Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple negative breast and serous ovarian cancers

N. J. Birkbak, Y. Li, S Pathania, A Greene-Colozzi, M Dreze, C Bowman-Colin, Z. Sztupinszki, M. Krzystanek, Miklos Diossy, N Tung, P D Ryan, J E Garber, D P Silver, J D Iglehart, Z C Wang, D Szuts, Z. Szallasi*, A L Richardson

*Corresponding author for this work

    Research output: Contribution to journalJournal articleResearchpeer-review

    117 Downloads (Pure)

    Abstract

    Platinum based therapy is an effective treatment for a subset of triple negative breast cancer and ovarian cancer patients. In order to increase response rate and decrease unnecessary use, robust biomarkers that predict response to therapy are needed. We performed an integrated genomic approach combining differential analysis of gene expression and DNA copy number in sensitive compared to resistant triple negative breast cancers in two independent neoadjuvant cisplatin treated cohorts. Functional relevance of significant hits was investigated in vitro by overexpression, knockdown and targeted inhibitor treatment. We identified two genes, the Bloom helicase (BLM) and Fanconi anemia complementation group I (FANCI), that have both increased DNA copy number and gene expression in the platinum sensitive cases. Increased level of expression of these two genes was also associated with platinum but not with taxane response in ovarian cancer. As a functional validation, we found that overexpression of BLM promotes DNA damage and induces sensitivity to cisplatin, but has no effect on paclitaxel sensitivity. A biomarker based on the expression levels of the BLM and FANCI genes is a potential predictor of platinum sensitivity in triple negative breast cancer and ovarian cancer. Through integrated analysis of gene expression and copy number data from two independent clinical trials in triple negative breast cancer, we identify two genes, BLM and FANCI, involved in double-strand DNA repair where increased expression is related to sensitivity to platinum induced DNA damage. Further functional validation reveals that overexpression of BLM alone promotes DNA damage.
    Original languageEnglish
    JournalAnnals of Oncology
    Volume29
    Issue number4
    Pages (from-to)903-909
    Number of pages7
    ISSN0923-7534
    DOIs
    Publication statusPublished - 2018

    Bibliographical note

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

    Keywords

    • gene expression based predictor of treatment sensitivity
    • ovarian cancer
    • platinum based chemotherapy
    • triple negative breast cancer

    Cite this

    Birkbak, N. J., Li, Y., Pathania, S., Greene-Colozzi, A., Dreze, M., Bowman-Colin, C., ... Richardson, A. L. (2018). Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple negative breast and serous ovarian cancers. Annals of Oncology, 29(4), 903-909. https://doi.org/10.1093/annonc/mdy049
    Birkbak, N. J. ; Li, Y. ; Pathania, S ; Greene-Colozzi, A ; Dreze, M ; Bowman-Colin, C ; Sztupinszki, Z. ; Krzystanek, M. ; Diossy, Miklos ; Tung, N ; Ryan, P D ; Garber, J E ; Silver, D P ; Iglehart, J D ; Wang, Z C ; Szuts, D ; Szallasi, Z. ; Richardson, A L. / Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple negative breast and serous ovarian cancers. In: Annals of Oncology. 2018 ; Vol. 29, No. 4. pp. 903-909.
    @article{2d81ef14e8b146c48ddc387d560a35f0,
    title = "Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple negative breast and serous ovarian cancers",
    abstract = "Platinum based therapy is an effective treatment for a subset of triple negative breast cancer and ovarian cancer patients. In order to increase response rate and decrease unnecessary use, robust biomarkers that predict response to therapy are needed. We performed an integrated genomic approach combining differential analysis of gene expression and DNA copy number in sensitive compared to resistant triple negative breast cancers in two independent neoadjuvant cisplatin treated cohorts. Functional relevance of significant hits was investigated in vitro by overexpression, knockdown and targeted inhibitor treatment. We identified two genes, the Bloom helicase (BLM) and Fanconi anemia complementation group I (FANCI), that have both increased DNA copy number and gene expression in the platinum sensitive cases. Increased level of expression of these two genes was also associated with platinum but not with taxane response in ovarian cancer. As a functional validation, we found that overexpression of BLM promotes DNA damage and induces sensitivity to cisplatin, but has no effect on paclitaxel sensitivity. A biomarker based on the expression levels of the BLM and FANCI genes is a potential predictor of platinum sensitivity in triple negative breast cancer and ovarian cancer. Through integrated analysis of gene expression and copy number data from two independent clinical trials in triple negative breast cancer, we identify two genes, BLM and FANCI, involved in double-strand DNA repair where increased expression is related to sensitivity to platinum induced DNA damage. Further functional validation reveals that overexpression of BLM alone promotes DNA damage.",
    keywords = "gene expression based predictor of treatment sensitivity, ovarian cancer, platinum based chemotherapy, triple negative breast cancer",
    author = "Birkbak, {N. J.} and Y. Li and S Pathania and A Greene-Colozzi and M Dreze and C Bowman-Colin and Z. Sztupinszki and M. Krzystanek and Miklos Diossy and N Tung and Ryan, {P D} and Garber, {J E} and Silver, {D P} and Iglehart, {J D} and Wang, {Z C} and D Szuts and Z. Szallasi and Richardson, {A L}",
    note = "This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com",
    year = "2018",
    doi = "10.1093/annonc/mdy049",
    language = "English",
    volume = "29",
    pages = "903--909",
    journal = "Annals of Oncology",
    issn = "0923-7534",
    publisher = "Oxford University Press",
    number = "4",

    }

    Birkbak, NJ, Li, Y, Pathania, S, Greene-Colozzi, A, Dreze, M, Bowman-Colin, C, Sztupinszki, Z, Krzystanek, M, Diossy, M, Tung, N, Ryan, PD, Garber, JE, Silver, DP, Iglehart, JD, Wang, ZC, Szuts, D, Szallasi, Z & Richardson, AL 2018, 'Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple negative breast and serous ovarian cancers', Annals of Oncology, vol. 29, no. 4, pp. 903-909. https://doi.org/10.1093/annonc/mdy049

    Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple negative breast and serous ovarian cancers. / Birkbak, N. J. ; Li, Y.; Pathania, S; Greene-Colozzi, A; Dreze, M; Bowman-Colin, C; Sztupinszki, Z.; Krzystanek, M.; Diossy, Miklos; Tung, N; Ryan, P D; Garber, J E; Silver, D P; Iglehart, J D; Wang, Z C; Szuts, D; Szallasi, Z.; Richardson, A L.

    In: Annals of Oncology, Vol. 29, No. 4, 2018, p. 903-909.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple negative breast and serous ovarian cancers

    AU - Birkbak, N. J.

    AU - Li, Y.

    AU - Pathania, S

    AU - Greene-Colozzi, A

    AU - Dreze, M

    AU - Bowman-Colin, C

    AU - Sztupinszki, Z.

    AU - Krzystanek, M.

    AU - Diossy, Miklos

    AU - Tung, N

    AU - Ryan, P D

    AU - Garber, J E

    AU - Silver, D P

    AU - Iglehart, J D

    AU - Wang, Z C

    AU - Szuts, D

    AU - Szallasi, Z.

    AU - Richardson, A L

    N1 - This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

    PY - 2018

    Y1 - 2018

    N2 - Platinum based therapy is an effective treatment for a subset of triple negative breast cancer and ovarian cancer patients. In order to increase response rate and decrease unnecessary use, robust biomarkers that predict response to therapy are needed. We performed an integrated genomic approach combining differential analysis of gene expression and DNA copy number in sensitive compared to resistant triple negative breast cancers in two independent neoadjuvant cisplatin treated cohorts. Functional relevance of significant hits was investigated in vitro by overexpression, knockdown and targeted inhibitor treatment. We identified two genes, the Bloom helicase (BLM) and Fanconi anemia complementation group I (FANCI), that have both increased DNA copy number and gene expression in the platinum sensitive cases. Increased level of expression of these two genes was also associated with platinum but not with taxane response in ovarian cancer. As a functional validation, we found that overexpression of BLM promotes DNA damage and induces sensitivity to cisplatin, but has no effect on paclitaxel sensitivity. A biomarker based on the expression levels of the BLM and FANCI genes is a potential predictor of platinum sensitivity in triple negative breast cancer and ovarian cancer. Through integrated analysis of gene expression and copy number data from two independent clinical trials in triple negative breast cancer, we identify two genes, BLM and FANCI, involved in double-strand DNA repair where increased expression is related to sensitivity to platinum induced DNA damage. Further functional validation reveals that overexpression of BLM alone promotes DNA damage.

    AB - Platinum based therapy is an effective treatment for a subset of triple negative breast cancer and ovarian cancer patients. In order to increase response rate and decrease unnecessary use, robust biomarkers that predict response to therapy are needed. We performed an integrated genomic approach combining differential analysis of gene expression and DNA copy number in sensitive compared to resistant triple negative breast cancers in two independent neoadjuvant cisplatin treated cohorts. Functional relevance of significant hits was investigated in vitro by overexpression, knockdown and targeted inhibitor treatment. We identified two genes, the Bloom helicase (BLM) and Fanconi anemia complementation group I (FANCI), that have both increased DNA copy number and gene expression in the platinum sensitive cases. Increased level of expression of these two genes was also associated with platinum but not with taxane response in ovarian cancer. As a functional validation, we found that overexpression of BLM promotes DNA damage and induces sensitivity to cisplatin, but has no effect on paclitaxel sensitivity. A biomarker based on the expression levels of the BLM and FANCI genes is a potential predictor of platinum sensitivity in triple negative breast cancer and ovarian cancer. Through integrated analysis of gene expression and copy number data from two independent clinical trials in triple negative breast cancer, we identify two genes, BLM and FANCI, involved in double-strand DNA repair where increased expression is related to sensitivity to platinum induced DNA damage. Further functional validation reveals that overexpression of BLM alone promotes DNA damage.

    KW - gene expression based predictor of treatment sensitivity

    KW - ovarian cancer

    KW - platinum based chemotherapy

    KW - triple negative breast cancer

    U2 - 10.1093/annonc/mdy049

    DO - 10.1093/annonc/mdy049

    M3 - Journal article

    VL - 29

    SP - 903

    EP - 909

    JO - Annals of Oncology

    JF - Annals of Oncology

    SN - 0923-7534

    IS - 4

    ER -