The CHEK2 gene I157T mutation and other alterations in its proximity increase the risk of sporadic colorectal cancer in the Czech population

Kleibl, Zdeněk; Havránek, Ondřej; Hlavata, I.; Novotný, Jan; Ševčı́k, Jan; Pohlreich, Petr; Souček, Pavel

doi:10.1016/j.ejca.2008.09.022

Cited by 39 publications

(38 citation statements)

References 29 publications

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“…Except for the c.542G>A (p.R181H) mutation, all other identified alterations were previously found in Czech breast, colorectal or pancreatic cancer patients [13,14,17]. The R181H was identified in breast and prostate cancer patients from Germany [18] and the USA [19], respectively, however, this variant most likely do not interfere with the function of the CHK2 (Align GVGD: Class C0) and together with c.538C>T (p.R180C -identified in one control subject) may represent neutral CHEK2 sequence variants.…”

Section: Resultsmentioning

confidence: 99%

“…Alteration c.475T>C (p.Y159H -previously described in one Czech breast cancer patient) affects highly conservative amino acid residue within the FHA-coding region (Align GVGD: Class C65) potentially influencing protein function [13]. Based on the computer prediction made in our previous studies, we deduced that intronic variants IVS1-5T>A and IVS2+24C>T may interfere with binding sites of splicing factors [13] and that IVS2-54C>T alters the most probable branching site [14], which both could lead to the aberrant splicing of CHEK2 mRNA, however, these hypotheses have not been confirmed using functional in vitro analyses so far. The most frequent c.470T>C (p.I157T) variant is localized within the conserved sequence of CHEK2 FHA domain.…”

Section: Resultsmentioning

confidence: 99%

“…We ascertained six different CHEK2 alterations localized within FHA-coding region (c.470T>C, c.475T>C, c.542G>A) or in its proximity (IVS1-5T>A, IVS2+24C>T, IVS2-54C>T (this variant was erroneously referred to as IVS2-55C>T in our previous publications [14,17]; Table 2). The overall fre- quency of CHEK2 alterations in the group of HL patients (5.7%) differed significantly from that characterized previously [13] in controls (2.8%; p = 0.04).…”

Section: Resultsmentioning

confidence: 99%

“…Clinical characteristics of patients are summarized in Table 1. Control group of 683 non-cancer individuals was described in detail previously including the results of CHEK2 mutation analysis [13,14]. All lymphoma patients and controls were of Caucasian origin from the same geographical area of the Czech Republic.…”

Section: Methodsmentioning

confidence: 99%

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

Havránek

Špaček

Hubáček

et al. 2011

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Checkpoint kinase 2 gene (CHEK2) codes for an important mediator of DNA damage response pathway. Mutations in the CHEK2 gene increase the risk of several cancer types, however, their role in Hodgkin lymphoma (HL) has not been studied so far. The most frequent CHEK2 alterations (including c.470T>C; p.I157T) cluster into the forkhead-associated (FHA) domaincoding region of the CHEK2 gene. We performed mutation analysis of the CHEK2 gene segment coding for FHA domain using denaturing high-performance liquid chromatography in 298 HL patients and analyzed the impact of characterized CHEK2 gene variants on the risk of HL development and progression-free survival (PFS). The overall frequency of CHEK2 alterations was significantly higher in HL patients (17/298; 5.7%) compared to the previously analyzed non-cancer controls (19/683; 2.8%; p = 0.04). Presence of any alteration within the analyzed region of the CHEK2 gene was associated with increased risk of HL development (OR = 2.11; 95% CI = 1.08 -4.13; p = 0.04). The most frequent I157T mutation was found in 4.0% of HL patients and 2.5% of controls (p = 0.22), however, the frequency of 5 other alterations (excluding I157T) was significantly higher in HL cases and associated with increased risk of HL development (OR = 5.81; 95% CI = 1.12 -30.12; p = 0.03). PFS in HL patients did not differ between CHEK2 mutation carriers and non-carriers. The predominant I157T mutation together with other alterations in its proximity represent moderate genetic predisposition factor increasing the risk of HL development.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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

Havránek

Špaček

Hubáček

et al. 2011

neo

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“…Positive associations were seen with the ovarian cystadenomas (P=0.005), borderline ovarian cancers (P=0.002) and low-grade invasive cancers (P=0.04) with I157T missense but there was no significant association in high grade invasive cancer (SzymanskaPasternak et al, 2006). In a study done regarding the effect of Ile157Thr mutation among 631 patients with colorectal cancer (CRC) in Czechoslovakia, the results were as following: Ile157Thr mutation of CHEK2 gene had significant association with sporadic CRC but there was no significant association with familial CRC (Kleibl et al, 2009). A research done regarding the evaluation of the relation between the variants of CHEK2 gene and malignant melanoma among 630 cases and 3700 controls in Poland, there was not significant association between the two factors (Debniak et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Lack of CHEK2 Gene Mutations in Differentiated Thyroid Carcinoma Patients using High Resolution Melting Analysis

Fayaz

Fard-Esfahani

Torbati³

2014

Asian Pacific Journal of Cancer Prevention

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Recently, mutations in the genes involved in cell cycle control, including CHEK2, are being considered as etiological factors in different kinds of cancers. The CHEK2 protein plays an important role in protecting damaged DNA from entering mitosis. In this study the potential effects of two common mutations IVS2+1G"A and Ile157Thr of CHEK2 gene in differentiated thyroid carcinoma (DTC) were evaluated. A total of 100 patients admitted to the Research Institute for Nuclear Medicine were diagnosed with DTC based on pathology reports of surgery samples. An additional 100 people were selected as a control group with no cancer history. PCR-HRM (high resolution melting) analysis was performed to deal with each of mutations in all case and control samples separately. During the analysis of IVS2+1G"A and Ile157Thr mutations of CHEK2 gene in the case and control groups, all the samples were identified as wild homozygote type. The finding suggests that IVS2+1G"A and Ile157Thr mutations of CHEK2 gene do not constitute a risk factor for DTC in the Iranian population. However, further studies with larger population are required to confirm the outcome.

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CHEK2 mutations and HNPCC‐related colorectal cancer

Suchy

Cybulski

Wokołorczyk

et al. 2010

Intl Journal of Cancer

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Recently, the 1100delC variant of cell cycle checkpoint kinase 2 (CHEK2) has been reported to confer a colorectal cancer risk in hereditary non-polyposis-colorectal cancer (HNPCC) and HNPCC-related families in the Netherlands. To investigate whether CHEK2 mutations confer increased cancer risk in HNPCC and HNPCC-related families in Poland, we genotyped 463 probands from HNPCC and HNPCC-related families, and 5,496 controls for 4 CHEK2 alleles (1100delC, IVS211G>A, del5395, I157T). All 463 probands were screened for mutations in the HNPCC-related genes MSH2, MLH1 and MSH6. A positive association was observed for HNPCC-related cancer and the I157T missense CHEK2 mutation (OR 5 1.7; p 5 0.007), but not for the truncating alleles (OR 5 1.0; p 5 1.0). The association with the I157T was seen both for the 117 cases who fulfill Amsterdam criteria (OR 5 1.9; p 5 0.1) and for the 346 cases who do not fulfill the criteria (OR 5 1.6; p 5 0.03). One hundred forty-five of the 463 families had a mutation in MSH2, MLH1 or MSH6 (MMR-positive families). A positive association between the CHEK2 I157T mutation and HNPCC-related cancer was observed only for MMR-negative cases (OR 5 2.1; p 5 0.0004), but not for MMR-positive cases (OR 5 0.8; p 5 0.9). The association with I157T was particularly strong for MMR-negative cases with familial colorectal cancer (2 or more first-degree relatives affected) (OR 5 2.5; p < 0.0001). We conclude that the I157T variant of CHEK2 increases the risk of colorectal cancer among MMR-negative, HNPCC/HNPCC-related families in Poland.

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The CHEK2 gene I157T mutation and other alterations in its proximity increase the risk of sporadic colorectal cancer in the Czech population

Cited by 39 publications

References 29 publications

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

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

Lack of CHEK2 Gene Mutations in Differentiated Thyroid Carcinoma Patients using High Resolution Melting Analysis

CHEK2 mutations and HNPCC‐related colorectal cancer

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