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Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity

HEBON Grp, de Jonge, M. M., Ritterhouse, L. L., de Kroon, C. D., Vreeswijk, M. P. G., Segal, J. P. & Puranik, R., 15-Dec-2019, In : Clinical Cancer Research. 25, 24, p. 7517-7526 10 p.

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  • Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity

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DOI

  • HEBON Grp
  • Marthe M. de Jonge
  • Lauren L. Ritterhouse
  • Cornelis D. de Kroon
  • Maaike P. G. Vreeswijk
  • Jeremy P. Segal
  • Rutika Puranik

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
Volume25
Issue number24
Publication statusPublished - 15-Dec-2019

    Keywords

  • UTERINE SEROUS CARCINOMA, BREAST-CANCER, MAINTENANCE THERAPY, TAMOXIFEN TREATMENT, CLEAR-CELL, OVARIAN, RISK, WOMEN, MUTATIONS, PROGNOSIS

ID: 118746559