The CHEK2 gene and inherited breast cancer susceptibility

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.     

p27蛋白在乳腺癌中的表达与预后的关系

基因是一种肿瘤抑制基因。它在人类一些恶性肿瘤的表达水平与预后呈正相关。本研究探讨其在乳腺癌中的表达水平与预后的关系。方法：用免疫组化检测Ｐ２７蛋白在６６例腺癌中的表达水平，然后用Ｘ＾２检验其与临床病理学特性的关系，Ｌｏｇ ｒａｎｋ检验Ｐ２７的表达与生存时间的关系，Ｃｏｘ回归模型作单因素和多因素预后分析。     

Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility

Cell cycle checkpoint kinase 2 (CHEK2) gene has been inconsistently associated with colorectal cancer (CRC), particularly the 1100delC variant. To generate large-scale evidence on whether the CHEK2 1100delC variant is associated with CRC susceptibility we have conducted a meta-analysis. Data were collected from the following electronic databases: PubMed, Excerpta Medica Database and Chinese Biomedical Literature Database, with the last report up to November 2010. The odds ratio (OR) and its 95% confidence interval (95% CI) were used to assess the strength of association. We evaluated the contrast of carriers versus non-carriers. Meta-analysis was performed in a fixed/random effect model by using the software Review Manager 4.2. A total of six studies including 4194 cases and 10,010 controls based on the search criteria were involved in this meta-analysis. A significant association of the CHEK2 1100delC variant with unselected CRC was found (OR=2.11, 95% CI=1.41-3.16, P=0.0003). We also found an association of the CHEK2 1100delC variant with familial CRC (OR=2.80, 95% CI=1.74-4.51, P<0.0001). However, the association was not established for sporadic CRC (OR=1.45, 95% CI=0.49-4.30, P=0.50). This meta-analysis demonstrates that the CHEK2 1100delC variant may be an important CRC-predisposing gene, which increases CRC risk.     

p21和p27基因多态性与非小细胞肺癌的相关性研究

目的：探讨p21和p27基因多态性与非小细胞肺癌（NSCLC）遗传易感性的关系。方法：应用聚合酶链反应-限制性片段长度多态性分析（PCR—RFLP）方法,分析202例NSCLC患者和265名健康对照人群p21基因3’非翻译区（3’UTR）和p27基因第109密码子多态性位点的基因型。结果：p21基因3’UTR突变型（C／T＋T／T）频率在病例组（72．8％）显著高于对照组（63．8％）,X^2=4．24,P=0．039。携带C／T和T／T基因型可显著增加这一人群NSCLC发病风险（经性别、年龄校正的OR=1．54,95％CI为1．03～2．30）。分层分析发现,p21基因突变型（C／T＋T／T）频率在不吸烟病例组（81．6％）和≥50岁病例组（73．1％）均显著高于对照组,携带C／T和T／T基因型可显著增高不吸烟者和≥50岁人群的NSCLC发病风险（经性别、年龄校正的OR分别为2．78和1．72,95％C1分剐为1．38～5．63和1．09～2．71）。p27基因型总体分布和分层分析在病例组和对照组差异无统计学意义。结论：p21基因3’UTR多态性可能与NSCLC的发病风险有关。p27基因多态性与NSCLC遗传易感性无关。     

CHEK2 1100delC is a susceptibility allele for HNPCC-related colorectal cancer

PURPOSE: The pathogenic CHEK2 1100delC variant is firmly established as a breast cancer susceptibility allele. Dutch CHEK2 1100delC breast cancer families frequently also include colorectal cancer cases, and the variant is particularly prevalent among breast cancer families with hereditary breast and colorectal cancer. Yet, it is still unclear whether CHEK2 1100delC also confers a colorectal cancer risk independent of its breast cancer risk. EXPERIMENTAL DESIGN: CHEK2 1100delC was genotyped in the index cases of 369 Dutch colorectal cancer families that had been excluded for familial breast cancer. The cohort included 132 cases with familial adenomatous polyposis (FAP) and FAP-related disease, and 237 cases with hereditary nonpolyposis colorectal cancer (HNPCC) and HNPCC-related disease. RESULTS: None of the FAP/FAP-related cases carried the CHEK2 1100delC variant. In contrast, CHEK2 1100delC was present in 10 of 237 (4.2%) HNPCC/HNPCC-related cases that was significantly more prevalent than the 1.0% Dutch population frequency (odds ratio, 4.3; 95% confidence interval, 1.7-10.7; P = 0.002). Nine of the 10 CHEK2 1100delC colorectal cancer cases met the revised Amsterdam and/or Bethesda criteria. The 10 CHEK2 1100delC colorectal cancer families had a high-risk cancer inheritance pattern, including 35 colorectal cancer cases, 9 cases with polyps, and 21 cases with other tumor types. CONCLUSION: Our analysis provides strong evidence that the 1100delC variant of CHEK2 confers a colorectal cancer risk in HNPCC/HNPCC-related families, supporting the hypothesis that CHEK2 is a multiorgan cancer susceptibility gene.     

CHEK2 and breast cancer risk

The BRCA1 et BRCA2 genes are involved in 2/3 of genetic predisposition with major risk of breast cancer. One or more genes remain to be identified. The CHEK2 gene is a good candidate. The CHEK2 gene mutation 1100delC is associated with a moderate increase of breast cancer risk (RR = 2). CHEK2 is probably one of the genetic factors associated with moderate risk, but however when associated with other variants, it could explain some familial breast cancer and sporadic cancer cases. It seems to be too early to include CHEK2 in genetic counselling at the present time.     

Common variants in the ATM, BRCA1, BRCA2, CHEK2 and TP53 cancer susceptibility genes are unlikely to increase breast cancer risk

Introduction

Certain rare, familial mutations in the ATM, BRCA1, BRCA2, CHEK2 or TP53 genes increase susceptibility to breast cancer but it has not, until now, been clear whether common polymorphic variants in the same genes also increase risk.

Methods

We have attempted a comprehensive, single nucleotide polymorphism (SNP)- and haplotype-tagging association study on each of these five genes in up to 4,474 breast cancer cases from the British, East Anglian SEARCH study and 4,560 controls from the EPIC-Norfolk study, using a two-stage study design. Nine tag SNPs were genotyped in ATM, together with five in BRCA1, sixteen in BRCA2, ten in CHEK2 and five in TP53, with the aim of tagging all other known, common variants. SNPs generating the common amino acid substitutions were specifically forced into the tagging set for each gene.

Results

No significant breast cancer associations were detected with any individual or combination of tag SNPs.

Conclusion

It is unlikely that there are any other common variants in these genes conferring measurably increased risks of breast cancer in our study population.     

CHEK2基因与乳腺癌的关系

CHEK2是一个重要的乳腺癌易感基因.同时,CHEK2基因突变与乳腺癌患者的病理特征及预后有一定关系.对CHEK2基因突变的检测可能对乳腺癌的治疗具有一定的指导作用.但CHEK2基因突变在中国人群中的作用尚待进一步研究.     

Single nucleotide polymorphisms in the p21 and bcl2 cancer susceptibility genes and breast cancer risk in Saudi Arabia

Certain single nucleotide polymorphisms (SNPs) in genes like p21 or bcl2 increase susceptibility to breast cancer but it has not, until now, been clear whether common polymorphic variants in the same genes also increase risk in Saudi Arabian population. The aim of this study was therefore to determine whether polymorphisms of p21 or Bcl2 might be associated with an increased risk of breast cancer in Saudi women. p21 (rs733590) C/T SNP was not found to be associated with breast cancer pathogenesis. However, we found that a reverse mutation T/C might be linked with breast cancer occurrence. Bcl2 genotypes were marginally associated overall with breast cancer risk. In addition, the alleles of this gene were significantly associated with risk of breast cancer. The allelic frequency of G was higher (0.68) in patients than in healthy women. AA vs. AG+GG genotype [OR=3.56 (1.24-10.68); P=0.008] was the dominant genotype. It is likely that these genes conferring measurably increased risks of breast cancer in our study population.     

Status of CHEK2 and p53 in patients with early-onset and conventional gastric cancer

Gastric cancer (GC) is the fourth most common cause of cancer-associated death. Based on the age at diagnosis, GC is divided into early-onset GC (EOGC; ≤45 years) and conventional GC (CGC; >45 years). Mutations in the cell cycle checkpoint kinase 2 (CHEK2) and TP53 genes are associated with several types of cancer; however, their genetic defects in GC remain poorly understood. The aim of the present study was to determine the subcellular distribution of the CHEK2 protein and its redistribution following DNA damage, to improve the understanding of the DNA damage response. Genetic alterations and patterns of expression of CHEK2 and p53 proteins were investigated to identify potential biological markers and indicators of GC development. Additionally, the affected signaling pathways and their clinical importance in GC development and associated syndromes were investigated. A total of 196 GC samples (89 CGC and 107 EOGC samples) were used in the present study. DNA from 53 samples (18 CGC and 35 EOGC samples) was sequenced using targeted next-generation sequencing technology to identify and compare common and rare mutations associated with GC. Subsequently, the cytoplasmic and nuclear expression levels of CHEK2, phosphorylated (p)-CHEK2 at threonine 68 and p53 in GC tissues were determined via immunohistochemistry. Sequencing resulted in the identification of 63 single nucleotide polymorphisms (SNPs) in the CHEK2 gene amongst 5 different variants, and the intron variant c.319+379A>G was the most common SNP. In the TP53 gene, 57 different alterations were detected amongst 9 variant types, and the missense variant c.215C>G was the most common. Nuclear CHEK2 expression was high in both the EOGC and CGC subtypes. However, the prevalence of cytoplasmic CHEK2 expression (P<0.001) and nuclear p-CHEK2 expression (P=0.011) was significantly higher in CGC compared with in EOGC tissues. There was a statistically significant difference between high and low cytoplasmic CHEK2 expression in patients with p53-positive EOGC compared with in patients with p53-positive CGC (P=0.002). The present study was designed to determine the association between CHEK2 and p53 expression patterns in patients with EOGC and CGC, as well as genetic alterations in the CHEK2 and TP53 genes.     

The CHEK2 I157T variant and colorectal cancer susceptibility: a systematic review and meta-analysis

Background: The cell cycle checkpoint kinase 2 (CHEK2) gene I157T variant may be associated with anincreased risk of colorectal cancer, but it is unclear whether the evidence is sufficient to recommend testing forthe mutation in clinical practice. Materials and Methods: We systematically searched PubMed, EMBASES,Elsevier and Springer for relevant articles before Apr 2012. Summary odds ratios (ORs) and 95% confidenceintervals (95% CIs) were calculated using a fixed-effects or random-effects models with Review Manager 5.0software. Results: A total of seven studies including 4,029 cases and 13,844 controls based on the search criteriawere included for analysis. A significant association of the CHEK2 I157T C variant with unselected CRC wasfound (OR = 1.61, 95% CI = 1.40–1.87, P < 0.001). We also found a significant association with sporadic CRC(OR = 1.48, 95% CI = 1.23–1.77, P < 0.001) and separately with familial CRC (OR = 1.97, 95% CI = 1.41–2.74, P< 0.001). Conclusion: This meta-analysis demonstrates that the CHEK2 I157T variant may be another importantCRC-predisposing gene, which increases CRC risk, especially in familial CRC.     

The CHEK2 I157T variant and breast cancer susceptibility: a systematic review and meta-analysis

Background: The cell cycle checkpoint kinase 2 (CHEK2) gene I157T variant may be associated with anincreased risk of breast cancer, but it is unclear whether the evidence is sufficient to recommend testing for themutation in clinical practice. Materials and Methods: We systematically searched PubMed, Embase, Elsevierand Springer for relevant articles published before Nov 2011. Summary odds ratio (OR) and 95% confidenceinterval (95% CI) incidence rates were calculated using a random-effects model with STATA (version 10.0)software. Results: A total of fifteen case-control studies, including 19,621 cases and 27,001 controls based on thesearch criteria, were included for analysis. A significant association was found between carrying the CHEK2I157T variant and increased risk of unselected breast cancer (OR = 1.48, 95% CI = 1.31–1.66, P < 0.0001), familialbreast cancer (OR = 1.48, 95% CI = 1.16–1.89, P < 0.0001), and early-onset breast cancer (OR = 1.47, 95% CI =1.29–1.66, P < 0.0001). We found an even stronger significant association between the CHEK2 I157T C variantand increased risk of lobular type breast tumors (OR = 4.17, 95% CI = 2.89–6.03, P < 0.0001). Conclusion: Ourresearch indicates that the CHEK2 I157T variant may be another important genetic mutation which increasesrisk of breast cancer, especially the lobular type.     

p27Kip1与消化系肿瘤关系的研究进展

p27Kipl定位于染色体12p13,含2个外显p27-方面抑制CDK激活,另一方面尚可抑制激活后的cyclin-CDK的活性,p27不仅在细胞周期增殖调控中起关键作用。而且与细胞的分化发育及凋亡也有关系。p27蛋白缺失或低表达在消化系恶性肿瘤中是一个较为普遍的现象。且低表达预示不良结局。     

Significance of Skp2 expression in human gastric carcinoma and the relationship between Skp2, p27 and PTEN expression

Objective： S-phase kinase-associated protein 2 （Skp2） is a positive regulator of G1-S transition and promotes ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. Its overexpression has been implicated in cell transformation and oncogenesis. In this study, we investigated significance of Skp2 expression in human gastric carcinoma and the relationship between Skp2, p27 and PTEN expression. Methods： Immunohistochemical analysis was performed on 138 surgical resected primary gastric carcinoma specimens, 102 paired metastasis carcinoma tissue specimens in lymph node from the same set of 138 surgical resected primary gastric carcinoma specimens, 30 dysplasia specimens, 30 intestinal metaplasia specimens, and 20 normal gastric mucosa specimens for Skp2 and performed on the same set of 138 surgical resected primary gastric carcinoma specimens for p27 and PTEN. Results： Skp2 labeling frequency % was increased dramatically in intestinal metaplasia, dysplasia, and primary gastric carcinoma compared with normal gastric mucosa （P=0.000, all the same）. Skp2 labeling frequency % in metastasis gastric carcinoma in lymph node was significantly higher than primary gastric carcinoma （P=0.037）. Skp2 labeling frequency % was positively associated with differentiated degree （rho=0.315, P=0.000）, vessel invasion （rho=0.303, P=0.000） and lymph node metastasis （rho=0.254, P=0.000） respectively. An inverse correlation of Skp2 was observed with both its biochemical target p27 expression in gastric carcinoma （rho=-0.451, P=0.000） and with its putative negative regulator, the PTEN tumor suppressor protein （rho=-0.480, P=0.000）. p27 expression had positive relationship with PTEN expression in gastric carcinoma （rho=0.642, P=0.000）. Conclusion： Skp2 overexpression is correlated with carcinogenesis and progression of gastric carcinoma： elevated Skp2 expression is correlated with decreased p27 and PTEN in gastric carcinoma, and p27 expression is parallel with PTEN expression. These suggest that PTEN may regulate expression of p27 through the Skp2 pathway, and the effects of Skp2, p27 and PTEN together play an important role in carcinogenesis and progression of gastric carcinoma.     

Evaluation of variants in the CHEK2, BRIP1 and PALB2 genes in an Irish breast cancer cohort

It has been proposed that rare variants within the double strand break repair genes CHEK2, BRIP1 and PALB2 predispose to breast cancer. The aim of this study was to evaluate the prevalence of these variants in an Irish breast cancer cohort and determine their contribution to the development of breast cancer in the west of Ireland. We evaluated the presence of CHEK2_1100delC variant in 903 breast cancer cases and 1,016 controls. Six previously described variants within BRIP1 and five within PALB2 were screened in 192 patients with early-onset or familial breast cancer. Where a variant was evident, it was then examined in the remainder of our 711 unselected breast cancer cases. CHEK2_1100delC was found in 5/903 (0.5%) breast cancer cases compared to 1/1016 (0.1%) controls. One mutation at BRIP1 (2392 C>T) was identified in the early-onset/familial cohort. Examination of this variant in the remainder of our cohort (711 cases) failed to identify any additional cases. None of the previously described PALB2 variants were demonstrated in the early-onset/familial cohort. We show evidence of CHEK2_1100delC and BRIP1 2392 C>T within the Irish population. CHEK2_1100delC and BRIP1 mutations incidence in Ireland is similar to that found in other unselected breast cancer cohorts from northern European countries. We found no evidence to suggest that PALB2 mutation is an important breast cancer predisposition gene in this population.     

CHEK2 mutations and the risk of papillary thyroid cancer

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 + 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 + 1G>A, 1100delC or del5395) was associated with a higher risk of thyroid cancer (OR = 5.7; p = 0.006), than was the missense mutation I157T (OR = 2.8; p = 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 = 0.05). A CHEK2 mutation was found in seven of 11 women (63%) with multiple primary cancers of the breast and thyroid (OR = 10; p = 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.     

CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours

We have recently shown that the CHEK2*1100delC mutation acts as a low penetrance breast cancer susceptibility allele. To investigate if other CHEK2 variants confer an increased risk of breast cancer, we have screened an affected individual with breast cancer from 68 breast cancer families. Five of these individuals were found to harbour germline variants in CHEK2. Three carried the 1100delC variant (4%). One of these three individuals also carried the missense variant, Arg180His. In the other two individuals, missense variants, Arg117Gly and Arg137Gln, were identified. These two missense variants reside within the Forkhead-associated domain of CHEK2, which is important for the function of the expressed protein. None of these missense variants were present in 300 healthy controls. Microdissected tumours with a germline mutation showed loss of the mutant allele suggesting a mechanism for tumorigenesis other than a loss of the wild type allele. This study provides further evidence that sequence variation in CHEK2 is associated with an increased risk of breast cancer, and implies that tumorigenesis in association with CHEK2 mutations does not involve loss of the wild type allele.     

Skp2与p27在大肠癌中的表达及临床病理关系的研究

Objective: The aim of this study was to study the expression and the clinical pathological relationship of p27 and Skp2 in the tissues of colorectal cancer,discuss the correlation between them.Methods: To determine the expressions of p27and Skp2 among 30 cases of colorectal cancer tissue specimen and 18 cases of normal colorectal tissue samples with immunohistochemistry SP method.Results: The average positive rate of p27 among the normal colorectal tissue samples was55.2%,which was obviously higher than that of colorectal cancer tissue samples(27.5%,P<0.05).The correlation between the expression of p27 and the degree of differentiation of colorectal cancer; Dukes stage and lymph node metastasis were distinctly negative(P<0.05).The average positive rate of Skp2 among the colorectal cancer tissue specimens was 9.5%,which was obviously higher than that of normal colorectal tissue samples(1.8%,P<0.05).There was an obviously negative correlation between the expression of Skp2 and the degree of differentiation of colorectal cancer(P<0.05),and the expression of Skp2 had no significant correlation with patients' age,sex,Dukes stage and lymph node metastasis(P>0.05).There was an negative correlation between the expression of p27 and Skp2(r=-0.806,P<0.01).Conclusion: The expression of Skp2 in the colorectal cancer tissues is correlative with the degradation of p27;Skp2,the oncogene of colorectal cancer,is involved in colorectal carcinogenesis,which may be the new target for the treatment of colorectal cancer.