Eerola, H* Dotaz Zobrazit nápovědu
The CHEK2 kinase is a tumor suppressor whose activation in response to DNA double-strand breaks contributes to cell cycle arrest or apoptosis. The c.1100delC mutation is associated with familial breast cancer, and tumors from mutation carriers show reduced or absent CHEK2 protein expression. We have here studied CHEK2 protein expression by immunohistochemistry on a tissue microarray of 611 unselected breast tumors and also evaluated the tumor characteristics among 1,297 unselected breast cancer patients defined for the c.1100delC germ line mutation status (2.5% carrier frequency). CHEK2 protein expression was reduced in 21.1% of the unselected breast cancers studied. Tumors with reduced CHEK2 expression had more often larger primary tumor size (pT3-4; nominal significance p = 0.002) compared to tumors with normal staining. A similar trend for larger tumor size was seen among the 37 breast tumors from c.1100delC germ line mutation carriers. Tumors from c.1100delC mutation carriers were of higher grade than those of noncarriers (nominal significance p = 0.02). The c.1100delC germ line mutation also associated strongly with bilateral breast cancer. No significant correlation was seen between CHEK2 status and hormone receptor status, histology, lymph node status, or overall survival. Copyright 2004 Wiley-Liss, Inc.
- MeSH
- checkpoint kinasa 2 MeSH
- duktální karcinom genetika metabolismus patologie MeSH
- imunoenzymatické techniky MeSH
- lidé MeSH
- lobulární karcinom genetika metabolismus patologie MeSH
- lymfatické uzliny patologie MeSH
- medulární karcinom genetika metabolismus patologie MeSH
- míra přežití MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- nádory prsu * genetika metabolismus patologie MeSH
- protein-serin-threoninkinasy * genetika metabolismus MeSH
- receptory pro estrogeny metabolismus MeSH
- receptory progesteronu metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- sekvenční delece MeSH
- staging nádorů MeSH
- zárodečné mutace * MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
CHEK2 (previously known as "CHK2") is a cell-cycle-checkpoint kinase that phosphorylates p53 and BRCA1 in response to DNA damage. A protein-truncating mutation, 1100delC in exon 10, which abolishes the kinase function of CHEK2, has been found in families with Li-Fraumeni syndrome (LFS) and in those with a cancer phenotype that is suggestive of LFS, including breast cancer. In the present study, we found that the frequency of 1100delC was 2.0% among an unselected population-based cohort of 1,035 patients with breast cancer. This was slightly, but not significantly (P=.182), higher than the 1.4% frequency found among 1,885 population control subjects. However, a significantly elevated frequency was found among those 358 patients with a positive family history (11/358 [3.1%]; odds ratio [OR] 2.27; 95% confidence interval [CI] 1.11-4.63; P=.021, compared with population controls). Furthermore, patients with bilateral breast cancer were sixfold more likely to be 1100delC carriers than were patients with unilateral cancer (95% CI 1.87-20.32; P=.007). Analysis of the 1100delC variant in an independent set of 507 patients with familial breast cancer with no BRCA1 and BRCA2 mutations confirmed a significantly elevated frequency of 1100delC (28/507 [5.5%]; OR 4.2; 95% CI 2.4-7.2; P=.0002), compared with controls, with a high frequency also seen in patients with only a single affected first-degree relative (18/291 [6.2%]). Finally, tissue microarray analysis indicated that breast tumors from patients with 1100delC mutations show reduced CHEK2 immunostaining. The results suggest that CHEK2 acts as a low-penetrance tumor-suppressor gene in breast cancer and that it makes a significant contribution to familial clustering of breast cancer-including families with only two affected relatives, which are more common than families that include larger numbers of affected women.
- MeSH
- bodová mutace MeSH
- CDC geny MeSH
- checkpoint kinasa 2 MeSH
- geny BRCA1 MeSH
- geny BRCA2 MeSH
- imunohistochemie MeSH
- lidé MeSH
- nádory prsu etiologie genetika MeSH
- protein-serin-threoninkinasy * MeSH
- proteinkinasy genetika nedostatek MeSH
- regulace genové exprese u nádorů MeSH
- rodokmen MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
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
The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P=0.0003) and BRCA2 (30%; P=0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P=0.0002), progesterone receptor (PR) negative (P=0.004) and were of higher grade (P=0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P=0.0006) and p53 was overabundant (47%; P<0.0000000001) among the difficult-to-treat ER/PR/ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of 'conditional haploinsufficiency' for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.
- MeSH
- ATM protein MeSH
- DNA vazebné proteiny * nedostatek metabolismus MeSH
- lidé MeSH
- nádorové supresorové proteiny * nedostatek metabolismus MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- nádory prsu * genetika metabolismus MeSH
- poškození DNA * genetika MeSH
- protein BRCA1 * nedostatek metabolismus MeSH
- protein BRCA2 * nedostatek metabolismus MeSH
- protein-serin-threoninkinasy * nedostatek metabolismus MeSH
- proteiny buněčného cyklu metabolismus MeSH
- receptor erbB-2 * nedostatek metabolismus MeSH
- receptory pro estrogeny * nedostatek metabolismus MeSH
- receptory progesteronu * nedostatek metabolismus MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
Hodosi and W.H. Eerola and R. Bardbcz -- Possibilities of production of histamine by halophilic bacteria isolated 63 -- from herring in food histamine intake models -- G. Abbruzzese -- Polyamines as poisons and protectors (Abstract) 114 -- H.C. Ha, P.M. Waster and R.A.
141 s. : il.
- Klíčová slova
- Evropská unie, aminy biogenní, mikrobiologie,
Horsch, -- T Baibach, M. Hogg, F. Sturm and C. Hollingsworth, -- C. Hay and B. Models, H Handels, J. Lundgren, H. Broberg and H. Eerola, J. Porrasmaa, -- A. Mie itine n and J.
Studies in health technology and informatics, ISSN 0926-9630 volume 68
xvii, 1009 stran : ilustrace, tabulky ; 25 cm
- Konspekt
- Lékařské vědy. Lékařství
- NLK Obory
- lékařská informatika
Eerola, J. Porrasmaa, H. Ruonamaa, and M. Hwang, J.-H. Cho, and H.-S. Exploration in a “Gray Area” -- Marika Toivanen, Heidi Häkkinen, Anne Eerola, Mikko Korpela, Anja Mursu (France) -- H. Harms, A. Rueter, M. Haucke, H. M. Yamanaka, H. Hosaka and H.
IFIP world conference series on medical informatics Studies in health technology and informatics
sv. ; 27 cm
- MeSH
- informační systémy MeSH
- lékařská informatika MeSH
- lékařství MeSH
- Publikační typ
- kongresy MeSH
- sborníky MeSH
- Konspekt
- Lékařské vědy. Lékařství
- NLK Obory
- lékařská informatika