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  • American Association for Cancer Research (AACR)  (2)
  • 1
    Online Resource
    Online Resource
    Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 18 ( 2017-09-15), p. 4755-4762
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 18 ( 2017-09-15), p. 4755-4762
    Abstract: Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 4755–62. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-17-1083
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Abstract 4887: Direct mutational consequences of CRISPR-cas9 gene-edited DNA repair genes
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4887-4887
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4887-4887
    Abstract: Cancer whole-genome sequencing has revealed characteristic mutational signatures associated with defective DNA repair that underpin human genetic diseases. To define the direct mutagenic effects of DNA repair deficiency at the genome-wide level, we investigate mutational signatures generated by CRISPR-Cas9-based knockouts of 42 genes involved in DNA repair/replication using a human-induced pluripotent stem cell line. Knockouts (Δ) of nine DNA repair genes reveal substitution/indel mutational signatures. Notably, dissection of signatures of defective mismatch repair (MMR) uncovers gene-specific characteristics including distinguishing features of ΔMLH1, ΔMSH2, and ΔMSH6 from ΔPMS2. This gene-specificity is also exhibited by hIPSCs derived from patients with autosomal recessive Constitutional Mismatch Repair Deficiency (CMMRD) that carry biallelic germline mutations of MMR genes. Furthermore, gene-specificity manifests in whole genome sequenced primary human cancers. Additionally, detailed analyses reveal putative sources of endogenous DNA damage that contribute to MMR signatures, including guanine oxidation, errors of DNA polymerases and reversed template slippage or double slippage. Finally, we find that using all mutational signatures of MMR-deficiency as identified in this study results in improved sensitivity and specificity in classifying MMR-deficient tumors, critical for accurate patient stratification for therapeutic intervention. Citation Format: Xueqing Zou, Gene Koh, Scott Nanda, Andrea Degasperi, Katie Urgo, Wendy Bushell, Chukwuma Agu, Vanesa Perez-Alonso, Daniel Rueda, Julia Foreman, Rebecca Harris, Josef Jiricny, Bill Skarnes, Serena Nik-Zainal. Direct mutational consequences of CRISPR-cas9 gene-edited DNA repair genes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4887.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-4887
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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