Publication

Refinement of high-risk endometrial cancer classification using DNA damage response biomarkers: a TransPORTEC initiative

Auguste, A., Genestie, C., De Bruyn, M., Adam, J., Le Formal, A., Drusch, F., Pautier, P., Crosbie, E. J., MacKay, H., Kitchener, H. C., Powell, M., Pollock, P. M., Mileshkin, L., Edmondson, R. J., Nout, R., Nijman, H. W., Creutzberg, C. L., Bosse, T. & Leary, A., Dec-2018, In : Modern Pathology. 31, 12, p. 1851-1861 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Auguste, A., Genestie, C., De Bruyn, M., Adam, J., Le Formal, A., Drusch, F., ... Leary, A. (2018). Refinement of high-risk endometrial cancer classification using DNA damage response biomarkers: a TransPORTEC initiative. Modern Pathology, 31(12), 1851-1861. https://doi.org/10.1038/s41379-018-0055-1

Author

Auguste, Aurélie ; Genestie, Catherine ; De Bruyn, Marco ; Adam, Julien ; Le Formal, Audrey ; Drusch, Françoise ; Pautier, Patricia ; Crosbie, Emma J ; MacKay, Helen ; Kitchener, Henry C ; Powell, Melanie ; Pollock, Pamela M ; Mileshkin, Linda ; Edmondson, Richard J ; Nout, Remi ; Nijman, Hans W ; Creutzberg, Carien L ; Bosse, Tjalling ; Leary, Alexandra. / Refinement of high-risk endometrial cancer classification using DNA damage response biomarkers : a TransPORTEC initiative. In: Modern Pathology. 2018 ; Vol. 31, No. 12. pp. 1851-1861.

Harvard

Auguste, A, Genestie, C, De Bruyn, M, Adam, J, Le Formal, A, Drusch, F, Pautier, P, Crosbie, EJ, MacKay, H, Kitchener, HC, Powell, M, Pollock, PM, Mileshkin, L, Edmondson, RJ, Nout, R, Nijman, HW, Creutzberg, CL, Bosse, T & Leary, A 2018, 'Refinement of high-risk endometrial cancer classification using DNA damage response biomarkers: a TransPORTEC initiative', Modern Pathology, vol. 31, no. 12, pp. 1851-1861. https://doi.org/10.1038/s41379-018-0055-1

Standard

Refinement of high-risk endometrial cancer classification using DNA damage response biomarkers : a TransPORTEC initiative. / Auguste, Aurélie; Genestie, Catherine; De Bruyn, Marco; Adam, Julien; Le Formal, Audrey; Drusch, Françoise; Pautier, Patricia; Crosbie, Emma J; MacKay, Helen; Kitchener, Henry C; Powell, Melanie; Pollock, Pamela M; Mileshkin, Linda; Edmondson, Richard J; Nout, Remi; Nijman, Hans W; Creutzberg, Carien L; Bosse, Tjalling; Leary, Alexandra.

In: Modern Pathology, Vol. 31, No. 12, 12.2018, p. 1851-1861.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Auguste A, Genestie C, De Bruyn M, Adam J, Le Formal A, Drusch F et al. Refinement of high-risk endometrial cancer classification using DNA damage response biomarkers: a TransPORTEC initiative. Modern Pathology. 2018 Dec;31(12):1851-1861. https://doi.org/10.1038/s41379-018-0055-1


BibTeX

@article{3303ac5d9fbc4cdb9c3fefc5212950d2,
title = "Refinement of high-risk endometrial cancer classification using DNA damage response biomarkers: a TransPORTEC initiative",
abstract = "The TransPORTEC consortium previouslclassified high-risk endometrial cancer including poor-risk histologies such as clear cells, into four molecular subtypes {"}POLE mutated,{"} {"}microsatellite unstable,{"} {"}TP53 mutated,{"} and {"}no specific molecular profile.{"} We evaluated whether DNA damage response biomarkers could further refine this high-risk tumors classification, in particular the heterogeneous {"}no specific molecular profile{"} and {"}TP53 mutated{"} subsets recently qualified as poor prognosis in high-risk endometrial cancer. DNA damage response biomarkers including proteins involved in DNA damage (delta-H2AX), homologous recombination (RAD51), regulators of error-prone Non Homologous End-Joining (DNA-pk, FANCD2), and PARP-1 were evaluated in 116 high-risk tumors by immunohistochemistry. CD8 and PD-1 expression by immunochemistry and mutation analyses were performed previously. Survival outcome were calculated using Kaplan-Meier and Log-rank test. None of the DNA damage response biomarkers alone were prognostic. However markers were informative within molecular subsets. Among the {"}no specific molecular profile{"} subset, delta-H2AX+ was significantly predictive of poor disease free survival (Hazard Ratio = 2.56; p = 0.026), and among {"}TP53 mutated,{"} a DNA-pk+/FANCD2-profile (favouring error-prone Non Homologous End-Joining) predicted worst disease free survival (Hazard Ratio = 4.95; p = 0.009) resulting in five distinct prognostic subgroups from best to worst prognosis: group1 {"}POLE mutated/Microsatellite unstable{"} > group2 {"}no specific molecular profile with no DNA damage{"} > group3 {"}TP53 mutated/Non Homologous End-Joining negative{"} > group4 {"}no specific molecular profile with high DNA damage{"} > group5 {"}TP53 mutated/Non Homologous End-Joining positive{"}; p = 0.0002). Actionable targets were also different among subsets. Group3 had significantly higher infiltration of PD-1+ immune cells (p = 0.003), segregating with group1. Group2 had frequent PI3K pathway mutations and ER positivity. While group5, with the worst prognosis, had high DNA damage and PARP-1 expression providing a rationale for PARP inhibition. Our findings have refined the TransPORTEC prognostic classification of high-risk endometrial cancer into five distinct subgroups by integrating DNA damage response biomarkers and identified molecular subtype-specific therapeutic strategies.",
keywords = "REPAIR DEFECTS, RADIOTHERAPY, SENSITIVITY, GAMMA-H2AX, DEFICIENCY, BRCA1, 53BP1",
author = "Aur{\'e}lie Auguste and Catherine Genestie and {De Bruyn}, Marco and Julien Adam and {Le Formal}, Audrey and Fran{\cc}oise Drusch and Patricia Pautier and Crosbie, {Emma J} and Helen MacKay and Kitchener, {Henry C} and Melanie Powell and Pollock, {Pamela M} and Linda Mileshkin and Edmondson, {Richard J} and Remi Nout and Nijman, {Hans W} and Creutzberg, {Carien L} and Tjalling Bosse and Alexandra Leary",
year = "2018",
month = "12",
doi = "10.1038/s41379-018-0055-1",
language = "English",
volume = "31",
pages = "1851--1861",
journal = "Modern Pathology",
issn = "0893-3952",
publisher = "Nature Publishing Group",
number = "12",

}

RIS

TY - JOUR

T1 - Refinement of high-risk endometrial cancer classification using DNA damage response biomarkers

T2 - a TransPORTEC initiative

AU - Auguste, Aurélie

AU - Genestie, Catherine

AU - De Bruyn, Marco

AU - Adam, Julien

AU - Le Formal, Audrey

AU - Drusch, Françoise

AU - Pautier, Patricia

AU - Crosbie, Emma J

AU - MacKay, Helen

AU - Kitchener, Henry C

AU - Powell, Melanie

AU - Pollock, Pamela M

AU - Mileshkin, Linda

AU - Edmondson, Richard J

AU - Nout, Remi

AU - Nijman, Hans W

AU - Creutzberg, Carien L

AU - Bosse, Tjalling

AU - Leary, Alexandra

PY - 2018/12

Y1 - 2018/12

N2 - The TransPORTEC consortium previouslclassified high-risk endometrial cancer including poor-risk histologies such as clear cells, into four molecular subtypes "POLE mutated," "microsatellite unstable," "TP53 mutated," and "no specific molecular profile." We evaluated whether DNA damage response biomarkers could further refine this high-risk tumors classification, in particular the heterogeneous "no specific molecular profile" and "TP53 mutated" subsets recently qualified as poor prognosis in high-risk endometrial cancer. DNA damage response biomarkers including proteins involved in DNA damage (delta-H2AX), homologous recombination (RAD51), regulators of error-prone Non Homologous End-Joining (DNA-pk, FANCD2), and PARP-1 were evaluated in 116 high-risk tumors by immunohistochemistry. CD8 and PD-1 expression by immunochemistry and mutation analyses were performed previously. Survival outcome were calculated using Kaplan-Meier and Log-rank test. None of the DNA damage response biomarkers alone were prognostic. However markers were informative within molecular subsets. Among the "no specific molecular profile" subset, delta-H2AX+ was significantly predictive of poor disease free survival (Hazard Ratio = 2.56; p = 0.026), and among "TP53 mutated," a DNA-pk+/FANCD2-profile (favouring error-prone Non Homologous End-Joining) predicted worst disease free survival (Hazard Ratio = 4.95; p = 0.009) resulting in five distinct prognostic subgroups from best to worst prognosis: group1 "POLE mutated/Microsatellite unstable" > group2 "no specific molecular profile with no DNA damage" > group3 "TP53 mutated/Non Homologous End-Joining negative" > group4 "no specific molecular profile with high DNA damage" > group5 "TP53 mutated/Non Homologous End-Joining positive"; p = 0.0002). Actionable targets were also different among subsets. Group3 had significantly higher infiltration of PD-1+ immune cells (p = 0.003), segregating with group1. Group2 had frequent PI3K pathway mutations and ER positivity. While group5, with the worst prognosis, had high DNA damage and PARP-1 expression providing a rationale for PARP inhibition. Our findings have refined the TransPORTEC prognostic classification of high-risk endometrial cancer into five distinct subgroups by integrating DNA damage response biomarkers and identified molecular subtype-specific therapeutic strategies.

AB - The TransPORTEC consortium previouslclassified high-risk endometrial cancer including poor-risk histologies such as clear cells, into four molecular subtypes "POLE mutated," "microsatellite unstable," "TP53 mutated," and "no specific molecular profile." We evaluated whether DNA damage response biomarkers could further refine this high-risk tumors classification, in particular the heterogeneous "no specific molecular profile" and "TP53 mutated" subsets recently qualified as poor prognosis in high-risk endometrial cancer. DNA damage response biomarkers including proteins involved in DNA damage (delta-H2AX), homologous recombination (RAD51), regulators of error-prone Non Homologous End-Joining (DNA-pk, FANCD2), and PARP-1 were evaluated in 116 high-risk tumors by immunohistochemistry. CD8 and PD-1 expression by immunochemistry and mutation analyses were performed previously. Survival outcome were calculated using Kaplan-Meier and Log-rank test. None of the DNA damage response biomarkers alone were prognostic. However markers were informative within molecular subsets. Among the "no specific molecular profile" subset, delta-H2AX+ was significantly predictive of poor disease free survival (Hazard Ratio = 2.56; p = 0.026), and among "TP53 mutated," a DNA-pk+/FANCD2-profile (favouring error-prone Non Homologous End-Joining) predicted worst disease free survival (Hazard Ratio = 4.95; p = 0.009) resulting in five distinct prognostic subgroups from best to worst prognosis: group1 "POLE mutated/Microsatellite unstable" > group2 "no specific molecular profile with no DNA damage" > group3 "TP53 mutated/Non Homologous End-Joining negative" > group4 "no specific molecular profile with high DNA damage" > group5 "TP53 mutated/Non Homologous End-Joining positive"; p = 0.0002). Actionable targets were also different among subsets. Group3 had significantly higher infiltration of PD-1+ immune cells (p = 0.003), segregating with group1. Group2 had frequent PI3K pathway mutations and ER positivity. While group5, with the worst prognosis, had high DNA damage and PARP-1 expression providing a rationale for PARP inhibition. Our findings have refined the TransPORTEC prognostic classification of high-risk endometrial cancer into five distinct subgroups by integrating DNA damage response biomarkers and identified molecular subtype-specific therapeutic strategies.

KW - REPAIR DEFECTS

KW - RADIOTHERAPY

KW - SENSITIVITY

KW - GAMMA-H2AX

KW - DEFICIENCY

KW - BRCA1

KW - 53BP1

U2 - 10.1038/s41379-018-0055-1

DO - 10.1038/s41379-018-0055-1

M3 - Article

VL - 31

SP - 1851

EP - 1861

JO - Modern Pathology

JF - Modern Pathology

SN - 0893-3952

IS - 12

ER -

ID: 62945926