carcinoma given the I157T mutation was 1.5 in Poland, 1.4 for the Finnish population, 3.6 in the German population and 4.5 in the Byelorussian population [ 16 ],[ 17 ],[ 37 ]. Our results confirmed also recently published research from another region of Poland (central Poland) conducted on a large group of patients with papillary thyroid cancer, which showed OR = 2.2 (p = 2.37 −10 ) [ 38 ].…”

Section: Resultssupporting

confidence: 92%

The c.470 T > C CHEK2 missense variant increases the risk of differentiated thyroid carcinoma in the Great Poland population

Kaczmarek-Ryś

Ziemnicka

Hryhorowicz

et al. 2015

Hered Cancer Clin Pract

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BackgroundDifferentiated thyroid carcinoma (DTC) originates from thyroid follicular epithelial cells and belongs to a group of slowly progressing tumors with a relatively good prognosis. However, recurrences and metastases are a serious problem in advanced stages. Furthermore, progression from a well differentiated thyroid carcinoma to an aggressive anaplastic one is possible.The majority of differentiated thyroid carcinomas are sporadic but a few alleles increasing the cancer risk are known. One of them is the c.470 T > C (p.I157T, rs17879961) missense substitution in the CHEK2 gene.Aim of the studyThe aim of this study was to investigate whether this specific CHEK2 alteration, c.470 T > C, predisposes the Great Poland (Wielkopolska) population to thyroid cancer.Methods602 differentiated thyroid carcinoma patients and 829 controls randomly selected from population were genotyped for the presence of the c.470C allele using pyrosequencing. Hardy-Weinberg Equilibrium (HWE) was tested for both groups by chi-square distribution and Fisher’s exact test. The odds ratios (ORs), 95% confidence intervals (CIs), and p-values were calculated using the R software.ResultsThe results of genotyping showed the presence of the c.470C allele in 51 patients with a frequency of 4.49%, while in a controls in 42 patients with a frequency of 2.53%. We demonstrated that in the Great Poland population the c.470C CHEK2 variant increases the risk of developing differentiated thyroid cancer almost twice (OR = 1.81, p = 0.004). The risk of papillary thyroid carcinoma in female patients homozygous for the c.470C allele was shown to increase almost 13-fold (OR = 12.81, p = 0.019).ConclusionsIdentification of c.470C CHEK2 gene variant ought to be taken into account by healthcare policymakers. Future well-designed and larger population studies are of great value in confirming these findings. Moreover, a combination of genetic factors together with environmental exposures should also be considered.Electronic supplementary materialThe online version of this article (doi:10.1186/s13053-015-0030-5) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 92%

The c.470 T > C CHEK2 missense variant increases the risk of differentiated thyroid carcinoma in the Great Poland population

Kaczmarek-Ryś

Ziemnicka

Hryhorowicz

et al. 2015

Hered Cancer Clin Pract

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“…Based on these data, it was difficult to figure out how this single polymorphism might be associated with a decreased cancer risk for individuals who were exposed to radiation. Instead, a gene-gene interaction of the ATM gene with BRCA1 has been reported [28, 52]. Therefore, it could be expected that the polygenic action of unidentified alleles or genes probably played a non-negligible role on the function of the rs1801516 polymorphism.…”

Section: Discussionmentioning

confidence: 99%

Gene-environment interaction for polymorphisms in ataxia telangiectasia-mutated gene and radiation exposure in carcinogenesis: results from two literature-based meta-analyses of 27120 participants

Zhao

Yang

et al. 2016

Oncotarget

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PurposeWe conducted two meta-analyses of ATM genetic polymorphisms and cancer risk in individuals with or without radiation exposure to determine whether there was a joint effect between the ATM gene and radiation exposure in carcinogenesis.Resultsrs1801516, which was the only ATM polymorphism investigated by more than 3 studies of radiation exposure, was eligible for the present study. The meta-analysis of 23333 individuals without radiation exposure from 24 studies showed no association between the rs1801516 polymorphism and cancer risk, without heterogeneity across studies. The meta-analysis of 3787 individuals with radiation exposure from 6 studies showed a significant association between the rs1801516 polymorphism and a decreased cancer risk, with heterogeneity across studies. There was a borderline-significant difference between the ORs of the two meta-analyses (P = 0.066), and the difference was significant when only Caucasians were included (P = 0.011).Materials and methodsPublications were identified by searching PubMed, EMBASE, Web of Science, and CNKI databases. Odds ratios (ORs) were calculated to estimate the association between ATM genetic polymorphisms and cancer risk. Tests of interaction were used to compare differences between the ORs of the two meta-analyses.ConclusionsOur meta-analyses confirmed the presence of a gene-environment interaction between the rs1801516 polymorphism and radiation exposure in carcinogenesis, whereas no association was found between the rs1801516 polymorphism and cancer risk for individuals without radiation exposure. The heterogeneity observed in the meta-analysis of individuals with radiation exposure might be due to gene-ethnicity or gene-gene interactions. Further studies are needed to elucidate sources of the heterogeneity.

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“…More recently, it has been reported that this conserved variant falling just upstream of the FAT kinase domain [ 23 ] may modify the genetic susceptibility to DTC and its clinical manifestation in carriers of a rare BRCA1 pathogenic variant. In particular, both ATM rs1801516 and BRCA1 rs16941 variants modify the impact of male gender on clinical variables [ 24 ]. An emerging hypothesis is that ATM is exploited in undamaged cells in other signalling pathways that DSBs repair in response to various stimuli or physiological situations such as hormonal exposure [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Common variants at the 9q22.33, 14q13.3 and ATM loci, and risk of differentiated thyroid cancer in the Cuban population

et al. 2015

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Background: The incidence of differentiated thyroid carcinoma (DTC) in Cuba is low and the contribution of host genetic factors to DTC in this population has not been investigated so far. Our goal was to assess the role of known risk polymorphisms in DTC cases living in Havana. We genotyped five polymorphisms located at the DTC susceptibility loci on chromosome 14q13.3 near NK2 homeobox 1 (NKX2-1), on chromosome 9q22.33 near Forkhead factor E1 (FOXE1) and within the DNA repair gene Ataxia-Telangiectasia Mutated (ATM) in 203 cases and 212 age-and sex-matched controls. Potential interactions between these polymorphisms and other DTC risk factors such as body surface area, body mass index, size, ethnicity, and, for women, the parity were also examined.Results: Significant association with DTC risk was found for rs944289 near NKX2-1 (OR per A allele = 1.6, 95% CI: 1.2-2.1), and three polymorphisms near or within FOXE1, namely rs965513 (OR per A allele = 1.7, 95% CI: 1.2-2.3), rs1867277 in the promoter region of the gene (OR per A allele = 1.5, 95% CI: 1.1-1.9) and the poly-alanine tract expansion polymorphism rs71369530 (OR per Long Allele = 1.8, 95% CI: 1.3-2.5), only the 2 latter remaining significant when correcting for multiple tests. Overall, no association between DTC and the coding SNP D1853N (rs1801516) in ATM (OR per A Allele = 1.1, 95% CI: 0.7-1.7) was seen. Nevertheless women who had 2 or more pregnancies had a 3.5-fold increase in risk of DTC if they carried the A allele (OR 3.5, 95% CI: 3.2-9.8) as compared to 0.8 (OR 0.8, 95% CI: 0.4-1.6) in those who had fewer than 2.Conclusions: We confirmed in the Cuban population the role of the loci previously associated with DTC susceptibility in European and Japanese populations through genome-wide association studies. Our results on ATM and the number of pregnancies raise interesting questions on the mechanisms by which oestrogens, or other hormones, alter the DNA damage response and DNA repair through the regulation of key effector proteins such as ATM. Due to the small size of our study and to multiple tests, all these results warrant further investigation.

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Variants in the ATM‐CHEK2‐BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma

Cited by 54 publications

References 39 publications

The c.470 T > C CHEK2 missense variant increases the risk of differentiated thyroid carcinoma in the Great Poland population

The c.470 T > C CHEK2 missense variant increases the risk of differentiated thyroid carcinoma in the Great Poland population

Gene-environment interaction for polymorphisms in ataxia telangiectasia-mutated gene and radiation exposure in carcinogenesis: results from two literature-based meta-analyses of 27120 participants

Common variants at the 9q22.33, 14q13.3 and ATM loci, and risk of differentiated thyroid cancer in the Cuban population

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