Gene Summary

Gene:CHEK2; checkpoint kinase 2
Aliases: CDS1, CHK2, LFS2, RAD53, hCds1, HuCds1, PP1425
Summary:In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:serine/threonine-protein kinase Chk2
Source:NCBIAccessed: 16 March, 2015


What does this gene/protein do?
Show (32)
Pathways:What pathways are this gene/protein implicaed in?
Show (5)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 16 March 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 16 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CHEK2 (cancer-related)

Economopoulou P, Dimitriadis G, Psyrri A
Beyond BRCA: new hereditary breast cancer susceptibility genes.
Cancer Treat Rev. 2015; 41(1):1-8 [PubMed] Related Publications
Approximately 5-10% of breast cancer cases might be inheritable, up to 30% of which are due to BRCA1/2 mutations. During the past few years and thanks to technology evolution, we have been witnesses of an intensive search of additional genes with similar characteristics, under the premise that successful gene discovery will provide substantial opportunities for primary and secondary prevention of breast cancer. Consequently, new genes have emerged as breast cancer susceptibility genes, including rare germline mutations in high penetrant genes, such as TP53 and PTEN, and more frequent mutations in moderate penetrant genes, such as CHEK2, ATM and PALB2. This review will summarize current data on new findings in breast cancer susceptibility genes.

Nam S, Chang HR, Jung HR, et al.
A pathway-based approach for identifying biomarkers of tumor progression to trastuzumab-resistant breast cancer.
Cancer Lett. 2015; 356(2 Pt B):880-90 [PubMed] Related Publications
Although trastuzumab is a successful targeted therapy for breast cancer patients with tumors expressing HER2 (ERBB2), many patients eventually progress to drug resistance. Here, we identified subpathways differentially expressed between trastuzumab-resistant vs. -sensitive breast cancer cells, in conjunction with additional transcriptomic preclinical and clinical gene datasets, to rigorously identify overexpressed, resistance-associated genes. From this approach, we identified 32 genes reproducibly upregulated in trastuzumab resistance. 25 genes were upregulated in drug-resistant JIMT-1 cells, which also downregulated HER2 protein by >80% in the presence of trastuzumab. 24 genes were downregulated in trastuzumab-sensitive SKBR3 cells. Trastuzumab sensitivity was restored by siRNA knockdown of these genes in the resistant cells, and overexpression of 5 of the 25 genes was found in at least one of five refractory HER2 + breast cancer. In summary, our rigorous computational approach, followed by experimental validation, significantly implicate ATF4, CHEK2, ENAH, ICOSLG, and RAD51 as potential biomarkers of trastuzumab resistance. These results provide further proof-of-concept of our methodology for successfully identifying potential biomarkers and druggable signal pathways involved in tumor progression to drug resistance.

Integrated genomic characterization of papillary thyroid carcinoma.
Cell. 2014; 159(3):676-90 [PubMed] Article available free on PMC after 23/10/2015 Related Publications
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.

Tung N, Battelli C, Allen B, et al.
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.
Cancer. 2015; 121(1):25-33 [PubMed] Related Publications
BACKGROUND: Next-generation sequencing (NGS) allows for simultaneous sequencing of multiple cancer susceptibility genes and, for an individual, may be more efficient and less expensive than sequential testing. The authors assessed the frequency of deleterious germline mutations among individuals with breast cancer who were referred for BRCA1 and BRCA2 (BRCA1/2) gene testing using a panel of 25 genes associated with inherited cancer predisposition.
METHODS: This was a cross-sectional study using NGS in 2158 individuals, including 1781 who were referred for commercial BRCA1/2 gene testing (cohort 1) and 377 who had detailed personal and family history and had previously tested negative for BRCA1/2 mutations (cohort 2).
RESULTS: Mutations were identified in 16 genes, most frequently in BRCA1, BRCA2, CHEK2, ATM, and PALB2. Among the participants in cohort 1, 9.3% carried a BRCA1/2 mutation, 3.9% carried a mutation in another breast/ovarian cancer susceptibility gene, and 0.3% carried an incidental mutation in another cancer susceptibility gene unrelated to breast or ovarian cancer. In cohort 2, the frequency of mutations in breast/ovarian-associated genes other than BRCA1/2 was 2.9%, and an additional 0.8% had an incidental mutation. In cohort 1, Lynch syndrome-related mutations were identified in 7 individuals. In contrast to BRCA1/2 mutations, neither age at breast cancer diagnosis nor family history of ovarian or young breast cancer predicted for other mutations. The frequency of mutations in genes other than BRCA1/2 was lower in Ashkenazi Jews compared with non-Ashkenazi individuals (P=.026).
CONCLUSIONS: Using an NGS 25-gene panel, the frequency of mutations in genes other than BRCA1/2 was 4.3%, and most mutations (3.9%) were identified in genes associated with breast/ovarian cancer.

Buza N, Xu F, Wu W, et al.
Recurrent chromosomal aberrations in intravenous leiomyomatosis of the uterus: high-resolution array comparative genomic hybridization study.
Hum Pathol. 2014; 45(9):1885-92 [PubMed] Related Publications
Uterine intravenous leiomyomatosis (IVL) is a distinct smooth muscle neoplasm with a potential of clinical aggressiveness due to its ability to extend into intrauterine and extrauterine vasculature. In this study, chromosomal alterations analyzed by oligonucleotide array comparative genomic hybridization were performed in 9 cases of IVL. The analysis was informative in all cases with multiple copy number losses and/or gains observed in each tumor. The most frequent recurrent loss of 22q12.3-q13.1 was observed in 6 tumors (66.7%), followed by losses of 22q11.23-q13.31, 1p36.13-p33, 2p25.3-p23.3, and 2q24.2-q32.2 and gains of 6p22.2, 2q37.3 and 10q22.2-q22.3, in decreasing order of frequency. Copy number variants were identified at 14q11.2, 15q11.1-q11.2, and 15q26.2. Genes mapping to the regions of loss include CHEK2, EWS, NF2, PDGFB, and MAP3K7IP1 on chromosome 22q, HEI10 on chromosome 14q, and succinate dehydrogenase subunit B, E2F2, ARID1A KPNA6, EIF3S2 , PTCH2, and PIK3R3 on chromosome 1p. Regional losses on chromosomes 22q and 1p and gains on chromosomes 12q showed overlaps with those previously observed in uterine leiomyosarcomas. In addition, presence of multiple chromosomal aberrations implies a higher level of genetic instability. Follow-up polymerase chain reaction (PCR) sequencing analysis of MED12 gene revealed absence of G> A transition at nucleotides c.130 or c.131 in all 9 cases, a frequent mutation found in uterine leiomyoma and its variants. In conclusion, this is the first report of high-resolution, genome-wide investigation of IVL by oligonucleotide array comparative genomic hybridization. The presence of high frequencies of recurrent regional loss involving several chromosomes is an important finding and likely related to the pathogenesis of the disease.

Yang J, Wu H, Wei S, et al.
HPV seropositivity joints with susceptibility loci identified in GWASs at apoptosis associated genes to increase the risk of Esophageal Squamous Cell Carcinoma (ESCC).
BMC Cancer. 2014; 14:501 [PubMed] Article available free on PMC after 23/10/2015 Related Publications
BACKGROUND: We previously showed that human papillomavirus (HPV) serostatus was not an independent risk factor for esophageal squamous cell carcinoma(ESCC) in nonsmokers and nondrinkers; however, HPV increased the risk in smokers.
METHODS: Here we investigated possible interactions between HPV16 serostatus and three susceptibility loci identified in GWASs at apoptosis associated genes with regard to risk of ESCC in a case-control study of 313 patients with ESCC and 314 healthy controls. The loci (CHK2 rs738722, C12orf51 rs2074356, and PLCE1 rs2274223) were genotyped, and the presence or absence of HPV16 in serum was measured by ELISA. Multivariable logistic regression was used to evaluate possible interactions of HPV16 serostatus and the three loci on the risk of ESCC.
RESULTS: A significant interaction was found between HPV16 serology and rs2074356 (P = 0.005, odds ratio [OR] 1.40, 95% confidence interval [CI] 1.11-1.77) or rs2274223 (P < 0.001, OR 1.53, 95% CI 1.23-1.91), but not for rs738722. For rs2074356, risk of ESCC was increased substantially in smokers (P < 0.001, OR 8.25, 95% CI 3.84-17.71) and drinkers (OR4.04, P = 0.001, 95% CI 1.79-9.10) who carried risk alleles (TT or TC genotype) and were HPV16-seropositive. Similar results were observed for rs2274223 in smokers (P < 0.001, OR6.06, 95% CI 2.85-12.88) and drinkers (P < 0.001, OR 5.43, 95% CI 2.51-11.76), but not for rs738722.
CONCLUSION: Consistent with the previous study, loci at rs2074356 and rs2274223 could increase the risk of ESCC, furthermore, there were significant interactions between HPV sero-status and the susceptibility loci on the risk of ESCC. This effect could be modified obviously by smoking and drinking.

Fayaz S, Fard-Esfahani P, Torbati PM
Lack of CHEK2 gene mutations in differentiated thyroid carcinoma patients using high resolution melting analysis.
Asian Pac J Cancer Prev. 2014; 15(12):5019-22 [PubMed] Related Publications
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 a larger population are required to confirm the outcome.

Tedaldi G, Danesi R, Zampiga V, et al.
First evidence of a large CHEK2 duplication involved in cancer predisposition in an Italian family with hereditary breast cancer.
BMC Cancer. 2014; 14:478 [PubMed] Article available free on PMC after 23/10/2015 Related Publications
BACKGROUND: CHEK2 is a multi-cancer susceptibility gene whose common germline mutations are known to contribute to the risk of developing breast and prostate cancer.
CASE PRESENTATION: Here, we describe an Italian family with a high number of cases of breast cancer and other types of tumour subjected to the MLPA test to verify the presence of BRCA1, BRCA2 and CHEK2 deletions and duplications. We identified a new 23-kb duplication in the CHEK2 gene extending from intron 5 to 13 that was associated with breast cancer in the family. The presence and localisation of the alteration was confirmed by a second analysis by Next-Generation Sequencing.
CONCLUSIONS: This finding suggests that CHEK2 mutations are heterogeneous and that techniques other than sequencing, such as MLPA, are needed to identify CHEK2 mutations. It also indicates that CHEK2 rare variants, such as duplications, can confer a high susceptibility to cancer development and should thus be studied in depth as most of our knowledge of CHEK2 concerns common mutations.

Ertych N, Stolz A, Stenzinger A, et al.
Increased microtubule assembly rates influence chromosomal instability in colorectal cancer cells.
Nat Cell Biol. 2014; 16(8):779-91 [PubMed] Related Publications
Chromosomal instability (CIN) is defined as the perpetual missegregation of whole chromosomes during mitosis and represents a hallmark of human cancer. However, the mechanisms influencing CIN and its consequences on tumour growth are largely unknown. We identified an increase in microtubule plus-end assembly rates as a mechanism influencing CIN in colorectal cancer cells. This phenotype is induced by overexpression of the oncogene AURKA or by loss of the tumour suppressor gene CHK2, a genetic constitution found in 73% of human colorectal cancers. Increased microtubule assembly rates are associated with transient abnormalities in mitotic spindle geometry promoting the generation of lagging chromosomes and influencing CIN. Reconstitution of proper microtubule assembly rates by chemical or genetic means suppresses CIN and thereby, unexpectedly, accelerates tumour growth in vitro and in vivo. Thus, we identify a fundamental mechanism influencing CIN in cancer cells and reveal its adverse consequence on tumour growth.

Silva FC, Lisboa BC, Figueiredo MC, et al.
Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients.
BMC Med Genet. 2014; 15:55 [PubMed] Article available free on PMC after 23/10/2015 Related Publications
BACKGROUND: Germ line mutations in BRCA1 and BRCA2 (BRCA1/2) and other susceptibility genes have been identified as genetic causes of hereditary breast and ovarian cancer (HBOC). To identify the disease-causing mutations in a cohort of 120 Brazilian women fulfilling criteria for HBOC, we carried out a comprehensive screening of BRCA1/2, TP53 R337H, CHEK2 1100delC, followed by an analysis of copy number variations in 14 additional breast cancer susceptibility genes (PTEN, ATM, NBN, RAD50, RAD51, BRIP1, PALB2, MLH1, MSH2, MSH6, TP53, CDKN2A, CDH1 and CTNNB1).
METHODS: Capillary sequencing and multiplex ligation-dependent probe amplification (MLPA) were used for detecting point mutations and copy number variations (CNVs), respectively, for the BRCA1 and BRCA2 genes; capillary sequencing was used for point mutation for both variants TP53 R337H and CHEK2 1100delC, and finally array comparative genomic hybridization (array-CGH) was used for identifying CNVs in the 14 additional genes.
RESULTS: The positive detection rate in our series was 26%. BRCA1 pathogenic mutations were found in 20 cases, including two cases with CNVs, whereas BRCA2 mutations were found in 7 cases. We also found three patients with the TP53 R337H mutation and one patient with the CHEK2 1100delC mutation. Seven (25%) pathogenic mutations in BRCA1/2 were firstly described, including a splice-site BRCA1 mutation for which pathogenicity was confirmed by the presence of an aberrant transcript showing the loss of the last 62 bp of exon 7. Microdeletions of exon 4 in ATM and exon 2 in PTEN were identified in BRCA2-mutated and BRCA1/2-negative patients, respectively.
CONCLUSIONS: In summary, our results showed a high frequency of BRCA1/2 mutations and a higher prevalence of BRCA1 (64.5%) gene. Moreover, the detection of the TP53 R337H variant in our series and the fact that this variant has a founder effect in our population prompted us to suggest that all female breast cancer patients with clinical criteria for HBOC and negative for BRCA1/2 genes should be tested for the TP53 R337H variant. Furthermore, the presence of genomic structural rearrangement resulting in CNVs in other genes that predispose breast cancer in conjunction with BRCA2 point mutations demonstrated a highly complex genetic etiology in Brazilian breast cancer families.

Zhang L, Chen LH, Wan H, et al.
Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas.
Nat Genet. 2014; 46(7):726-30 [PubMed] Article available free on PMC after 23/10/2015 Related Publications
Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.

Akaike Y, Masuda K, Kuwano Y, et al.
HuR regulates alternative splicing of the TRA2β gene in human colon cancer cells under oxidative stress.
Mol Cell Biol. 2014; 34(15):2857-73 [PubMed] Article available free on PMC after 23/10/2015 Related Publications
Hu antigen R (HuR) regulates stress responses through stabilizing and/or facilitating the translation of target mRNAs. The human TRA2β gene encodes splicing factor transformer 2β (Tra2β) and generates 5 mRNA isoforms (TRA2β1 to -5) through alternative splicing. Exposure of HCT116 colon cancer cells to sodium arsenite stimulated checkpoint kinase 2 (Chk2)- and mitogen-activated protein kinase p38 (p38(MAPK))-mediated phosphorylation of HuR at positions S88 and T118. This induced an association between HuR and the 39-nucleotide (nt) proximal region of TRA2β exon 2, generating a TRA2β4 mRNA that includes exon 2, which has multiple premature stop codons. HuR knockdown or Chk2/p38(MAPK) double knockdown inhibited the arsenite-stimulated production of TRA2β4 and increased Tra2β protein, facilitating Tra2β-dependent inclusion of exons in target pre-mRNAs. The effects of HuR knockdown or Chk2/p38(MAPK) double knockdown were also confirmed using a TRA2β minigene spanning exons 1 to 4, and the effects disappeared when the 39-nt region was deleted from the minigene. In endogenous HuR knockdown cells, the overexpression of a HuR mutant that could not be phosphorylated (with changes of serine to alanine at position 88 [S88A], S100A, and T118A) blocked the associated TRA2β4 interaction and TRA2β4 generation, while the overexpression of a phosphomimetic HuR (with mutations S88D, S100D, and T118D) restored the TRA2β4-related activities. Our findings revealed the potential role of nuclear HuR in the regulation of alternative splicing programs under oxidative stress.

Zhang JW, Zhang SS, Song JR, et al.
Autophagy inhibition switches low-dose camptothecin-induced premature senescence to apoptosis in human colorectal cancer cells.
Biochem Pharmacol. 2014; 90(3):265-75 [PubMed] Related Publications
Recently, several studies indicated that senescent tumor cells are resistant to apoptosis in chemotherapy. They may return to cell cycle, thus act as stumbling blocks in anticancer treatments. In the present study, we found that, in human colorectal cancer cells, low-dose camptothecin (CPT) simultaneously induced autophagy and premature senescence through AMPK-TSC2-mTOR pathway and ATM-Chk2-p53-p21 pathway respectively. What's important is the suppression of autophagy substantially increased apoptosis and greatly attenuated senescence possibly by blocking p53/p21 pathway, which suggests that autophagy plays an indispensable role in sustaining cell senescence caused by low-dose CPT. The combination of low-dose CPT and autophagy inhibitor, a way to lead senescent cells to die, would be potentially valuable in cancer therapy.

Liou JS, Wu YC, Yen WY, et al.
Inhibition of autophagy enhances DNA damage-induced apoptosis by disrupting CHK1-dependent S phase arrest.
Toxicol Appl Pharmacol. 2014; 278(3):249-58 [PubMed] Related Publications
DNA damage has been shown to induce autophagy, but the role of autophagy in the DNA damage response and cell fate is not fully understood. BO-1012, a bifunctional alkylating derivative of 3a-aza-cyclopenta[a]indene, is a potent DNA interstrand cross-linking agent with anticancer activity. In this study, BO-1012 was found to reduce DNA synthesis, inhibit S phase progression, and induce phosphorylation of histone H2AX on serine 139 (γH2AX) exclusively in S phase cells. Both CHK1 and CHK2 were phosphorylated in response to BO-1012 treatment, but only depletion of CHK1, but not CHK2, impaired BO-1012-induced S phase arrest and facilitated the entry of γH2AX-positive cells into G2 phase. CHK1 depletion also significantly enhanced BO-1012-induced cell death and apoptosis. These results indicate that BO-1012-induced S phase arrest is a CHK1-dependent pro-survival response. BO-1012 also resulted in marked induction of acidic vesicular organelle (AVO) formation and microtubule-associated protein 1 light chain 3 (LC3) processing and redistribution, features characteristic of autophagy. Depletion of ATG7 or co-treatment of cells with BO-1012 and either 3-methyladenine or bafilomycin A1, two inhibitors of autophagy, not only reduced CHK1 phosphorylation and disrupted S phase arrest, but also increased cleavage of caspase-9 and PARP, and cell death. These results suggest that cells initiate S phase arrest and autophagy as pro-survival responses to BO-1012-induced DNA damage, and that suppression of autophagy enhances BO-1012-induced apoptosis via disruption of CHK1-dependent S phase arrest.

Tavtigian SV, Chenevix-Trench G
Growing recognition of the role for rare missense substitutions in breast cancer susceptibility.
Biomark Med. 2014; 8(4):589-603 [PubMed] Article available free on PMC after 23/10/2015 Related Publications
Most cancer susceptibility genes function as tumor suppressors; accordingly, the focus of mutation screening in breast cancer families has been to identify protein-truncating mutations. However, it is now clear that, for some breast cancer susceptibility genes, a significant proportion of the burden of disease comes from rare missense substitutions. Among genes that have been extensively evaluated, BRCA1, BRCA2, PALB2 and BRIP1 stand as examples where the majority of mutations lead to protein truncation;TP53 provides a counter example, where the majority of pathogenic variants are missense substitutions. In ATM and CHEK2, missense substitutions are probably equally or more important in terms of their frequency and attributable risk. Therefore, ongoing efforts to identify new susceptibility genes should not ignore missense variation.

Kean S
Breast cancer. The 'other' breast cancer genes.
Science. 2014; 343(6178):1457-9 [PubMed] Related Publications

Zhao T, Sun Q, del Rincon SV, et al.
Gallotannin imposes S phase arrest in breast cancer cells and suppresses the growth of triple-negative tumors in vivo.
PLoS One. 2014; 9(3):e92853 [PubMed] Article available free on PMC after 23/10/2015 Related Publications
Triple-negative breast cancers are associated with poor clinical outcomes and new therapeutic strategies are clearly needed. Gallotannin (Gltn) has been previously demonstrated to have potent anti-tumor properties against cholangiocarcinoma in mice, but little is known regarding its capacity to suppress tumor outgrowth in breast cancer models. We tested Gltn for potential growth inhibitory properties against a variety of breast cancer cell lines in vitro. In particular, triple-negative breast cancer cells display higher levels of sensitivity to Gltn. The loss of proliferative capacity in Gltn exposed cells is associated with slowed cell cycle progression and S phase arrest, dependent on Chk2 phosphorylation and further characterized by changes to proliferation related genes, such as cyclin D1 (CcnD1) as determined by Nanostring technology. Importantly, Gltn administered orally or via intraperitoneal (IP) injections greatly reduced tumor outgrowth of triple-negative breast cells from mammary fat pads without signs of toxicity. In conclusion, these data strongly suggest that Gltn represents a novel approach to treat triple-negative breast carcinomas.

Alkema NG, Tomar T, van der Zee AG, et al.
Checkpoint kinase 2 (Chk2) supports sensitivity to platinum-based treatment in high grade serous ovarian cancer.
Gynecol Oncol. 2014; 133(3):591-8 [PubMed] Related Publications
OBJECTIVE: Platinum-based chemotherapy is the standard treatment in advanced stage high grade serous ovarian cancer (HGSOC), but the majority of patients will relapse with drug-resistant disease. Platinum induces double-strand DNA breaks and subsequently activation of the DNA damage response (DDR). Drugs targeting DDR pathway components have gained major interest to be combined with chemotherapy as they could increase the therapeutic window. In the present study, we investigated the activation status of the Ataxia Telangiectasia Mutated (ATM) signaling axis within the DDR in a large, well-defined cohort of advanced stage HGSOC patients.
METHODS: Pre-therapy activation status of the ATM signaling axis of the DDR was determined by immunohistochemistry in 125 chemo-naive advanced stage HGSOC patients. Ovarian cancer cell lines with stable checkpoint kinase 2 (Chk2) knock down were used to study cell cycle distribution and survival in long-term clonogenic survival assays.
RESULTS: All ATM signaling axis components showed high expression levels. In two well-defined groups with the largest contrast in treatment response, high expression of Chk2 was related to good response (OR=0.132; P=0.014). Chk2 depletion abrogated the cisplatin-induced S-phase cell cycle arrest and caused increased resistance to cisplatin in long-term clonogenic survival assays.
CONCLUSIONS: Chk2 is related to good response to platinum-based chemotherapy in advanced stage HGSOC patients. Chk2-depleted ovarian cancer cell lines have diminished platinum sensitivity, suggesting that Chk2 should not be considered a therapeutic target along with platinum-based treatment in HGSOC patients.

Bo S, Hui H, Li W, et al.
Chk1, but not Chk2, is responsible for G2/M phase arrest induced by diallyl disulfide in human gastric cancer BGC823 cells.
Food Chem Toxicol. 2014; 68:61-70 [PubMed] Related Publications
Diallyl disulfide (DADS) has been shown to cause G2/M phase cell cycle arrest in several human cancers. Here we demonstrate a mechanism by which DADS induces G2/M phase arrest in BGC823 human gastric cancer cells via Chk1. From cell cycle gene array results, we next confirmed that cyclin B1 expression was decreased by DADS, while the expression of p21, GADD45α and p53 were increased. Despite the lack of change in Chk1 gene expression in response to DADS according to the array analysis, intriguingly overexpression of Chk1, but not Chk2, exhibited increased accumulation in G2/M phase. Moreover, overexpression of Chk1 promoted the effect of DADS-induced G2/M arrest. Augmented phosphorylation of Chk1 by DADS was observed in Chk1-transfected cells, followed by downregulation of Cdc25C and cyclin B1 proteins. In contrast, phosphorylated Chk2 showed no obvious change in Chk2-transfected cells after DADS treatment. Furthermore, knockdown of Chk1 by siRNA partially abrogated DADS-induced downregulation of Cdc25C and cyclin B1 proteins and G2/M arrest. In contrast, knockdown of Chk2 did not show these effects. Therefore, these data indicate that DADS may specifically modulate Chk1 phosphorylation, and DADS-induced G2/M phase arrest in BGC823 cells could result in part from Chk1-mediated inhibition of the Cdc25C/cyclin B1 pathway.

Yunlan L, Juan Z, Qingshan L
Antitumor activity of di-n-butyl-(2,6-difluorobenzohydroxamato)tin(IV) against human gastric carcinoma SGC-7901 cells via G2/M cell cycle arrest and cell apoptosis.
PLoS One. 2014; 9(3):e90793 [PubMed] Article available free on PMC after 23/10/2015 Related Publications
Di-n-butyl-(2,6-difluorobenzohydroxamato)Tin(IV) (DBDFT), a potential antitumor agent against malignancies, exhibited high activities both in vitro and in vivo. Flow cytometric analysis showed that treatment with DBDFT against Human Gastric Carcinoma (SGC-7901) cells induced a concentration and time-dependent cell accumulation in the G2/M phase of the cell cycle with a parallel depletion of the percentage of cells in G0/G1, the cell apoptosis was observed by characteristic morphological changes and AnnexinV/PI dual-immunofluorescence staining. Fluorescence quantitative FQ- PCR and western blot results showed that G2/M-phase arrest was correlated with up-regulation of cyclin dependent kinase inhibitor p21, Chk2 and CyclinB1, whereas the expressions of other G2/M regulatory check-point protein, Cdc2, and feedback loop protein Cdc25C were obviously down-regulated in a p53-independent manner after the SGC-7901 cells were treated with DBDFT (2.5, 5.0, 7.5 µmol·L(-1)) compared with the control. Furthermore, the up-regulation of Bax and down-regulation of Bcl-2 as well as the activation of caspase-3 were observed, which indicated that DBDFT treatment triggered the mitochondrial apoptotic pathway with an increase of Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss and caspase-9 activation in DBDFT treated SGC-7901 cells. In summary, the results illustrated the involvement of multiple signaling pathways targeted by DBDFT in mediating G2/M cell cycle arrest and apoptosis in SGC-7901 cells, which suggested that DBDFT might have therapeutic potential against gastric carcinoma as an effective compound.

Kaufmann WK, Carson CC, Omolo B, et al.
Mechanisms of chromosomal instability in melanoma.
Environ Mol Mutagen. 2014; 55(6):457-71 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
A systems biology approach was applied to investigate the mechanisms of chromosomal instability in melanoma cell lines. Chromosomal instability was quantified using array comparative genomic hybridization to identify somatic copy number alterations (deletions and duplications). Primary human melanocytes displayed an average of 8.5 alterations per cell primarily representing known polymorphisms. Melanoma cell lines displayed 25 to 131 alterations per cell, with an average of 68, indicative of chromosomal instability. Copy number alterations included approximately equal numbers of deletions and duplications with greater numbers of hemizygous (-1,+1) alterations than homozygous (-2,+2). Melanoma oncogenes, such as BRAF and MITF, and tumor suppressor genes, such as CDKN2A/B and PTEN, were included in these alterations. Duplications and deletions were functional as there were significant correlations between DNA copy number and mRNA expression for these genes. Spectral karyotype analysis of three lines confirmed extensive chromosomal instability with polyploidy, aneuploidy, deletions, duplications, and chromosome rearrangements. Bioinformatic analysis identified a signature of gene expression that was correlated with chromosomal instability but this signature provided no clues to the mechanisms of instability. The signature failed to generate a significant (P = 0.105) prediction of melanoma progression in a separate dataset. Chromosomal instability was not correlated with elements of DNA damage response (DDR) such as radiosensitivity, nucleotide excision repair, expression of the DDR biomarkers γH2AX and P-CHEK2, nor G1 or G2 checkpoint function. Chromosomal instability in melanoma cell lines appears to influence gene function but it is not simply explained by alterations in the system of DDR.

Wójcicka A, Czetwertyńska M, Świerniak M, et al.
Variants in the ATM-CHEK2-BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma.
Genes Chromosomes Cancer. 2014; 53(6):516-23 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
The risk of developing papillary thyroid carcinoma (PTC), the most frequent form of thyroid malignancy, is elevated up to 8.6-fold in first-degree relatives of PTC patients. The familial risk could be explained by high-penetrance mutations in yet unidentified genes, or polygenic action of low-penetrance alleles. Since the DNA-damaging exposure to ionizing radiation is a known risk factor for thyroid cancer, polymorphisms in DNA repair genes are likely to affect this risk. In a search for low-penetrance susceptibility alleles we employed Sequenom technology to genotype deleterious polymorphisms in ATM, CHEK2, and BRCA1 in 1,781 PTC patients and 2,081 healthy controls. As a result of the study, we identified CHEK2 rs17879961 (OR = 2.2, P = 2.37e-10) and BRCA1 rs16941 (odds ratio [OR] = 1.16, P = 0.005) as risk alleles for PTC. The ATM rs1801516 variant modifies the risk associated with the BRCA1 variant by 0.78 (P = 0.02). Both the ATM and BRCA1 variants modify the impact of male gender on clinical variables: T status (P = 0.007), N status (P = 0.05), and stage (P = 0.035). Our findings implicate an important role of variants in the ATM- CHEK2- BRCA1 axis in modification of the genetic predisposition to PTC and its clinical manifestations.

Sadri N, Surrey LF, Fraker DL, Zhang PJ
Retroperitoneal dedifferentiated liposarcoma lacking MDM2 amplification in a patient with a germ line CHEK2 mutation.
Virchows Arch. 2014; 464(4):505-9 [PubMed] Related Publications
Germ line mutations in genes that encode proteins involved in the DNA damage response predispose patients to a variety of tumors. Checkpoint kinase 2, encoded by the CHEK2 gene, is important in transducing the DNA damage response. Germ line CHEK2 mutations are seen in a subset of patients with a familial breast cancer and sarcoma phenotype. We report a case of retroperitoneal dedifferentiated liposarcoma in a 61-year-old female with germ line CHEK2 mutation. MDM2 gene amplification normally present and used to aid in the diagnosis of retroperitoneal dedifferentiated liposarcoma was absent in this case. Lack of MDM2 overexpression has similarly been reported in liposarcomas arising in patients with germ line TP53 mutations. We propose this case may highlight a nonamplified MDM2 phenotype in well- and dedifferentiated liposarcomas arising in patients with germ line mutations of genes involved in p53-associated DNA damage response pathways.

Ferreira AC, Robaina MC, Rezende LM, et al.
Histone deacetylase inhibitor prevents cell growth in Burkitt's lymphoma by regulating PI3K/Akt pathways and leads to upregulation of miR-143, miR-145, and miR-101.
Ann Hematol. 2014; 93(6):983-93 [PubMed] Related Publications
Burkitt lymphoma (BL) is an aggressive B-cell lymphoma more common in children comprising one third of pediatric non-Hodgkin lymphoma cases. The recent discovery in BL pathogenesis highlighted the activation of PI3K pathway in cooperation with Myc in the development of BL. In this study, we demonstrated that PI3K/Akt pathway is a target to histone deacetylase inhibitor (HDACi) in BL cells. The combination of HDACi (sodium butyrate, NaB) and chemotherapy (VP-16) inhibited 51 % of the proliferation and enhanced the blockage of the cell cycle progression at G2/M with a concurrent decrease in the S phase. Microarray profiling showed a synergistic action of NaB/VP-16 combination through the differential regulation of 1,413 genes. Comparing VP-16 treatment with the NaB/VP-16 combination, 318 genes were deregulated: 250 genes were downregulated, and 68 were upregulated when compared with untreated cells. Among these genes, six (CDKN1A, CCND1, FAS, CHEK2, MDM4, and SESN2) belong to the p53-signaling pathway. The activation of this signaling pathway is usually induced by stress signals and ultimately leads to cell cycle arrest. Besides, the inhibition of the cell growth was related to reduced Akt phosphorylation, and decrease of c-Myc protein expression by about 60 % (p ≤ 0.005). Moreover, HDACi enhanced miR-101, miR-143, and miR-145 levels in BL cell line, which were inversely associated with the levels of miR-101, miR-143, and miR-145 found to be extremely downregulated in the sample of BL patients. We highlight the fact that effective combinations of HDACis with other target drugs could improve BL therapy in the future.

Huzarski T, Cybulski C, Wokolorczyk D, et al.
Survival from breast cancer in patients with CHEK2 mutations.
Breast Cancer Res Treat. 2014; 144(2):397-403 [PubMed] Related Publications
The purpose of this study is to estimate 10-year survival rates for patients with early onset breast cancer, with and without a CHEK2 mutation and to identify prognostic factors among CHEK2-positive breast cancer patients. 3,592 women with stage I to stage III breast cancer, diagnosed at or below age 50, were tested for four founder mutations in the CHEK2 gene. Information on tumor characteristics and on treatments received was retrieved from medical records. Dates of death were obtained from the Poland Vital Statistics Registry. Survival curves were generated for the mutation-positive and -negative sub-cohorts. Predictors of survival were determined among CHEK2 carriers using the Cox proportional hazards model. 3,592 patients were eligible for the study, of whom 140 (3.9 %) carried a CHEK2-truncating mutation and 347 (9.7 %) carried a missense mutation. The mean follow-up was 8.9 years. The 10-year survival for all CHEK2 mutation carriers was 78.8 % (95 % CI 74.6-83.2 %) and for non-carriers was 80.1 % (95 % CI 78.5-81.8 %). Among women with a CHEK2-positive breast cancer, the adjusted hazard ratio associated with ER-positive status was 0.88 (95 % CI 0.48-1.62). Among women with an ER-positive breast cancer, the adjusted hazard ratio associated with a CHEK2 mutation was 1.31 (95 % CI 0.97-1.77). The survival of women with breast cancer and a CHEK2 mutation is similar to that of patients without a CHEK2 mutation.

Dong YS, Hou WG, Li XL, et al.
Genetic association of CHEK2, GSTP1, and ERCC1 with glioblastoma in the Han Chinese population.
Tumour Biol. 2014; 35(5):4937-41 [PubMed] Related Publications
Glioblastoma (GBM), a deadly brain tumor, is the most malignant glioma. It mainly occurs in adults and occurs significantly more in males than in females. We genotyped 19 tag single nucleotide polymorphisms (tSNPs) from 13 genes in a case-control study of the Han Chinese population to identify genetic factors contributing to the risk of GBM. These tSNPs were genotyped by Sequenom MassARRAY RS1000. Statistical analysis was performed using χ(2) test and SNPStats, a website software. Using χ(2) test, we found that the distribution of two tSNPs (rs2267130 in checkpoint kinase 2 (CHEK2), p = 0.040; rs1695 in GSTP1, p = 0.023) allelic frequencies had significant difference between cases and controls. When we analyzed all of the tSNPs using the SNPStats software, we found that rs1695 in GSTP1 decreased the risk of GBM in log-additive model (OR = 0.56, 95% CI, 0.34-0.94, p = 0.022). Besides, we found that there is an interaction between rs3212986 in excision repair cross-complementing group 1 (ERCC1) and gender under codominant and recessive models. The gene polymorphisms in CHEK2, GSTP1, and ERCC1 may be involved in GBM in the Han Chinese population. Since our sample size is small, further investigation needs to be performed.

Singh R, Kalra RS, Hasan K, et al.
Molecular characterization of collaborator of ARF (CARF) as a DNA damage response and cell cycle checkpoint regulatory protein.
Exp Cell Res. 2014; 322(2):324-34 [PubMed] Related Publications
CARF is an ARF-binding protein that has been shown to regulate the p53-p21-HDM2 pathway. CARF overexpression was shown to cause growth arrest of human cancer cells and premature senescence of normal cells through activation of the p53 pathway. Because replicative senescence involves permanent withdrawal from the cell cycle in response to DNA damage response-mediated signaling, in the present study we investigated the relationship between CARF and the cell cycle and whether it is involved in the DNA damage response. We demonstrate that the half-life of CARF protein is less than 60 min, and that in cycling cells CARF levels are highest in G2 and early prophase. Serially passaged normal human skin and stromal fibroblasts showed upregulation of CARF during replicative senescence. Induction of G1 growth arrest and senescence by a variety of drugs was associated with increase in CARF expression at the transcriptional and translational level and was seen to correlate with increase in DNA damage response and checkpoint proteins, ATM, ATR, CHK1, CHK2, γH2AX, p53 and p21. Induction of growth arrest by oncogenic RAS and shRNA-mediated knockdown of TRF2 in cancer cells also caused upregulation of CARF. We conclude that CARF is associated with DNA damage response and checkpoint signaling pathways.

Li Y, Geng P, Jiang W, et al.
Enhancement of radiosensitivity by 5-Aza-CdR through activation of G2/M checkpoint response and apoptosis in osteosarcoma cells.
Tumour Biol. 2014; 35(5):4831-9 [PubMed] Related Publications
Radiation resistance is a major problem preventing successful treatment. Therefore, identifying sensitizers is vitally important for radiotherapy success. Epigenetic events such as DNA methylation have been proposed to mediate the sensitivity of tumor therapy. In this study, we investigated the influence of demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-CdR) on the radiosensitivity of human osteosarcoma cell lines. 5-Aza-CdR was capable of sensitizing three osteosarcoma cells to irradiation in a time-dependent manner, with the maximum effect attained by 48 h. Pretreatment with 5-Aza-CdR synchronized cells in G2/M phase of the cell cycle and enhanced irradiation-induced apoptosis compared with irradiation alone in SaOS2, HOS, and U2OS cells. Moreover, 5-Aza-CdR restored mRNA expressions of 14-3-3σ, CHK2, and DAPK-1 in the three cells, accompanied with demethylation of their promoters. These findings demonstrate that demethylation with 5-Aza-CdR increases radiosensitivity in some osteosarcoma cells through arresting cells at G2/M phase and increasing apoptosis, which is partly mediated by upregulation of 14-3-3σ, CHK2, and DAPK-1 genes, suggesting that 5-Aza-CdR may be a potential radiosensitizer to improve the therapy effect in osteosarcoma.

Islam MA, Thomas SD, Murty VV, et al.
c-Myc quadruplex-forming sequence Pu-27 induces extensive damage in both telomeric and nontelomeric regions of DNA.
J Biol Chem. 2014; 289(12):8521-31 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
Quadruplex-forming DNA sequences are present throughout the eukaryotic genome, including in telomeric DNA. We have shown that the c-Myc promoter quadruplex-forming sequence Pu-27 selectively kills transformed cells (Sedoris, K. C., Thomas, S. D., Clarkson, C. R., Muench, D., Islam, A., Singh, R., and Miller, D. M. (2012) Genomic c-Myc quadruplex DNA selectively kills leukemia. Mol. Cancer Ther. 11, 66-76). In this study, we show that Pu-27 induces profound DNA damage, resulting in striking chromosomal abnormalities in the form of chromatid or chromosomal breaks, radial formation, and telomeric DNA loss, which induces γ-H2AX in U937 cells. Pu-27 down-regulates telomeric shelterin proteins, DNA damage response mediators (RAD17 and RAD50), double-stranded break repair molecule 53BP1, G2 checkpoint regulators (CHK1 and CHK2), and anti-apoptosis gene survivin. Interestingly, there are no changes of DNA repair molecules H2AX, BRCA1, and the telomere maintenance gene, hTERT. ΔB-U937, where U937 cells stably transfected with deleted basic domain of TRF2 is partially sensitive to Pu-27 but exhibits no changes in expression of shelterin proteins. However, there is an up-regulation of CHK1, CHK2, H2AX, BRCA1, and survivin. Telomere dysfunction-induced foci assay revealed co-association of TRF1with γ-H2AX in ATM deficient cells, which are differentially sensitive to Pu-27 than ATM proficient cells. Alt (alternating lengthening of telomere) cells are relatively resistant to Pu-27, but there are no significant changes of telomerase activity in both Alt and non-Alt cells. Lastly, we show that this Pu-27-mediated sensitivity is p53-independent. The data therefore support two conclusions. First, Pu-27 induces DNA damage within both telomeric and nontelomeric regions of the genome. Second, Pu-27-mediated telomeric damage is due, at least in part, to compromise of the telomeric shelterin protein complex.

Suspitsin EN, Yanus GA, Sokolenko AP, et al.
Development of breast tumors in CHEK2, NBN/NBS1 and BLM mutation carriers does not commonly involve somatic inactivation of the wild-type allele.
Med Oncol. 2014; 31(2):828 [PubMed] Related Publications
Somatic inactivation of the remaining allele is a characteristic feature of cancers arising in BRCA1 and BRCA2 mutation carriers, which determines their unprecedented sensitivity to some DNA-damaging agents. Data on tumor-specific status of the involved gene in novel varieties of hereditary breast cancer (BC) remain incomplete. We analyzed 32 tumors obtained from 30 patients with non-BRCA1/2 BC-associated germ-line mutations: 25 women were single mutation carriers (7 BLM, 15 CHEK2 and 3 NBN/NBS1) and 5 were double mutation carriers (2 BLM/BRCA1, 1 CHEK2/BLM, 1 CHEK2/BRCA1 and 1 NBN/BLM). Losses of heterozygosity affecting the wild-type allele were detected in none of the tumors from BLM mutation carriers, 3/18 (17 %) CHEK2-associated BC and 1/4 (25 %) NBN/NBS1-driven tumors. The remaining 28 BC were subjected to the sequence analysis of entire coding region of the involved gene; no somatic mutations were identified. We conclude that the tumor-specific loss of the wild-type allele is not characteristic for BC arising in CHEK2, NBN/NBS1 and BLM mutation carriers. Rarity of "second-hit" inactivation of the involved gene in CHEK2-, NBN/NBS1- and BLM-associated BC demonstrates their substantial biological difference from BRCA1/2-driven cancers and makes them poorly suitable for the clinical trials with cisplatin and PARP inhibitors.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. CHEK2, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 16 March, 2015     Cancer Genetics Web, Established 1999