@article{50549dd6af194b0685184a072d6148ef,
title = "Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity",
abstract = "Purpose: Whether endometrial carcinoma (EC) should be considered part of the gBRCA1/2-associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether ECs occurring in gBRCA carriers are enriched for clinicopathologic and molecular characteristics, thereby supporting a causal relationship.Experimental Design: Thirty-eight gBRCA carriers that developed EC were selected from the nationwide cohort study on hereditary breast and ovarian cancer in the Netherlands (HEBON), and these were supplemented with four institutional cases. Tumor tissue was retrieved via PALGA (Dutch Pathology Registry). Nineteen morphologic features were scored and histotype was determined by three expert gyneco-logic pathologists, blinded for molecular analyses (UCM-OncoPlus Assay including 1213 genes). ECs with LOH of the gBRCA-wild-type allele (gBRCA/LOHpos) were defined {"}gBRCA-associated,{"} those without LOH (gBRCA/LOHneg) were defined {"}sporadic.{"}Results: LOH could be assessed for 40 ECs (30 gBRCA1, 10 gBRCA2), of which 60% were gBRCA/LOHpos. gBRCA/LOHpos ECs were more frequently of nonendometrioid (58%, P = 0.001) and grade 3 histology (79%, P <0.001). All but two were in the TP53-mutated TCGA-subgroup (91.7%, P <0.001). In contrast, gBRCA/LOHneg ECs were mainly grade 1 endometrioid EC (94%) and showed a more heterogeneous distribution of TCGA-molecular subgroups: POLE-mutated (6.3%), MSI-high (25%), NSMP (62.5%), and TP53-mutated (6.3%).Conclusions: We provide novel evidence in favor of EC being part of the gBRCA-associated HBOC-syndrome. gBRCA-associated ECs are enriched for EC subtypes associated with unfavorable clinical outcome. These findings have profound therapeutic consequences as these patients may benefit from treatment strategies such as PARP inhibitors. In addition, it should influence counseling and surveillance of gBRCA carriers.",
keywords = "UTERINE SEROUS CARCINOMA, BREAST-CANCER, MAINTENANCE THERAPY, TAMOXIFEN TREATMENT, CLEAR-CELL, OVARIAN, RISK, WOMEN, MUTATIONS, PROGNOSIS",
author = "{de Jonge}, {Marthe M.} and Ritterhouse, {Lauren L.} and {de Kroon}, {Cornelis D.} and Vreeswijk, {Maaike P. G.} and Segal, {Jeremy P.} and Rutika Puranik and Rookus, {M. A.} and Hogervorst, {F. B. L.} and {van Leeuwen}, {F. E.} and Adank, {M. A.} and Schmidt, {M. K.} and Jenner, {D. J.} and Collee, {J. M.} and {van den Ouweland}, {A. M. W.} and Hooning, {M. J.} and Boere, {I. A.} and {van Asperen}, {C. J.} and P. Devilee and {van der Luijt}, {R. B.} and {van Cronenburg}, {T. C. T. E. F.} and Wevers, {M. R.} and Mensenkamp, {A. R.} and Ausems, {M. G. E. M.} and Koudijs, {M. J.} and Meijers-Heijboer, {H. E. J.} and {van Os}, {T. A. M.} and {van Engelen}, K. and Gille, {J. J. P.} and Gomez-Garcia, {E. B.} and Blok, {M. J.} and {de Boer}, M. and Oosterwijk, {J. C.} and {van der Hout}, {A. H.} and Mourits, {M. J.} and {de Bock}, {G. H.} and S. Siesling and J. Verloop and {van den Broek}, {E. C.} and Harry Hollema and Smit, {Vincent T. H. B. M.} and Howitt, {Brooke E.} and Tjalling Bosse and {HEBON Group}",
note = "Funding Information: The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating center), Amsterdam, the Netherlands: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, M.K. Schmidt, and D.J. Jenner; Erasmus Medical Center, Rotterdam, the Netherlands: J.M. Collee, A.M.W. van den Ouweland, M.J. Hooning, and I.A. Boere; Leiden University Medical Center, Leiden, the Netherlands: C.J. van Asperen, P. Devilee, R.B. van der Luijt, and T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands: M.R. Wevers and A.R. Mensenkamp; University Medical Center Utrecht, Utrecht, the Netherlands: M.G.E.M. Ausems and M.J. Koudijs; Amsterdam Medical Center, Amsterdam, the Netherlands: H.E.J. Meijers-Heijboer and T.A.M. van Os; VU University Medical Center, Amsterdam, the Netherlands: K. van Engelen and J.J.P. Gille; Maastricht University Medical Center, Maastricht, the Netherlands: E.B. Gomez-Garcia, M.J. Blok, and M. de Boer; University of Groningen, Groningen, the Netherlands: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, and G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, the Netherlands: S. Siesling and J.Verloop; and the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA): E.C. van den Broek. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection. The authors thank E.J. Dreef and N.T. ter Haar (LUMC) for their technical assistance, Sabah Kadri and Sushant Patil (UC) for their bioinformatics assistance, and Wilbert Zwart (NKI). They thank all pathology departments from the hospitals that have send pathology material for study purposes, including the NKI-AVL Biobank. M.M. de Jonge thanks the {"}Leids Universiteits Fonds/Fonds Van Trigt{"} and the {"}Rene Vogels Foundation{"} for their financial support in the form of an International Travel Grant. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, and NKI2007-3756, the Netherlands Organisation for Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12-054. This work was supported by internal departmental funds [Stanford University School of Medicine (to B.E. Howitt) and Leiden University Medical Center (to T. Bosse)]. M.M. de Jonge received an International Travel Grant from the {"}Leids Universiteits Fonds/Fonds Van Trigt{"} and the {"}Rene Vogels Foundation.{"} Publisher Copyright: {\textcopyright}2019 American Association for Cancer Research.",
year = "2019",
month = dec,
day = "15",
doi = "10.1158/1078-0432.ccr-19-0848",
language = "English",
volume = "25",
pages = "7517--7526",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "24",
}