Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity

Marthe M. de Jonge, Lauren L. Ritterhouse, Cornelis D. de Kroon, Maaike P. G. Vreeswijk, Jeremy P. Segal, Rutika Puranik, M. A. Rookus, F. B. L. Hogervorst, F. E. van Leeuwen, M. A. Adank, M. K. Schmidt, D. J. Jenner, J. M. Collee, A. M. W. van den Ouweland, M. J. Hooning, I. A. Boere, C. J. van Asperen, P. Devilee, R. B. van der Luijt, T. C. T. E. F. van CronenburgM. R. Wevers, A. R. Mensenkamp, M. G. E. M. Ausems, M. J. Koudijs, H. E. J. Meijers-Heijboer, T. A. M. van Os, K. van Engelen, J. J. P. Gille, E. B. Gomez-Garcia, M. J. Blok, M. de Boer, J. C. Oosterwijk, A. H. van der Hout, M. J. Mourits, G. H. de Bock, S. Siesling, J. Verloop, E. C. van den Broek, Harry Hollema, Vincent T. H. B. M. Smit, Brooke E. Howitt, Tjalling Bosse*, HEBON Group

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)7517-7526
Number of pages10
JournalClinical Cancer Research
Issue number24
Publication statusPublished - 15 Dec 2019


  • RISK


Dive into the research topics of 'Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity'. Together they form a unique fingerprint.

Cite this