American Association for Cancer Research
10780432ccr190848-sup-218900_3_supp_5672050_pv8tzg.pdf (165.11 kB)

Supplementary Fig. S5 from Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity

Download (165.11 kB)
journal contribution
posted on 2023-03-31, 21:06 authored by Marthe M. de Jonge, Lauren L. Ritterhouse, Cornelis D. de Kroon, Maaike P.G. Vreeswijk, Jeremy P. Segal, Rutika Puranik, Harry Hollema, Matti A. Rookus, Christi J. van Asperen, Flora E. van Leeuwen, Vincent T.H.B.M. Smit, Brooke E. Howitt, Tjalling Bosse

Class 4/5 mutations and Tumor Mutational Burden stratified by loss of heterozygosity status.


Dutch Cancer Society

Netherlands Organisation for Scientific Research

Pink Ribbon






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. 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 gynecologic 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.” 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%). 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.