I157T Dotaz Zobrazit nápovědu
Cell cycle checkpoint kinase 2 (CHEK2) is a transducer of cellular responses to DNA damage. The CHEK2 1100delC has previously been shown to be a low-penetrance breast cancer susceptibility allele. We have evaluated the role of another CHEK2 variant, I157T in the FHA domain of the gene, for association with breast cancer. I157T was found at a significantly higher frequency in the population-based series of breast cancer patients (77/1035, 7.4%, odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.06-1.95, p = 0.021) than among population controls (100/1885, 5.3%). The frequency in the familial breast cancer patients was not elevated (28/507, 5.5%, OR = 1.04, 95% CI = 0.68-1.61). The I157T protein, that undermines cellular responses to ionizing radiation and shows deficiency in substrate recognition in vivo, was expressed at normal level in tumor tissues as well as in cultured cells. The I157T protein was stable and it dimerized with the wild-type CHEK2 co-expressed in human cells. These functional properties of the I157T protein suggest that this variant may have negative effect on the pool of normal CHEK2 protein in heterozygous carrier cells by formation of heterodimers with wild-type CHEK2. The I157T variant may be associated with breast cancer risk, but the risk is lower than for 1100delC. Copyright 2004 Wiley-Liss, Inc.
- MeSH
- checkpoint kinasa 2 MeSH
- genetická predispozice k nemoci * MeSH
- imunohistochemie MeSH
- lidé MeSH
- nádory prsu * etiologie genetika MeSH
- odds ratio MeSH
- poškození DNA MeSH
- protein-serin-threoninkinasy * genetika MeSH
- replikace DNA MeSH
- studie případů a kontrol MeSH
- tolerance záření MeSH
- tumor supresorové geny MeSH
- zárodečné mutace * MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.
- MeSH
- checkpoint kinasa 2 genetika MeSH
- duktální karcinom slinivky břišní genetika MeSH
- genetická predispozice k nemoci MeSH
- geny BRCA2 * MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory slinivky břišní genetika MeSH
- protein BRCA2 genetika MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- zárodečné mutace MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Checkpoint kinase 2 (CHEK2) gene codes for an important mediator of DNA damage response pathway. Its mutations increase risk of several types of cancer. We analysed selected CHEK2 mutations in 631 Czech colorectal cancer (CRC) patients. The increased risk of CRC was associated with mutations in CHEK2 gene region involving fork head-associated domain [39/631 (6.2%) cases versus 19/683 (2.8%) controls; odds ratio (OR)=2.3; 95% confidence interval (CI)=1.3-4.0; p=0.003], and with the most frequent I157T mutation [30/631 (4.8%) cases versus 17/683 (2.5%) controls; OR=2.0; 95% CI=1.1-3.6; p=0.03]. Prevalence of 1100delC mutation in CRC patients (4/631) did not differ from that in the control population (2/730; p=0.4). The deletion of 5395 bp was not found in any of the successfully analysed CRC cases. We observed no association of analysed mutations with CRC family history. We conclude that the I157T and other alterations in its proximity predispose to sporadic but not to familial CRC in the Czech population.
- MeSH
- dědičné nádorové syndromy genetika MeSH
- delece genu MeSH
- dospělí MeSH
- financování organizované MeSH
- genetická predispozice k nemoci MeSH
- kolorektální nádory genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- mutační analýza DNA metody MeSH
- protein-serin-threoninkinasy genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- staging nádorů MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
Checkpoint kinase 2 gene (CHEK2) alterations increase risk of several cancer types. We analyzed selected CHEK2 alterations in 270 Czech pancreatic cancer patients and in 683 healthy controls. The pancreatic cancer risk was higher in individuals who inherited rare alterations in CHEK2 region involving forkhead-associated domain other than I157T (OR=5.14; 95% CI=0.94-28.23) but the observed association was non-significant (p=0.057). The most frequent I157T mutation did not alter the pancreatic cancer risk and neither the followed deletion of 5395bp nor c.1100delC were found in any of pancreatic cases. We conclude that the I157T, other alterations in its proximity, del5395 and c.1100delC in CHEK2 do not predispose to pancreatic cancer risk in the Czech population.
- MeSH
- exony MeSH
- genetická predispozice k nemoci MeSH
- lidé MeSH
- nádory slinivky břišní enzymologie epidemiologie genetika MeSH
- protein-serin-threoninkinasy genetika MeSH
- sekvenční delece MeSH
- studie případů a kontrol MeSH
- terciární struktura proteinů MeSH
- tumor supresorové geny MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
The CHEK2 gene mutations I157T (c.470T>C) and IVS2+1G>A affecting the forkhead-associated domain (FHA) have been shown to increase the risk of breast cancer development in several populations. We analyzed the CHEK2 gene segment coding for FHA domain in 673 unselected breast cancer patients and 683 controls from the Czech Republic using the denaturant high-performance liquid chromatography. The found frequency of predominant FHA alteration I157T did not differ between breast cancer patients (19/673; 2.82%) and controls (17/683; 2.49%; P=0.71). Besides this mutation we characterized another nine alterations-six located within FHA coding sequence and three occurring in introns 1 or 2). Eight variants occurred once each in patients with breast cancer and two were present in controls. Three alterations found in breast cancer patients were novel missense variants (Y159H, T172A, and L174F) affecting highly conservative residues in FHA domain. Despite the lack of association of I157T mutation with breast cancer development in our population we deduced that the FHA domain is the subject of rare population-specific alterations that might modify risk of various cancers.
- MeSH
- duktální karcinom prsu epidemiologie genetika patologie MeSH
- financování organizované MeSH
- genetická predispozice k nemoci MeSH
- incidence MeSH
- intraduktální neinfiltrující karcinom epidemiologie genetika patologie MeSH
- lidé MeSH
- lobulární karcinom genetika patologie MeSH
- missense mutace genetika MeSH
- nádory prsu genetika patologie MeSH
- prognóza MeSH
- protein-serin-threoninkinasy genetika MeSH
- studie případů a kontrol MeSH
- terciární struktura proteinů MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- srovnávací studie MeSH
- Geografické názvy
- Česká republika MeSH
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) domain-coding 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.
- MeSH
- DNA nádorová genetika MeSH
- dospělí MeSH
- Hodgkinova nemoc genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- míra přežití MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace genetika MeSH
- mutační analýza DNA MeSH
- polymerázová řetězová reakce MeSH
- prognóza MeSH
- protein-serin-threoninkinasy genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- staging nádorů MeSH
- terciární struktura proteinů MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Checkpoint kinase 2 (CHEK2, Chk2) emerges as an important signal transducer of cellular responses to DNA damage and a candidate tumor suppressor whose defects contribute to molecular pathogenesis of diverse types of human malignancies, both sporadic and hereditary. Here, we briefly outline the molecular properties, regulation and physiological role of CHEK2, and review in more detail its defects that predispose to tumors, with particular emphasis on familial breast cancer. The frequency, penetrance and epidemiological as well as clinical significance of the two most studied breast cancer-predisposing variants of the CHEK2 gene, 1100delC and I157T, are highlighted in more depth, and additional CHEK2 mutations and their cancer relevance are discussed as well. These recent findings are considered also from a broader perspective of CHEK2 as the integral component of the ataxia telangiectasia-mutated-CHEK2-p53 pathway within the genome integrity maintenance system and a barrier against tumor progression. Finally, the potential value of information about the CHEK2 status in family counseling and optimizition of individualized cancer treatment is discussed.
