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  1. Article ; Online: Frameshift mutations in peripheral blood as a biomarker for surveillance of lynch syndrome.

    Song, Yurong / Loomans-Kropp, Holli / Baugher, Ryan N / Somerville, Brandon / Baxter, Shaneen S / Kerr, Travis D / Plona, Teri M / Mellott, Stephanie D / Young, Todd B / Lawhorn, Heidi E / Wei, Lei / Hu, Qiang / Liu, Song / Hutson, Alan / Pinto, Ligia / Potter, John D / Sei, Shizuko / Gelincik, Ozkan / Lipkin, Steven M /
    Gebert, Johannes / Kloor, Matthias / Shoemaker, Robert H

    Journal of the National Cancer Institute

    2024  

    Abstract: Background: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, which lead to high microsatellite instability (MSI-H) and frameshift mutations (FSMs) at coding ... ...

    Abstract Background: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, which lead to high microsatellite instability (MSI-H) and frameshift mutations (FSMs) at coding mononucleotide repeats (cMNRs) in the genome. Recurrent FSMs in these regions are thought to play a central role in the increased risk of various cancers. However, there are no biomarkers currently available for the surveillance of MSI-H-associated cancers.
    Methods: An FSM-based biomarker panel was developed and validated by targeted next generation sequencing of supernatant DNA from cultured MSI-H colorectal cancer cells. This supported selection of 122-FSM targets as potential biomarkers. This biomarker panel was then tested using matched tumor, adjacent normal tissue, and buffy coat (53 samples), and blood-derived cell-free DNA (cfDNA; 38 samples) obtained from 45 cases of MSI-H/MMR deficient (MMRd) patients/carriers. cfDNA from 84 healthy individuals was also sequenced to assess background noise.
    Results: Recurrent FSMs at cMNRs were detectable not only in tumors, but also in cfDNA from MSI-H/MMRd cases including a LS carrier with a varying range of target detection (up to 85.2%), whereas they were virtually undetectable in healthy individuals. ROC analysis showed high sensitivity and specificity (AUC = 0.94) of the investigated panel.
    Conclusions: We demonstrated that FSMs can be detected in cfDNA from MSI-H/MMRd cases and asymptomatic carriers. The 122-target FSM panel described here has promise as a tool for improved surveillance of MSI-H/MMRd carriers with the potential to reduce the frequency of invasive screening methods for this high-cancer-risk cohort.
    Language English
    Publishing date 2024-03-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2992-0
    ISSN 1460-2105 ; 0027-8874 ; 0198-0157
    ISSN (online) 1460-2105
    ISSN 0027-8874 ; 0198-0157
    DOI 10.1093/jnci/djae060
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer.

    Song, Yurong / Kerr, Travis D / Sanders, Chelsea / Dai, Lisheng / Baxter, Shaneen S / Somerville, Brandon / Baugher, Ryan N / Mellott, Stephanie D / Young, Todd B / Lawhorn, Heidi E / Plona, Teri M / Xu, Bingfang / Wei, Lei / Hu, Qiang / Liu, Song / Hutson, Alan / Karim, Baktiar / Burkett, Sandra / Difilippantonio, Simone /
    Pinto, Ligia / Gebert, Johannes / Kloor, Matthias / Lipkin, Steven M / Sei, Shizuko / Shoemaker, Robert H

    Frontiers in oncology

    2023  Volume 13, Page(s) 1223915

    Abstract: Background: Genome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g., : Methods: To better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop ... ...

    Abstract Background: Genome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g.,
    Methods: To better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop vaccines and therapeutic testing platforms for this high-risk population, we generated organoids and an orthotopic mouse model from intestine tumors developed in a Msh2-deficient mouse model, and followed with a detailed characterization.
    Results: The organoids were shown to be of epithelial origin with stem cell features, to have a high frameshift mutation frequency with MSI-H and chromosome instability, and intra- and inter-tumor heterogeneity. An orthotopic model using intra-cecal implantation of tumor fragments derived from organoids showed progressive tumor growth, resulting in the development of adenocarcinomas mixed with mucinous features and distant metastasis in liver and lymph node.
    Conclusions: The established organoids with characteristics of MSI-H cancers can be used to study MMRd cancer biology. The orthotopic model, with its distant metastasis and expressing frameshift peptides, is suitable for evaluating the efficacy of neoantigen-based vaccines or anticancer drugs in combination with other therapies.
    Language English
    Publishing date 2023-09-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2023.1223915
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Comparison of Eight Technologies to Determine Genotype at the UGT1A1 (TA)

    Sissung, Tristan M / Barbier, Roberto H / Price, Douglas K / Plona, Teri M / Pike, Kristen M / Mellott, Stephanie D / Baugher, Ryan N / Whiteley, Gordon R / Soppet, Daniel R / Venzon, David / Berman, Arlene / Rajan, Arun / Giaccone, Giuseppe / Meltzer, Paul / Figg, William D

    International journal of molecular sciences

    2020  Volume 21, Issue 3

    Abstract: To ensure accuracy ... ...

    Abstract To ensure accuracy of
    MeSH term(s) Alleles ; Genotype ; Genotyping Techniques/methods ; Glucuronosyltransferase/genetics ; Humans ; Irinotecan ; Pharmacogenetics ; Polymerase Chain Reaction ; Polymorphism, Genetic
    Chemical Substances Irinotecan (7673326042) ; UGT1A1 enzyme (EC 2.4.1.-) ; Glucuronosyltransferase (EC 2.4.1.17)
    Language English
    Publishing date 2020-01-30
    Publishing country Switzerland
    Document type Comparative Study ; Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms21030896
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing.

    Biswas, Kajal / Couillard, Martin / Cavallone, Luca / Burkett, Sandra / Stauffer, Stacey / Martin, Betty K / Southon, Eileen / Reid, Susan / Plona, Teri M / Baugher, Ryan N / Mellott, Stephanie D / Pike, Kristen M / Albaugh, Mary E / Maedler-Kron, Chelsea / Hamel, Nancy / Tessarollo, Lino / Marcus, Victoria / Foulkes, William D / Sharan, Shyam K

    Cell death & disease

    2021  Volume 12, Issue 9, Page(s) 838

    Abstract: Hereditary non-polyposis colorectal cancer, now known as Lynch syndrome (LS) is one of the most common cancer predisposition syndromes and is caused by germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes. A common founder GPV in PMS2 ... ...

    Abstract Hereditary non-polyposis colorectal cancer, now known as Lynch syndrome (LS) is one of the most common cancer predisposition syndromes and is caused by germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes. A common founder GPV in PMS2 in the Canadian Inuit population, NM_000535.5: c.2002A>G, leads to a benign missense (p.I668V) but also acts as a de novo splice site that creates a 5 bp deletion resulting in a truncated protein (p.I668*). Individuals homozygous for this GPV are predisposed to atypical constitutional MMR deficiency with a delayed onset of first primary malignancy. We have generated mice with an equivalent germline mutation (Pms2c.1993A>G) and demonstrate that it results in a splicing defect similar to those observed in humans. Homozygous mutant mice are viable like the Pms2 null mice. However, unlike the Pms2 null mice, these mutant mice are fertile, like humans homozygous for this variant. Furthermore, these mice exhibit a significant increase in microsatellite instability and intestinal adenomas on an Apc mutant background. Rectification of the splicing defect in human and murine fibroblasts using antisense morpholinos suggests that this novel mouse model can be valuable in evaluating the efficacy aimed at targeting the splicing defect in PMS2 that is highly prevalent among the Canadian Inuits.
    MeSH term(s) Adenomatous Polyposis Coli Protein/genetics ; Animals ; Base Sequence ; DNA Mismatch Repair/genetics ; Disease Models, Animal ; Exons/genetics ; Fertility/genetics ; Fibroblasts/metabolism ; Founder Effect ; Male ; Meiosis ; Mice, Inbred C57BL ; Microsatellite Instability ; Mismatch Repair Endonuclease PMS2/genetics ; Mismatch Repair Endonuclease PMS2/metabolism ; Morpholinos/pharmacology ; Mutation/genetics ; Polyps/pathology ; RNA Splicing/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Spermatozoa/pathology ; Testis/pathology ; Mice
    Chemical Substances Adenomatous Polyposis Coli Protein ; Morpholinos ; RNA, Messenger ; Mismatch Repair Endonuclease PMS2 (EC 3.6.1.3)
    Language English
    Publishing date 2021-09-06
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-021-04130-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Pharmacogenomics Implementation at the National Institutes of Health Clinical Center.

    Sissung, Tristan M / McKeeby, Jon W / Patel, Jharana / Lertora, Juan J / Kumar, Parag / Flegel, Willy A / Adams, Sharon D / Eckes, Ellen J / Mickey, Frank / Plona, Teri M / Mellot, Stephanie D / Baugher, Ryan N / Wu, Xiaolin / Soppet, Daniel R / Barcus, Mary E / Datta, Vivekananda / Pike, Kristen M / DiPatrizio, Gary / Figg, William D /
    Goldspiel, Barry R

    Journal of clinical pharmacology

    2018  Volume 57 Suppl 10, Page(s) S67–S77

    Abstract: The National Institutes of Health Clinical Center (NIH CC) is the largest hospital in the United States devoted entirely to clinical research, with a highly diverse spectrum of patients. Patient safety and clinical quality are major goals of the hospital, ...

    Abstract The National Institutes of Health Clinical Center (NIH CC) is the largest hospital in the United States devoted entirely to clinical research, with a highly diverse spectrum of patients. Patient safety and clinical quality are major goals of the hospital, and therapy is often complicated by multiple cotherapies and comorbidities. To this end, we implemented a pharmacogenomics program in 2 phases. In the first phase, we implemented genotyping for HLA-A and HLA-B gene variations with clinical decision support (CDS) for abacavir, carbamazepine, and allopurinol. In the second phase, we implemented genotyping for drug-metabolizing enzymes and transporters: SLCO1B1 for CDS of simvastatin and TPMT for CDS of mercaptopurine, azathioprine, and thioguanine. The purpose of this review is to describe the implementation process, which involves clinical, laboratory, informatics, and policy decisions pertinent to the NIH CC.
    MeSH term(s) Biomedical Research/organization & administration ; Decision Support Systems, Clinical ; Genotype ; Humans ; Medical Informatics ; National Institutes of Health (U.S.)/organization & administration ; Organizational Policy ; Pharmacogenetics/methods ; United States
    Language English
    Publishing date 2018-02-18
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 188980-1
    ISSN 1552-4604 ; 0091-2700 ; 0021-9754
    ISSN (online) 1552-4604
    ISSN 0091-2700 ; 0021-9754
    DOI 10.1002/jcph.993
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  6. Article ; Online: Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair.

    Bradford, Porcia T / Goldstein, Alisa M / Tamura, Deborah / Khan, Sikandar G / Ueda, Takahiro / Boyle, Jennifer / Oh, Kyu-Seon / Imoto, Kyoko / Inui, Hiroki / Moriwaki, Shin-Ichi / Emmert, Steffen / Pike, Kristen M / Raziuddin, Arati / Plona, Teri M / DiGiovanna, John J / Tucker, Margaret A / Kraemer, Kenneth H

    Journal of medical genetics

    2010  Volume 48, Issue 3, Page(s) 168–176

    Abstract: Background: The frequency of cancer, neurologic degeneration and mortality in xeroderma pigmentosum (XP) patients with defective DNA repair was determined in a four decade natural history study.: Methods: All 106 XP patients admitted to the National ... ...

    Abstract Background: The frequency of cancer, neurologic degeneration and mortality in xeroderma pigmentosum (XP) patients with defective DNA repair was determined in a four decade natural history study.
    Methods: All 106 XP patients admitted to the National Institutes of Health from 1971 to 2009 were evaluated from clinical records and follow-up.
    Results: In the 65 per cent (n=69) of patients with skin cancer, non-melanoma skin cancer (NMSC) was increased 10,000-fold and melanoma was increased 2000-fold in patients under age 20. The 9 year median age at diagnosis of first non-melanoma skin cancer (NMSC) (n=64) was significantly younger than the 22 year median age at diagnosis of first melanoma (n=38)-a relative age reversal from the general population suggesting different mechanisms of carcinogenesis between NMSC and melanoma. XP patients with pronounced burning on minimal sun exposure (n=65) were less likely to develop skin cancer than those who did not. This may be related to the extreme sun protection they receive from an earlier age, decreasing their total ultraviolet exposure. Progressive neurologic degeneration was present in 24% (n=25) with 16/25 in complementation group XP-D. The most common causes of death were skin cancer (34%, n=10), neurologic degeneration (31%, n=9), and internal cancer (17%, n=5). The median age at death (29 years) in XP patients with neurodegeneration was significantly younger than those XP patients without neurodegeneration (37 years) (p=0.02).
    Conclusion: This 39 year follow-up study of XP patients indicates a major role of DNA repair genes in the aetiology of skin cancer and neurologic degeneration.
    MeSH term(s) Adolescent ; Adult ; Aged ; Child ; Child, Preschool ; DNA Repair ; Female ; Follow-Up Studies ; Humans ; Infant ; Male ; Melanoma/complications ; Melanoma/genetics ; Middle Aged ; Neurodegenerative Diseases/complications ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/mortality ; Receptor, Melanocortin, Type 1/genetics ; Retrospective Studies ; Skin Neoplasms/complications ; Skin Neoplasms/genetics ; Skin Neoplasms/mortality ; Xeroderma Pigmentosum/complications ; Xeroderma Pigmentosum/genetics ; Young Adult
    Chemical Substances Receptor, Melanocortin, Type 1
    Language English
    Publishing date 2010-11-19
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 220881-7
    ISSN 1468-6244 ; 0022-2593
    ISSN (online) 1468-6244
    ISSN 0022-2593
    DOI 10.1136/jmg.2010.083022
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