ORCID Profile
0000-0002-9002-350X
Current Organisation
National Cancer Centre Singapore
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Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685621
Abstract: Detail description of the functional categorization of analyzed CHEK2 missense variants.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952450.V1
Abstract: Validation of KAP1-pS473 and CHK2-pS516 antibodies. b A, /b Parental RPE, RPE1–CHEK2-KO cells or RPE1–CHEK2-KO cells transfected with the wild-type or mutant pEGFP–CHEK2 were left untreated or were exposed to ionizing radiation (5 Gy, 3 hours). After fixation, cells were probed with KAP1-pS473 antibody. Representative images are shown. b B, /b Quantification of b A /b . The mean nuclear intensity of the KAP1-pS473 signal is plotted. Each dot represents one cell more than 300 cells were analyzed. Red line, error bars and numbers indicate mean ± SDs. Statistical significance was evaluated by the Mann–Whitney test (****, i P /i 0.0001). A representative experiment is shown from two independent replicates. b C, /b Cells were grown and treated as in b A /b and were probed with CHK2-pS516 antibody. Representative images are shown. b D, /b Quantification of b C /b . The mean nuclear intensity of the CHK2-pS516 signal is plotted. Each dot represents one cell more than 300 cells were analyzed. Red line, error bars and numbers indicate mean ± SDs. Statistical significance was evaluated by the Mann–Whitney test (****, i P /i 0.0001). A representative experiment is shown from two independent replicates. b E, /b Cells were grown and treated as in A. Whole-cell lysates were analyzed by immunoblotting with indicated antibodies.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952444.V1
Abstract: Kinase KAP1 and CHK2 assays ( b A /b ). The bar graphs show results of kinase assays for 430 i CHEK2 /i missense variants. In both assays, variants with normalized relative CHK2 activity (mean WT-activity = 1) exceeding that of the weakest signal of WT replicas (not shown) were categorized functionally WT-like, variants with normalized signal intensity lower than the strongest signal for any of kinase-dead/empty EGFP vector controls (in-frame exon 7 deletion–p.D265_H282del not shown) were categorized as functionally impaired. Variants with normalized CHK2 activities between these ranges were categorized functionally intermediate (0.428–0.705 and 0.479–0.710 for KAP1 and CHK2 assay, respectively indicated by red and yellow dashed lines). Scatterplot combines results from both assays showing 340 concordant (circles) and 90 discordant (crosses) variants. The nuclear-to-cytoplasmic ratio ( b B /b ) bar graph (left) displays all missense variants and a set of protein-truncating i CHEK2 /i variants (dark red bars at left, zoomed part of the graph). The missense variants, p.R521W and p.R521Q, with an aberrant localization are highlighted as bright-red bars the arrows denote WT (green bar) and catalytically-dead in-frame p.D265_H282del variant (white bar). The highest and lowest mean nuclear/cytoplasmic ratio values from all WT replicates are indicated by green dashed lines. Of all missense variants analyzed by ScanR microscopy, only codon 521 alterations revealed aberrant intracellular localization with intense cytoplasmic positivity (right), reminiscent of mislocalization of the c.1100delC (p.T367fsX size bar, 10 μm) variant. In comparison, the in-frame deletion p.D265_H282del revealed normal intranuclear accumulation, similar to WT. b C, /b Scatter plots depicting correlations between assays performed in this study and previous analyses of i CHEK2 /i VUS. Studies of Kleiblova i et al. /i ( a href="#bib17" target="_blank" /a ) and Boonen et al. ( a href="#bib18" target="_blank" /a ) used phosphorylation of KAP1 as a functional readout whereas the study of Delimitsou i et al. /i ( a href="#bib25" target="_blank" /a ) used a yeast growth retardation assay. The dots are colored according to the results of the KAP1 assay in this study (red, impaired yellow, intermediate green, wild-type–like). Blue line represents linear regression, R, correlation coefficient i P /i , i P /i value. The scatter plot does not show the p.Arg512Trp variant classified by Boonen et al. as intermediate with impaired nuclear localization in our localization assay.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952441
Abstract: Results of KAP1 and CHK2 kinase assays for 430 successfully analyzed missense i CHEK2 /i variants (shown as an average relative CHK2 kinase activity). Bars are colored as functionally WT-like (green), intermediate (IM yellow), and impaired (ID red), respectively, with thresholds for IM variants (0.428 and 0.479) and ID variants (0.705 and 0.710) for KAP1 and CHK2 assays, respectively (dashed lines). Error bars represent standard errors of mean. Color/gray letters for protein variants indicate concordant/discordant functional assays result, respectively. Blue boxes denote conserved CHK2 domains. DNL, variants that do not localize into the nucleus.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685609.V1
Abstract: Frequencies of all reported germline CHEK2 variant carriers and carriers of variants concordantly categorized by functional our kinase assays in breast cancer patients and controls in 12 analyzed population datasets.
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.CCR-23-0212
Abstract: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, h ering the clinical utility of germline genetic testing (GGT). We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952420
Abstract: Detail description of the functional categorization of analyzed CHEK2 missense variants.
Publisher: Oxford University Press (OUP)
Date: 10-2018
Abstract: Growing evidence suggests a role for cancer susceptibility genes such as BRCA2 and PALB2 in young-onset colorectal cancers. Using a cohort of young colorectal cancer patients, we sought to identify and provide functional evidence for germline pathogenic variants of DNA repair genes not typically associated with colorectal cancer. We recruited 88 patients with young-onset colorectal cancers seen at a general oncology center. Whole-exome sequencing was performed to identify variants in DNA repair and colorectal cancer predisposition genes. Pathogenic BRCA2 and PALB2 variants were analyzed using immunoblot and immunofluorescence on patient-derived lymphoblastoid cells. In general, our cohort displayed characteristic features of young-onset colorectal cancers. Most patients had left-sided tumors and were diagnosed at late stages. Four patients had familial adenomatous polyposis, as well as pathogenic APC variants. We identified 12 pathogenic variants evenly distributed between DNA repair and colorectal cancer predisposition genes. Six patients had pathogenic variants in colorectal cancer genes: APC (n = 4) and MUTYH monoallelic (n = 2). Another six had pathogenic variants in DNA repair genes: ATM (n = 1), BRCA2 (n = 1), PALB2 (n = 1), NTHL1 (n = 1), and WRN (n = 2). Pathogenic variants BRCA2 c.9154C T and PALB2 c.1059delA showed deficient homologous recombination repair, evident from the impaired RAD51 nuclear localization and foci formation. A substantial portion of pathogenic variants in young-onset colorectal cancer was found in DNA repair genes not previously associated with colorectal cancer. This may have implications for the management of patients. Further studies are needed to ascertain the enrichment of pathogenic DNA repair gene variants in colorectal cancers.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952444
Abstract: Kinase KAP1 and CHK2 assays ( b A /b ). The bar graphs show results of kinase assays for 430 i CHEK2 /i missense variants. In both assays, variants with normalized relative CHK2 activity (mean WT-activity = 1) exceeding that of the weakest signal of WT replicas (not shown) were categorized functionally WT-like, variants with normalized signal intensity lower than the strongest signal for any of kinase-dead/empty EGFP vector controls (in-frame exon 7 deletion–p.D265_H282del not shown) were categorized as functionally impaired. Variants with normalized CHK2 activities between these ranges were categorized functionally intermediate (0.428–0.705 and 0.479–0.710 for KAP1 and CHK2 assay, respectively indicated by red and yellow dashed lines). Scatterplot combines results from both assays showing 340 concordant (circles) and 90 discordant (crosses) variants. The nuclear-to-cytoplasmic ratio ( b B /b ) bar graph (left) displays all missense variants and a set of protein-truncating i CHEK2 /i variants (dark red bars at left, zoomed part of the graph). The missense variants, p.R521W and p.R521Q, with an aberrant localization are highlighted as bright-red bars the arrows denote WT (green bar) and catalytically-dead in-frame p.D265_H282del variant (white bar). The highest and lowest mean nuclear/cytoplasmic ratio values from all WT replicates are indicated by green dashed lines. Of all missense variants analyzed by ScanR microscopy, only codon 521 alterations revealed aberrant intracellular localization with intense cytoplasmic positivity (right), reminiscent of mislocalization of the c.1100delC (p.T367fsX size bar, 10 μm) variant. In comparison, the in-frame deletion p.D265_H282del revealed normal intranuclear accumulation, similar to WT. b C, /b Scatter plots depicting correlations between assays performed in this study and previous analyses of i CHEK2 /i VUS. Studies of Kleiblova i et al. /i ( a href="#bib17" target="_blank" /a ) and Boonen et al. ( a href="#bib18" target="_blank" /a ) used phosphorylation of KAP1 as a functional readout whereas the study of Delimitsou i et al. /i ( a href="#bib25" target="_blank" /a ) used a yeast growth retardation assay. The dots are colored according to the results of the KAP1 assay in this study (red, impaired yellow, intermediate green, wild-type–like). Blue line represents linear regression, R, correlation coefficient i P /i , i P /i value. The scatter plot does not show the p.Arg512Trp variant classified by Boonen et al. as intermediate with impaired nuclear localization in our localization assay.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952405
Abstract: Frequencies of all reported germline CHEK2 variant carriers and carriers of variants concordantly categorized by functional our kinase assays in breast cancer patients and controls in 12 analyzed population datasets.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952426
Abstract: Funnel plot (left) and forest plots (right) for in idual datasets of breast cancer cases and controls from 12 datasets (10 countries) stratified according to the functional categorization.
Publisher: Cold Spring Harbor Laboratory
Date: 30-01-2020
DOI: 10.1101/2020.01.29.926139
Abstract: Family history has traditionally been an essential part of clinical care to assess health risks. However, declining sequencing costs have precipitated a shift towards genomics-first approaches in population screening programs, with less emphasis on family history assessment. We evaluated the utility of family history for genomic sequencing selection. We analysed whole genome sequences of 1750 healthy research participants, with and without preselection based on standardised family history collection, screening 95 cancer genes. The frequency of likely pathogenic/ pathogenic (LP/P) variants in 884 participants with no family history available (FH not available group) (2%) versus 866 participants with family history available (FH available group) (3.1%) was not significant ( p =0.158). However, within the FH available group, amongst 73 participants with an increased family history cancer risk (increased FH risk), 1 in 7 participants carried a LP/P variant inferring a six-fold increase compared with 1 in 47 participants assessed at average family history cancer risk (average FH risk) and a seven-fold increase compared to the FH not available group. The enrichment was further pronounced (up to 18-fold) when assessing the 25 cancer genes in the ACMG 59-gene panel. Furthermore, 63 participants had an increased family history cancer risk in absence of an apparent LP/P variant. Our findings show that systematic family history collection remains critical for health risk assessment, providing important actionable data and augmenting the yield from genomic data. Family history also highlights the potential impact of additional hereditary, environmental and behavioural influences not reflected by genomic sequencing.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952435.V1
Abstract: Presence of analyzed i CHEK2 /i missense variants categorized according to the functional assays in patients with breast cancer (BC pts red numbers) and matched controls (dark green numbers). The association with breast cancer risk (odds ratio OR) were calculated for prevalent variants having ≥10 carriers among patients or controls, respectively. Colors of the numbers in the last column highlight significant association with moderate-or-higher risk (red OR 2), low risk (OR 2), protective variants (green) or variants without significant impact on breast cancer risk (black). Gray rows display variants that were discordant in the kinase assays. DNL, variants that do not localize into the nucleus.
Publisher: Cold Spring Harbor Laboratory
Date: 08-2019
DOI: 10.1101/MCS.A004093
Abstract: Germline pathogenic variants in BRCA1/2 account for one-third of familial breast cancers. The majority of BRCA1 function requires heterodimerization with BARD1. In contrast to BRCA1 , BARD1 is a low-penetrance gene with an unclear clinical relevance, partly because of limited functional evidence. Using patient-derived lymphoblastoid cells, we functionally characterized two pathogenic variants (c.1833dupT, c.2099delG) and three variants of uncertain significance (VUSs) (c.73G C, c.1217G A, c.1918C A). Three of these patients had breast cancers, whereas the remaining had colorectal cancers ( n = 3). Both patients with pathogenic variants (c.1833dupT, c.2099delG) developed breast cancers with aggressive disease phenotypes such as triple-negative breast cancer and high cancer grades. As BARD1 encompasses multiple functional domains, including those of apoptosis and homologous recombination repair, we hypothesized that the function being impaired would correspond with the domain where the variant was located. Variants c.1918C A, c.1833dupT, c.1217G A, and c.2099delG, located within and proximal to apoptotic domains of ankyrin and BRCT, were associated with impaired apoptosis. Conversely, apoptosis function was preserved in c.73G C, which was distant from the ankyrin domain. All variants displayed normal BRCA1 heterodimerization and RAD51 colocalization, consistent with their location being distal to BRCA1—and RAD51-binding domains. In view of deficient apoptosis, VUSs (c.1217G A and c.1918C A) may be pathogenic or likely pathogenic variants. In summary, functional analysis of BARD1 VUSs requires a combination of assays and, more importantly, the use of appropriate functional assays with consideration to the variant's location.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2017
DOI: 10.1038/S41598-017-10333-X
Abstract: Associations of sarcoma with inherited cancer syndromes implicate genetic predisposition in sarcoma development. However, due to the apparently sporadic nature of sarcomas, little attention has been paid to the role genetic susceptibility in sporadic sarcoma. To address this, we performed targeted-genomic sequencing to investigate the prevalence of germline mutations in known cancer-associated genes within an Asian cohort of sporadic sarcoma patients younger than 50 years old. We observed 13.6% (n = 9) amongst 66 patients harbour at least one predicted pathogenic germline mutation in 10 cancer-associated genes including ATM , BRCA2, ERCC4, FANCC, FANCE, FANCI, MSH6, POLE, SDHA and TP53 . The most frequently affected genes are involved in the DNA damage repair pathway, with a germline mutation prevalence of 10.6%. Our findings suggests that genetic predisposition plays a larger role than expected in our Asian cohort of sporadic sarcoma, therefore clinicians should be aware of the possibility that young sarcoma patients may be carriers of inherited mutations in cancer genes and should be considered for genetic testing, regardless of family history. The prevalence of germline mutations in DNA damage repair genes imply that therapeutic strategies exploiting the vulnerabilities resulting from impaired DNA repair may be promising areas for translational research.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685618
Abstract: List of all analyzed CHEK2 variants with results of KAP1/CHK2 kinase and localization assays and the results from recent previously published functional analyses of the CHEK2 VUS.
Publisher: Elsevier BV
Date: 06-2016
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685612
Abstract: Characteristics of 12 case-control datasets from the ENIGMA consortium partners.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952450
Abstract: Validation of KAP1-pS473 and CHK2-pS516 antibodies. b A, /b Parental RPE, RPE1–CHEK2-KO cells or RPE1–CHEK2-KO cells transfected with the wild-type or mutant pEGFP–CHEK2 were left untreated or were exposed to ionizing radiation (5 Gy, 3 hours). After fixation, cells were probed with KAP1-pS473 antibody. Representative images are shown. b B, /b Quantification of b A /b . The mean nuclear intensity of the KAP1-pS473 signal is plotted. Each dot represents one cell more than 300 cells were analyzed. Red line, error bars and numbers indicate mean ± SDs. Statistical significance was evaluated by the Mann–Whitney test (****, i P /i 0.0001). A representative experiment is shown from two independent replicates. b C, /b Cells were grown and treated as in b A /b and were probed with CHK2-pS516 antibody. Representative images are shown. b D, /b Quantification of b C /b . The mean nuclear intensity of the CHK2-pS516 signal is plotted. Each dot represents one cell more than 300 cells were analyzed. Red line, error bars and numbers indicate mean ± SDs. Statistical significance was evaluated by the Mann–Whitney test (****, i P /i 0.0001). A representative experiment is shown from two independent replicates. b E, /b Cells were grown and treated as in A. Whole-cell lysates were analyzed by immunoblotting with indicated antibodies.
Publisher: Springer Science and Business Media LLC
Date: 19-11-2020
DOI: 10.1038/S41525-020-00157-6
Abstract: We have identified six patients harbouring distinct germline BAP1 mutations. In this study, we functionally characterise known BAP1 pathogenic and likely benign germline variants out of these six patients to aid in the evaluation and classification of unknown BAP1 germline variants. We found that pathogenic germline variants tend to encode truncated proteins, show diminished expression of epithelial-mesenchymal transition (EMT) markers, are localised in the cytosol and have reduced deubiquitinase capabilities. We show that these functional assays are useful for BAP1 variant curation and may be added in the American College of Medical Genetics and Genomics (ACMG) criteria for BAP1 variant classification. This will allow clinicians to distinguish between BAP1 pathogenic and likely benign variants reliably and may aid to quickly benchmark newly identified BAP1 germline variants. Classification of novel BAP1 germline variants allows clinicians to inform predisposed patients and relevant family members regarding potential cancer risks, with appropriate clinical interventions implemented if required.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952453
Abstract: Geographical origin of analyzed i CHEK2 /i missense variants.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952453.V1
Abstract: Geographical origin of analyzed i CHEK2 /i missense variants.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.C.6742698
Abstract: AbstractPurpose: Germline pathogenic variants in i CHEK2 /i confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense i CHEK2 /i variants of uncertain significance (VUS) have been identified, h ering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 i CHEK2 /i missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using i CHEK2 /i -complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1– i CHEK2 /i -knockout cells. Concordant results in both functional assays were used to categorize i CHEK2 /i VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired ( i N /i = 102), functionally intermediate ( i N /i = 12), or functionally wild-type (WT)–like ( i N /i = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of i CHEK2 /i missense VUS found in patients with breast cancer (3,660/4,436 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating i CHEK2 /i variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers. /
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685621.V1
Abstract: Detail description of the functional categorization of analyzed CHEK2 missense variants.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952411
Abstract: Characteristics of 12 case-control datasets from the ENIGMA consortium partners.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952414
Abstract: List of all analyzed CHEK2 variants with results of KAP1/CHK2 kinase and localization assays and the results from recent previously published functional analyses of the CHEK2 VUS.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952414.V1
Abstract: List of all analyzed CHEK2 variants with results of KAP1/CHK2 kinase and localization assays and the results from recent previously published functional analyses of the CHEK2 VUS.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952435
Abstract: Presence of analyzed i CHEK2 /i missense variants categorized according to the functional assays in patients with breast cancer (BC pts red numbers) and matched controls (dark green numbers). The association with breast cancer risk (odds ratio OR) were calculated for prevalent variants having ≥10 carriers among patients or controls, respectively. Colors of the numbers in the last column highlight significant association with moderate-or-higher risk (red OR 2), low risk (OR 2), protective variants (green) or variants without significant impact on breast cancer risk (black). Gray rows display variants that were discordant in the kinase assays. DNL, variants that do not localize into the nucleus.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.C.6742698.V1
Abstract: AbstractPurpose: Germline pathogenic variants in i CHEK2 /i confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense i CHEK2 /i variants of uncertain significance (VUS) have been identified, h ering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 i CHEK2 /i missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using i CHEK2 /i -complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1– i CHEK2 /i -knockout cells. Concordant results in both functional assays were used to categorize i CHEK2 /i VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired ( i N /i = 102), functionally intermediate ( i N /i = 12), or functionally wild-type (WT)–like ( i N /i = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of i CHEK2 /i missense VUS found in patients with breast cancer (3,660/4,436 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating i CHEK2 /i variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers. /
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952411.V1
Abstract: Characteristics of 12 case-control datasets from the ENIGMA consortium partners.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.C.6742698.V2
Abstract: AbstractPurpose: Germline pathogenic variants in i CHEK2 /i confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense i CHEK2 /i variants of uncertain significance (VUS) have been identified, h ering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 i CHEK2 /i missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using i CHEK2 /i -complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1– i CHEK2 /i -knockout cells. Concordant results in both functional assays were used to categorize i CHEK2 /i VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired ( i N /i = 102), functionally intermediate ( i N /i = 12), or functionally wild-type (WT)–like ( i N /i = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of i CHEK2 /i missense VUS found in patients with breast cancer (3,660/4,436 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating i CHEK2 /i variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers. /
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685618.V1
Abstract: List of all analyzed CHEK2 variants with results of KAP1/CHK2 kinase and localization assays and the results from recent previously published functional analyses of the CHEK2 VUS.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685609
Abstract: Frequencies of all reported germline CHEK2 variant carriers and carriers of variants concordantly categorized by functional our kinase assays in breast cancer patients and controls in 12 analyzed population datasets.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952405.V1
Abstract: Frequencies of all reported germline CHEK2 variant carriers and carriers of variants concordantly categorized by functional our kinase assays in breast cancer patients and controls in 12 analyzed population datasets.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685612.V1
Abstract: Characteristics of 12 case-control datasets from the ENIGMA consortium partners.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952441.V1
Abstract: Results of KAP1 and CHK2 kinase assays for 430 successfully analyzed missense i CHEK2 /i variants (shown as an average relative CHK2 kinase activity). Bars are colored as functionally WT-like (green), intermediate (IM yellow), and impaired (ID red), respectively, with thresholds for IM variants (0.428 and 0.479) and ID variants (0.705 and 0.710) for KAP1 and CHK2 assays, respectively (dashed lines). Error bars represent standard errors of mean. Color/gray letters for protein variants indicate concordant/discordant functional assays result, respectively. Blue boxes denote conserved CHK2 domains. DNL, variants that do not localize into the nucleus.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952426.V1
Abstract: Funnel plot (left) and forest plots (right) for in idual datasets of breast cancer cases and controls from 12 datasets (10 countries) stratified according to the functional categorization.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952420.V1
Abstract: Detail description of the functional categorization of analyzed CHEK2 missense variants.
Publisher: Springer Science and Business Media LLC
Date: 13-05-2020
Location: Singapore
No related grants have been discovered for Sock Hoai Chan.