CHEK2 1100delC in patients with metachronous cancers of the breast and the colorectum

BACKGROUND: Development of multiple primary tumors is a hallmark of hereditary cancer. At least 1/10 of breast cancers and colorectal cancers occur because of heredity and recently the cell cycle kinase 2, CHEK2 1100delC allele has been identified at a particularly high frequency in families with hereditary breast and colorectal cancer. METHODS: We utilized the Southern Sweden population-based cancer registry to identify women with double primary breast and colorectal cancer and sequenced tumor material in order to assess the contribution of the CHEK2 1100delC to the development of such metachronous tumors. RESULTS: Among the 75 patients successfully analyzed, 2 (2.5%) carried the CHEK2 1100delC allele. which was not significantly different (p = 0.26) from the 1% (3/300) carriers identified in the control group. CONCLUSION: In summary, our data suggest that the CHEK2 1100delC is not a major cause of double primary breast and colorectal cancer in Sweden, which suggests that this patient group should not routinely be screened for the CHEK2 1100delC variant

Low frequency of CHEK2 1100delC allele in Australian multiple-case breast cancer families: functional analysis in heterozygous individuals

A protein-truncating variant of CHEK2, 1100delC, is associated with a moderate increase in breast cancer risk. We have determined the prevalence of this allele in index cases from 300 Australian multiple-case breast cancer families, 95% of which had been found to be negative for mutations in BRCA1 and BRCA2. Only two (0.6%) index cases heterozygous for the CHEK2 mutation were identified. All available relatives in these two families were genotyped, but there was no evidence of co-segregation between the CHEK2 variant and breast cancer. Lymphoblastoid cell lines established from a heterozygous carrier contained approximately 20% of the CHEK2 1100delC mRNA relative to wild-type CHEK2 transcript. However, no truncated CHK2 protein was detectable. Analyses of expression and phosphorylation of wild-type CHK2 suggest that the variant is likely to act by haploinsufficiency. Analysis of CDC25A degradation, a downstream target of CHK2, suggests that some compensation occurs to allow normal degradation of CDC25A. Such compensation of the 1100delC defect in CHEK2 might explain the rather low breast cancer risk associated with the CHEK2 variant, compared to that associated with truncating mutations in BRCA1 or BRCA2

Detecting differential allelic expression using high-resolution melting curve analysis: application to the breast cancer susceptibility gene CHEK2

<p>Abstract</p> <p>Background</p> <p>The gene <it>CHEK2 </it>encodes a checkpoint kinase playing a key role in the DNA damage pathway. Though <it>CHEK2 </it>has been identified as an intermediate breast cancer susceptibility gene, only a small proportion of high-risk families have been explained by genetic variants located in its coding region. Alteration in gene expression regulation provides a potential mechanism for generating disease susceptibility. The detection of differential allelic expression (DAE) represents a sensitive assay to direct the search for a functional sequence variant within the transcriptional regulatory elements of a candidate gene. We aimed to assess whether <it>CHEK2 </it>was subject to DAE in lymphoblastoid cell lines (LCLs) from high-risk breast cancer patients for whom no mutation in <it>BRCA1</it> or <it>BRCA2</it> had been identified.</p> <p>Methods</p> <p>We implemented an assay based on high-resolution melting (HRM) curve analysis and developed an analysis tool for DAE assessment.</p> <p>Results</p> <p>We observed allelic expression imbalance in 4 of the 41 LCLs examined. All four were carriers of the truncating mutation 1100delC. We confirmed previous findings that this mutation induces non-sense mediated mRNA decay. In our series, we ruled out the possibility of a functional sequence variant located in the promoter region or in a regulatory element of <it>CHEK2 </it>that would lead to DAE in the transcriptional regulatory milieu of freely proliferating LCLs.</p> <p>Conclusions</p> <p>Our results support that HRM is a sensitive and accurate method for DAE assessment. This approach would be of great interest for high-throughput mutation screening projects aiming to identify genes carrying functional regulatory polymorphisms.</p

Revolutions in Lipid Isomer Resolution: Application of Ultrahigh-Resolution Ion Mobility to Reveal Lipid Diversity

Many families of lipid isomers remain unresolved by contemporary liquid chromatography-mass spectrometry approaches, leading to a significant underestimation of the structural diversity within the lipidome. While ion mobility coupled to mass spectrometry has provided an additional dimension of lipid isomer resolution, some isomers require a resolving power beyond the capabilities of conventional platforms. Here, we present the application of high-resolution traveling-wave ion mobility for the separation of lipid isomers that differ in (i) the location of a single carbon-carbon double bond, (ii) the stereochemistry of the double bond (cis or trans), or, for glycerolipids, (iii) the relative substitution of acyl chains on the glycerol backbone (sn-position). Collisional activation following mobility separation allowed identification of the carbon-carbon double-bond position and sn-position, enabling confident interpretation of variations in mobility peak abundance. To demonstrate the applicability of this method, double-bond and sn-position isomers of an abundant phosphatidylcholine composition were resolved in extracts from a prostate cancer cell line and identified by comparison to pure isomer reference standards, revealing the presence of up to six isomers. These findings suggest that ultrahigh-resolution ion mobility has broad potential for isomer-resolved lipidomics and is attractive to consider for future integration with other modes of ion activation, thereby bringing together advanced orthogonal separations and structure elucidation to provide a more complete picture of the lipidome.</p

Mutations of the CHEK2 gene in patients with cancer and their presence in the Latin American population

Artículo científicoCHEK2 (Checkpoint Kinase 2) encodes CHK2, a serine/threonine kinase involved in maintaining the G1/S and G2/M checkpoints and repair of double-strand DNA breaks via homologous recombination. Functions of CHK2 include the prevention of damaged cells from going through the cell cycle or proliferating and the maintenance of chromosomal stability. CHEK2 mutations have been reported in a variety of cancers including glioblastoma, ovarian, prostate, colorectal, gastric, thyroid, and lung cancer in studies performed mainly in White populations. The most studied mutation in CHEK2 is c.1100delC, which was associated with increased risk of breast cancer. The objective of this study was to compile mutations in CHEK2 identified in cancer genomics studies in different populations and especially in Latin American individualsIntroduction. -- Search of cancer genomics data repositories and the GWAS catalog. -- Literature review of Latin American studies. -- Results. -- CHEK2 mutations in the data genomics repositories. -- CHEK2 mutations in Latinos reported in the literature. -- Discussion