Alterations of CHEK2 forkhead-associated domain increase the risk of Hodgkin lymphoma

Havránek, Ondřej; Špaček, Martin; Hubáček, Petr; Móciková, Heidi; Marková, Jana; Trněný, Marek; Kleibl, Zdeněk

doi:10.4149/neo_2011_05_392

Cited by 13 publications

(6 citation statements)

References 23 publications

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“…Also carriers reported more frequently family history of thyroid cancer, prostate cancer and endometrial cancer. These results further support that CHEK2 is a cancer susceptibility gene associated with increased risk of cancer at several different sites, including breast, prostate, thyroid, colon, kidney, stomach, (low‐grade) ovarian, bladder, chronic lymphocytic leukemia, Hodgkin lymphoma and a reduced risk of other cancers (lung and laryngeal cancer) . The current study suggests that the risk of sarcoma and non‐Hodgkin lymphoma may also be increased.…”

Section: Discussionsupporting

confidence: 83%

“…These results further support that CHEK2 is a cancer susceptibility gene associated with increased risk of cancer at several different sites, including breast, prostate, thyroid, colon, kidney, stomach, (low-grade) ovarian, bladder, chronic lymphocytic leukemia, Hodgkin lymphoma and a reduced risk of other cancers (lung and laryngeal cancer). [30][31][32][33][34][35][36] The current study suggests that the risk of sarcoma and non-Hodgkin lymphoma may also be increased. Of note, CHEK2 mutations were first detected in patients with Li-Fraumeni type families, and in the original studies of CHEK2 mutations and Li-Fraumeni syndrome, cancers of the breast, colon, ovary, endometrium, kidney, stomach were reported.…”

Section: Discussionmentioning

confidence: 63%

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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: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 63%

CHEK2mutations and the risk of papillary thyroid cancer

et al. 2015

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“…Previous studies have revealed an association between the CHEK2 I157T variant and cancer susceptibility. However, the results were conflicting, including an increased risk (Cybulski et al, 2004a(Cybulski et al, , 2004b(Cybulski et al, , 2007a(Cybulski et al, , 2007bKilpivaara et al, 2004Kilpivaara et al, , 2006Bogdanova et al, 2005;Irmejs et al, 2006;Kleibl et al, 2009;Serrano-Fernandez et al, 2009;Havranek et al, 2011;Domagala et al, 2012), a reduced risk , and no association (Dufault et al, 2004;Debniak et al, 2008;Kleibl et al, 2008;Konstantinova et al, 2009Konstantinova et al, , 2010Mohelnikova-Duchonova et al, 2010;Bayram et al, 2012Bayram et al, , 2013.…”

Section: Introductionmentioning

confidence: 94%

The Effect of CHEK2 Variant I157T on Cancer Susceptibility: Evidence from a Meta-Analysis

Han

Guo

Liu

2013

DNA and Cell Biology

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Cell cycle checkpoint kinase 2 (CHEK2) is a checkpoint kinase that plays an important role in the DNA damage signaling network. Numerous epidemiological studies have evaluated the association between the CHEK2 I157T variant and cancer susceptibility. However, the results of these studies on the association remain conflicting. The main purpose of this study was to integrate previous results and explore whether the CHEK2 I157T variant is associated with cancer susceptibility. PubMed, Embase (before 2012-10-1), Google Scholar, and CBMdisc were searched for studies on the relationship of the CHEK2 I157T variant and the incidence of cancer. Eligible articles were included for data extraction. The main outcome was the frequency of CHEK2 I157T polymorphisms between cases and controls. Comparison of the distribution of SNP was mainly performed using Review Manager 5.0. The odds ratio (OR) and its 95% confidence interval (95% CI) were used to assess the strength of association. In total, 26,336 cases and 44,219 controls from 18 case-control studies were used in this meta-analysis, and significant associations of the CHEK2 I157T variant with cancer susceptibility were found (OR, 1.39; 95% CI, 1.19-1.63; p<0.0001), breast cancer (OR=1.58, 95% CI=1.42-1.75, p<0.00001) and colorectal cancer (OR=1.67, 95% CI=1.24-2.26, p=0.0008). We also found an association of the CHEK2 I157T variant with familial cases (OR=1.85, 95% CI=1.51-2.26, p<0.00001). However, the association was not established for other types of cancer (OR=1.09, 95% CI=0.75-1.57, p=0.66). This meta-analysis demonstrates that the CHEK2 I157T variant was an important cancer gene, which increases cancer risk, especially in breast and colorectal cancer in Caucasian, and the bioinformatic analysis showed this change was mainly attributed to the decreased hydrophobicity of CHEK2 157T.

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“…Cell cycle checkpoint kinase 2 (CHEK2) has been identified as a type of serine/threonine protein kinase, located in chromosome 22 q12.1 of humans and yeast. It has been confirmed as an important mediator of the DNA damage response pathway, and as a susceptibility gene in several types of cancer (16,17). As a tumor suppressor gene, CHEK2 is vital for the induction of cell cycle arrest and cell apoptosis following DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Associations between mutations of the cell cycle checkpoint kinase 2 gene and gastric carcinogenesis

Hong

Shi

Zhang

et al. 2017

Molecular Medicine Reports

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Gastric cancer is the most common malignant tumor of the digestive system. The etiology of gastric cancer is complex, and susceptibility at the genetic level remains to be fully elucidated in genetic investigations. In the present study, mutations of the cell cycle checkpoint kinase 2 (CHEK2) gene and its association with gastric cancer were examined. Reverse transcription‑quantitative polymerase chain reaction technology was used to detect the expression of CHEK2 and it was found that the expression of CHEK2 was low in gastric cancer. Using sequencing analysis, it was found that the low expression level of CHEK2 was associated with expression of its mutation. The present study also established a CHEK2‑overexpressing mutant and confirmed that CHEK2 promoted gastric cancer cell proliferation. Overexpression of the CHEK2 mutation was confirmed to promote cancer cell migration and invasion. Furthermore, western blot analysis results revealed that overexpression of the CHEK2 mutation downregulated E‑cadherin and upregulated vimentin expression, indicating the mechanism underlying the altered biological behavior. These results suggested that there was a correlation between mutation of the CHEK2 gene and gastric cancer, and provided an experimental basis for antitumor drug investigation and development according to its mutation target.

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Alterations of CHEK2 forkhead-associated domain increase the risk of Hodgkin lymphoma

Cited by 13 publications

References 23 publications

CHEK2mutations and the risk of papillary thyroid cancer

CHEK2mutations and the risk of papillary thyroid cancer

The Effect of CHEK2 Variant I157T on Cancer Susceptibility: Evidence from a Meta-Analysis

Associations between mutations of the cell cycle checkpoint kinase 2 gene and gastric carcinogenesis

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