The role of ATM-CHEK2-BRCA1 axis in determination of genetic predisposition and clinical presentation of papillary thyroid carcinoma

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

doi:10.1530/endoabs.35.p1129

Cited by 10 publications

(12 citation statements)

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“…Of note, the association between the I157T allele and thyroid cancer was also confirmed in a recent study from central Poland of 1,781 patients with papillary thyroid cancer and 2,081 healthy control reported odds ratio of 2.2 (p < 0.0001), but truncating mutations were not analyzed and data on family history and other primary cancers were not provided. 29 CHEK2 mutations are associated with a number of cancers; we found that a positive family history of breast cancer, lymphoma and sarcoma was more common in CHEK2 carriers than in non-carriers and the difference was significant (p < 0.05). Also carriers reported more frequently family history of thyroid cancer, prostate cancer and endometrial cancer.…”

Section: Discussionmentioning

confidence: 68%

“…In aggregate, these data provide evidence that both truncating and missense mutations of CHEK2 confer thyroid cancer risk, and that a truncating mutation appears to confer a higher risk than the missense mutation. Of note, the association between the I157T allele and thyroid cancer was also confirmed in a recent study from central Poland of 1,781 patients with papillary thyroid cancer and 2,081 healthy control reported odds ratio of 2.2 ( p < 0.0001), but truncating mutations were not analyzed and data on family history and other primary cancers were not provided …”

Section: Discussionmentioning

confidence: 73%

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CHEK2mutations and the risk of papillary thyroid cancer

et al. 2015

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Mutations in the cell cycle checkpoint kinase 2 (CHEK2) tumor suppressor gene are associated with multi-organ cancer susceptibility including cancers of the breast and prostate. A genetic association between thyroid and breast cancer has been suggested, however little is known about the determinants of this association. To characterize the association of CHEK2 mutations with thyroid cancer, we genotyped 468 unselected patients with papillary thyroid cancer and 468 (matched) cancer-free controls for four founder mutations of CHEK2 (1100delC, IVS2 1 1G>A, del5395 and I157T). We compared the family histories reported by patients with a CHEK2 mutation to those of non-carriers. A CHEK2 mutation was seen in 73 of 468 (15.6%) unselected patients with papillary thyroid cancer, compared to 28 of 460 (6.0%) age-and sex-matched controls (OR 3.3; p < 0.0001). A truncating mutation (IVS2 1 1G>A, 1100delC or del5395) was associated with a higher risk of thyroid cancer (OR 5 5.7; p 5 0.006), than was the missense mutation I157T (OR 5 2.8; p 5 0.0001). CHEK2 mutation carriers reported a family history of breast cancer 2.2 times more commonly than non-carriers (16.4% vs.8.1%; p 5 0.05). A CHEK2 mutation was found in seven of 11 women (63%) with multiple primary cancers of the breast and thyroid (OR 5 10; p 5 0.0004). These results suggest that CHEK2 mutations predispose to thyroid cancer, familial aggregations of breast and thyroid cancer and to double primary cancers of the breast and thyroid.Thyroid cancer is one of the most common cancers in young women. 1 The most common type of thyroid cancer is papillary thyroid cancer, which comprises 80% of all thyroid tumors. 2 Approximately 5% of cases of papillary thyroid cancer are familial. 3 Epidemiologic data suggests that inherited factors contribute to papillary thyroid cancer. 4 A familial association between thyroid and breast cancer has been suggested; a prior history of thyroid cancer is a risk factor for breast cancer and vice versa (relative risks in the range of 1.7-12.4). 5-11 However, outside of a rare inherited syndrome of cancer susceptibility called Cowden syndrome (caused by PTEN mutations) in which both breast and thyroid cancer risks are increased, the genetic basis for the association between these two cancers has not been established. 12 Cell cycle checkpoint kinase 2 (CHEK2) is a key component of the DNA damage pathway. [13][14][15][16] Four founder alleles of CHEK2 are present in Poland, three of these result in a truncated CHEK2 protein (c.1100delC, c.444 1 1G>A, del5395) and the fourth (c.470T>C) is a missense substitution of an isoleucine for a threonine in exon 3. 17 All these alleles were associated with multi-organ cancer susceptibility, including cancers of the breast and thyroid. [18][19][20] In the current study, we wished to better characterize the association between CHEK2 mutations and thyroid cancer. We genotyped 468 unselected patients with papillary thyroid cancer and 468 matched cancer-free controls for four founder mutations of CHEK2. We also ...

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 73%

CHEK2mutations and the risk of papillary thyroid cancer

et al. 2015

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“…The same variant also modifies the risk for ionizing radiation-induced or sporadic papillary thyroid carcinoma in addition to BRCA1 and p53 variants (Akulevich et al, 2009;Wojcicka et al, 2014). Although association of ATM and risk of breast cancer has been reported as well, this was not confirmed in a recent meta-analysis (Gao et al, 2010).…”

Section: Discussionmentioning

confidence: 96%

Updated Field Synopsis and Systematic Meta-Analyses of Genetic Association Studies in Cutaneous Melanoma: The MelGene Database

Antonopoulou

Stefanaki

Lill

et al. 2015

Journal of Investigative Dermatology

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We updated a field synopsis of genetic associations of cutaneous melanoma (CM) by systematically retrieving and combining data from all studies in the field published as of August 31, 2013. Data were available from 197 studies, which included 83,343 CM cases and 187,809 controls and reported on 1,126 polymorphisms in 289 different genes. Random-effects meta-analyses of 81 eligible polymorphisms evaluated in >4 data sets confirmed 20 single-nucleotide polymorphisms across 10 loci (TYR, AFG3L1P, CDK10, MYH7B, SLC45A2, MTAP, ATM, CLPTM1L, FTO, and CASP8) that have previously been published with genome-wide significant evidence for association (P<5 × 10(-8)) with CM risk, with certain variants possibly functioning as proxies of already tagged genes. Four other loci (MITF, CCND1, MX2, and PLA2G6) were also significantly associated with 5 × 10(-8)

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“…Several germline changes have been reported to predispose to DTC, including variants in microRNA-146a, ATM-CHEK2-BRCA1 pathway, TERT gene, and 5 SNPs pinpointed by GWAS study (2)(3)(4)(5)(12)(13)(14)(15). So far, no study revealed the influence of germline (inherited) variants on the overall mortality of patients with thyroid cancer.…”

Section: Discussionmentioning

confidence: 99%

Association between GWAS-Derived rs966423 Genetic Variant and Overall Mortality in Patients with Differentiated Thyroid Cancer

Świerniak

Wójcicka

Czetwertyńska

et al. 2016

Clinical Cancer Research

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Purpose: Five germline genetic variants (rs116909374, rs965513, rs944289, rs966423, and rs2439302) have been associated in genome-wide association studies (GWAS) with increased risk of differentiated thyroid cancer (DTC), but their role in mortality of patients has not been established. Also, no preoperative marker of the clinical outcome of thyroid cancer had yet been identified. The aim of the study was to investigate the relationship between the variants and overall mortality in patients with DTC.Experimental Design: Retrospective study of 1,836 patients (1,643 women, 193 men) with median age at diagnosis of 49 years and overall median follow-up time of 8.7 years after initial treatment at a single comprehensive cancer center between 1990 and 2013.Results: Among 5 variants, rs966423 was associated with increased mortality, which was 6.4% (33 of 518) versus 3.7% (47 of 1,259) in TT carriers versus CC/CT carriers (P ¼ 0.017). The HR of TT versus TC/CC carriers was 1.6 [95% confidence interval (CI), 1.02-2.49; P ¼ 0.038] after adjustment for age at diagnosis and sex. Importantly, the association of rs966423 with mortality remained valid when clinicopathologic risk factors were included in the model (HR, 1.89; 95% CI, 1.14-3.13; P ¼ 0.014). Higher rs966423-associated patient mortality of TT versus CC/CT carriers was also observed in interaction with angioinvasion (adjusted HR, 3.48; 95% CI, 1.67-7.22; P < 0.001), lymph node metastasis (adjusted HR, 3.47; 95% CI, 1.16-10.4; P ¼ 0.018), extrathyroidal invasion (adjusted HR, 2.07; 95% CI, 1.15-3.73; P ¼ 0.013).Conclusions: The presence of the rs966423-TT genotype was associated with a significant increase in overall mortality of patients with DTC. Contrary to BRAF mutation and other somatic changes, the status of germline rs966423 is known before the treatment and might be used in the management of mortality risk by means of modification of therapy.

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The role of ATM-CHEK2-BRCA1 axis in determination of genetic predisposition and clinical presentation of papillary thyroid carcinoma

Cited by 10 publications

References 36 publications

CHEK2mutations and the risk of papillary thyroid cancer

CHEK2mutations and the risk of papillary thyroid cancer

Updated Field Synopsis and Systematic Meta-Analyses of Genetic Association Studies in Cutaneous Melanoma: The MelGene Database

Association between GWAS-Derived rs966423 Genetic Variant and Overall Mortality in Patients with Differentiated Thyroid Cancer

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