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  • 1
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    Online Resource
    Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore
    Wiley ; 2021
    In:  International Journal of Cancer Vol. 148, No. 3 ( 2021-02), p. 637-645
    Details
    In: International Journal of Cancer, Wiley, Vol. 148, No. 3 ( 2021-02), p. 637-645
    Abstract: What's new? Extensive databases of BRCA1/2 variants have helped researchers develop diagnostic and treatment strategies for breast cancer. However, most of this information has been obtained from populations of European descent. In the present study, the authors were able to identify an ancient founder mutation in BRCA1 that is pathogenic and may be common among individuals of Han Chinese descent. In addition to its importance for appropriate patient care, this approach to studying ancestry‐specific variants may also aid in developing techniques to detect pathogenic mutations that might otherwise be missed.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    URL: Article
    DOI: 10.1002/ijc.v148.3
    DOI: 10.1002/ijc.33241
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 218257-9
    detail.hit.zdb_id: 1474822-8
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  • 2
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    Functional analysis of clinical BARD1 germline variants
    Cold Spring Harbor Laboratory ; 2019
    In:  Molecular Case Studies Vol. 5, No. 4 ( 2019-08), p. a004093-
    Details
    In: Molecular Case Studies, Cold Spring Harbor Laboratory, Vol. 5, No. 4 ( 2019-08), p. 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.
    Type of Medium: Online Resource
    ISSN: 2373-2865 , 2373-2873
    URL: Article
    DOI: 10.1101/mcs.a004093
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2019
    detail.hit.zdb_id: 2835759-0
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  • 3
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    Functional characterisation guides classification of novel BAP1 germline variants
    Springer Science and Business Media LLC ; 2020
    In:  npj Genomic Medicine Vol. 5, No. 1 ( 2020-11-19)
    Details
    In: npj Genomic Medicine, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2020-11-19)
    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.
    Type of Medium: Online Resource
    ISSN: 2056-7944
    URL: Article
    DOI: 10.1038/s41525-020-00157-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2813848-X
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  • 4
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    Molecular connections between circadian rhythm and genome maintenance pathways
    Bioscientifica ; 2021
    In:  Endocrine-Related Cancer Vol. 28, No. 2 ( 2021-02), p. R55-R66
    Details
    In: Endocrine-Related Cancer, Bioscientifica, Vol. 28, No. 2 ( 2021-02), p. R55-R66
    Abstract: Co-ordinated oscillation of mammalian circadian clock and cell cycle is essential for cellular and organismal homeostasis. Existing preclinical, epidemiological, molecular and biochemical evidence reveals a robust interplay between circadian clock, genome instability and cancer. Furthermore, recent investigations have demonstrated that the alterations in circadian clock perturb genome stability by modulating the cell-cycle timing, altering DNA replication fork progression, influencing DNA damage response (DDR) and DNA repair efficiency. In this review, we examine the most recent findings from different eukaryotic model systems and discuss the functional interaction between circadian factors with key DNA replication, DDR and DNA repair genes.
    Type of Medium: Online Resource
    ISSN: 1351-0088 , 1479-6821
    URL: Article
    DOI: 10.1530/ERC-20-0372
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2021
    detail.hit.zdb_id: 2010895-3
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  • 5
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    Online Resource
    Functional analysis of germline RAD51C missense variants highlight the role of RAD51C in replication fork protection
    Oxford University Press (OUP) ; 2023
    In:  Human Molecular Genetics Vol. 32, No. 8 ( 2023-04-06), p. 1401-1409
    Details
    In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 32, No. 8 ( 2023-04-06), p. 1401-1409
    Abstract: Monoallelic or biallelic RAD51C germline mutations results in chromosome instability disorders such as Fanconi anemia and cancers. The bona fide function of RAD51C is to assist RAD51 nucleoprotein filament onto single-strand DNA to complete homologous recombination (HR) repair. In addition to HR repair, the role of RAD51C in DNA replication is emerging when replication forks are transiently or irreversibly stalled. We identified novel RAD51C variants of uncertain significance (VUS) from breast, ovarian, pancreatic and gastric cancer patients and functionally characterized the effect of these variants in replication fork protection and double-strand breaks (DSB’s) repair. In RAD51C-deficient Chinese hamster CL-V4B cells, expression of RAD51C F164S, A87E, L134S and E49K variants heightened sensitivity to mitomycin C (MMC), etoposide and PARP inhibition. Differently, expression of subset of RAD51C variants R24L, R24W and R212H displayed mild sensitivity to MMC, etoposide and PARP inhibition. Further functional characterization of a subset of variants revealed that Rad51C F164S, A87E, L134S and E49K variants displayed reduced RAD51 foci formation and increased overall nuclear single strand DNA levels in the presence of replication stress. Additionally, DNA fiber assay revealed that RAD51C F164S, A87E, L134S and E49K variants displayed defective replication fork protection upon prolonged fork stalling. Investigations using patient-derived lymphoblastoid cell line carrying heterozygous RAD51C L134S variant showed an impairment in RAD51 chromatin association and replication fork protection, suggestive of deleteriousness of this VUS variant. Overall, our findings provide more insights into molecular roles of RAD51C in replication fork integrity maintenance and in DSB repair.
    Type of Medium: Online Resource
    ISSN: 0964-6906 , 1460-2083
    URL: Article
    DOI: 10.1093/hmg/ddac281
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474816-2
    SSG: 12
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  • 6
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    Abstract 2780: IL13RA2 is differentially regulated in papillary thyroid carcinoma versus follicular thyroid carcinoma
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2780-2780
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2780-2780
    Abstract: The interleukin-13 receptor alpha2 (IL13RA2), which is known to overexpressed in glioblastoma multiforme, plays a role in various cellular processes such as cell migration that may contribute to tumor progression. Studies have attributed IL13RA2 to invasion and metastasis in cancers of the ovary, breast, and pancreas but the pathological role of IL13RA2 in thyroid cancer is still unclear. This study aims to evaluate the expression of IL13RA2 in thyroid carcinomas and examine the role of IL13RA2 in progression of papillary thyroid cancer (PTC). We performed IL13RA2 immunochemical staining on tissue microarrays of 137 thyroid carcinomas and observed that IL13RA2 expression was significantly correlated with advanced tumor stage (pT3 / pT4; p=0.001) and regional lymph node metastasis (pN1; p & lt;0.001). Moreover, the staining scores of IL13RA2 were significantly higher in PTC compared to follicular and anaplastic subtypes (p & lt;0.02) and correlated with advanced tumor stage amongst PTC samples (pT3 / pT4; p=0.028). This differential profile of IL13RA2 in PTC was further validated in thyroid cancer cell lines overexpressing IL13RA2 to assay the effects on cell proliferation, cell migration and epithelial-mesenchymal transition (EMT) using CCK-8, transwell migration assay, qRT-PCR and western blot analyses. Knockdown of IL13RA2 in the PTC subtype B-CPAP cell line showed significantly reduced cell viability, cell migration and EMT markers including N-cadherin, Vimentin and Snail. Exogenous overexpression of IL13RA2 in another PTC cell line, K1 increased cell migration and EMT although cell proliferation was not affected. In summary, we demonstrated that IL13RA2 is differentially regulated in PTC and is involved in cell migration by enhancing EMT. The underlying molecular mechanisms on how IL13RA2 drives progression of thyroid cancer remains to be further investigated. Citation Format: Siao Ting Chong, Catherine Y. Kok, Khee Ming Tan, Shou Ping Guan, Siang Hui Lai, Cindy Lim, Jiancheng Hu, Charles Sturgis, Charis Eng, Paula Y. Lam, Joanne Ngeow. IL13RA2 is differentially regulated in papillary thyroid carcinoma versus follicular thyroid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2780.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2780
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Multiple neoplasia in a patient with Gitelman syndrome harboring germline monoallelic MUTYH mutation
    Springer Science and Business Media LLC ; 2020
    In:  npj Genomic Medicine Vol. 5, No. 1 ( 2020-09-18)
    Details
    In: npj Genomic Medicine, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2020-09-18)
    Abstract: Gitelman syndrome is a rare, recessively inherited disease characterized by chronic hypokalemia and hypomagnesemia as a result of defective electrolyte co-transport at the level of the distal convoluted tubule of the kidney. Here, we present the first report of a patient with Gitelman syndrome who developed multiple neoplasia including colorectal polyposis, synchronous colorectal cancers, recurrent breast fibroadenomata and a desmoid tumor. Whole-exome sequencing confirmed germline compound heterozygous mutations of c.179C  〉  T and c.1326C  〉  G in SLC12A3 , and in addition, identified a monoallelic germline c.934-2A  〉  G splice site mutation in MUTYH . In vitro , magnesium deficiency potentiated oxidative DNA damage in lymphoblastoid cell lines derived from the same patient. We postulate that monoallelic MUTYH mutations may manifest in the presence of cooperative non-genetic mechanisms, in this case possibly magnesium deficiency from Gitelman syndrome.
    Type of Medium: Online Resource
    ISSN: 2056-7944
    URL: Article
    DOI: 10.1038/s41525-020-00146-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2813848-X
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  • 8
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    Impact of Variant Reclassification in Cancer Predisposition Genes on Clinical Care
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  JCO Precision Oncology , No. 5 ( 2021-11), p. 577-584
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 5 ( 2021-11), p. 577-584
    Abstract: Genetic testing has clinical utility in the management of patients with hereditary cancer syndromes. However, the increased likelihood of encountering a variant of uncertain significance in individuals of non-European descent such as Asians may be challenging to both clinicians and patients. This study aims to evaluate the impact of variant reclassification in an Asian country with variants of uncertain significance reported in cancer predisposition genes. METHODS A retrospective analysis of patients seen at the Cancer Genetics Service at the National Cancer Centre Singapore between February 2014 and March 2020 was conducted. The frequency, direction, and time to variant reclassification were evaluated by comparing the reclassified report against the original report. RESULTS A total of 1,412 variants of uncertain significance were reported in 49.9% (845 of 1,695) of patients. Over 6 years, 6.7% (94 of 1,412) of variants were reclassified. Most variants of uncertain significance (94.1%, 80 of 85) were downgraded to benign or likely benign variant, with a smaller proportion of variants of uncertain significance (5.9%, 5 of 85) upgraded to pathogenic or likely pathogenic variant. Actionable variants of uncertain significance upgrades and pathogenic or likely pathogenic variant downgrades, which resulted in management changes, happened in 31.0% (39 of 126) of patients. The median and mean time taken for reclassification were 1 and 1.62 year(s), respectively. CONCLUSION We propose a clinical guideline to standardize management of patients reported to have variants of uncertain significance. Management should be based on the patient’s personal history, family history, and variant interpretation. For clinically relevant or suspicious variants of uncertain significance, follow-up is recommended every 2 years, as actionable reclassifications may happen during this period.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.20.00399
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 9
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    Germline Pathogenic Variants in Homologous Recombination and DNA Repair Genes in an Asian Cohort of Young-Onset Colorectal Cancer
    Oxford University Press (OUP) ; 2018
    In:  JNCI Cancer Spectrum Vol. 2, No. 4 ( 2018-10-01)
    Details
    In: JNCI Cancer Spectrum, Oxford University Press (OUP), Vol. 2, No. 4 ( 2018-10-01)
    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. Methods 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. Results 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. Conclusion 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.
    Type of Medium: Online Resource
    ISSN: 2515-5091
    URL: Article
    DOI: 10.1093/jncics/pky054
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
    detail.hit.zdb_id: 2975772-1
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  • 10
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    Online Resource
    Automatic DNA replication tract measurement to assess replication and repair dynamics at the single-molecule level
    Oxford University Press (OUP) ; 2022
    In:  Bioinformatics Vol. 38, No. 18 ( 2022-09-15), p. 4395-4402
    Details
    In: Bioinformatics, Oxford University Press (OUP), Vol. 38, No. 18 ( 2022-09-15), p. 4395-4402
    Abstract: DNA fibre assay has a potential application in genomic medicine, cancer and stem cell research at the single-molecule level. A major challenge for the clinical and research implementation of DNA fibre assays is the slow speed in which manual analysis takes place as it limits the clinical actionability. While automatic detection of DNA fibres speeds up this process considerably, current publicly available software have limited features in terms of their user interface for manual correction of results, which in turn limit their accuracy and ability to account for atypical structures that may be important in diagnosis or investigative studies. We recognize that core improvements can be made to the GUI to allow for direct interaction with automatic results to preserve accuracy as well as enhance the versatility of automatic DNA fibre detection for use in variety of situations. Results To address the unmet needs of diverse DNA fibre analysis investigations, we propose DNA Stranding, an open-source software that is able to perform accurate fibre length quantification (13.22% mean relative error) and fibre pattern recognition (R  & gt; 0.93) with up to six fibre patterns supported. With the graphical interface, we developed, user can conduct semi-automatic analyses which benefits from the advantages of both automatic and manual processes to improve workflow efficiency without compromising accuracy. Availability and implementation The software package is available at https://github.com/lgole/DNAStranding. Supplementary information Supplementary data are available at Bioinformatics online.
    Type of Medium: Online Resource
    ISSN: 1367-4803 , 1367-4811
    URL: Article
    DOI: 10.1093/bioinformatics/btac533
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1468345-3
    SSG: 12
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