Comparing mutation frequencies for homologous recombination genes in uterine serous and high-grade serous ovarian carcinomas: A case for homologous recombination deficiency testing in uterine serous carcinoma.

To compare the frequencies of somatic homologous recombination (HR) gene mutations identified in next-generation sequencing (NGS) genomic profiling of uterine serous carcinomas (USCs) and high-grade serous ovarian carcinomas (HGSOCs). Data for this analysis was obtained from AACR Project GENIE, a multi-institutional dataset of clinical-grade NGS genomic profiling results for many cancer sites and histologic subtypes, through cBioPortal. Patient/specimen groups used for analysis were USC and HGSOC. 14 HR genes were queried for each group with respect to mutation frequency. For each HR gene, the difference in mutation frequency between the two groups was evaluated using Fisher's exact test. The threshold for statistical significance was p-value < .05. In the USC group, there were 457 samples from 451 patients. In the HGSOC group, there were 1537 samples from 1515 patients. The most frequently mutated HR gene for USC was BRCA2 (4.84%) and for HGSOC was BRCA1 (9.07%). Mutation frequency was significantly different between USC and HGSOC for BRCA 1 (p < .001) and BRCA2 (p = .0379). For the 12 non-BRCA HR genes, mutation frequency was not significantly different between USC and HGSOC. The rate of patients with at least one HR gene mutation in their profiled tumor was 16.85% for USC and 25.21% of HGSOC. Most USC patients with a somatic HR mutation had only one HR gene mutated. Somatic HR gene mutations were commonly identified in NGS genomic profiling of USC. Mutation frequencies for non-BRCA HR genes were not significantly different between USC and HGSOC. These data add to the growing rationale for HR deficiency tumor testing and targeting (e.g., with PARP inhibitors) in future clinical trial development for women with USC.

Wallbillich JJ ，Morris RT ，Ali-Fehmi R 《-》

Germline mutations of the DNA repair pathways in uterine serous carcinoma.

Treatment options are limited for patients with uterine serous carcinoma (USC). Knowledge of USC's somatic mutation landscape is rapidly increasing, but its role in hereditary cancers remains unclear. We aim to evaluate the frequency and characteristics of germline mutations in genes commonly implicated in carcinogenesis, including those within homologous recombination (HR) and mismatch repair (MMR) pathways in patients with pure USC. By using targeted capture exome sequencing, 43 genes were analyzed in a cohort of 7 consecutive patients with paired tumor and non-tumor USC samples in our institutional tumor repository. Mutations predicted to have damaging effects on protein function are validated by Sanger Sequencing. We found 21 germline mutations in 11 genes in our USC cohort. Five patients harbored 7 germline mutations (33.3%) within genes involved in the HR pathway, RAD51D being the most common. Four patients had 9 (42.8%) germline mutations in hereditary colon cancer genes, most commonly MLH. All patients (42.7%) who are platinum-sensitive had HR germline mutations (RAD50, NBN, ATM). Patients with HER2 overexpression (2/7, 28.6%) had germline HR mutations and were platinum-sensitive. Three patients in our cohort reported a personal history of breast cancer, one with HR germline mutation, and 2 in patients with germline mutations in HCC genes. In addition, 5 out of 7 patients had germline mutations in genes associated with growth factor signaling pathway. A significant proportion of our cohort harbor germline mutations in DNA repair genes. This may be associated with the high rate of breast cancer in our patients and their family, and suggests a targeted cohort for genetic counseling. If validated in a larger cohort, our findings may allow clinicians to expand therapeutic options to include targeted therapies and inclusion of USC patient in preventative and genetic counseling.

Frimer M ，Levano KS ，Rodriguez-Gabin A ，Wang Y ，Goldberg GL ，Horwitz SB ，Hou JY ... -  《-》

Ovarian high-grade serous carcinoma with transitional-like (SET) morphology: a homologous recombination-deficient tumor.

Thirteen years ago, we pointed out that ovarian transitional cell carcinomas (TCCs) and conventional high-grade serous carcinomas (HGSCs) had similar genetic alterations and clinical behavior. Consequently, ovarian TCC is now classified as a morphologic variant of HGSC. Defective homologous recombination, resulting from genetic or epigenetic inactivation of DNA damage repair genes, such as BRCA1/2, occurs in approximately 50% of the HGSCs. Although BRCA mutations have been associated with HGSCs with solid, pseudoendometrioid or transitional (SET) features, little is known about the role of non-BRCA homologous recombinationrepair (HRR) genes and the HRR status in these tumors. Using two commercially available assays (Myriad Genetics MyChoice CDx Plus test and SOPHiA Dx Homologous Recombination Deficiency Solution), we study mutations of BRCA1/2 and non-BRCA HRR genes (ATM, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), and the HRR status in 19 HGSCs with SET features and 20 HGSCs with classic morphology. We also studied, as control cases, 5 endometrioid carcinomas, 1 clear cell carcinoma, 2 low-grade serous carcinomas, and 1 malignant Brenner tumor. Seven HGSCs with SET features (7/19; 37%) showed BRCA mutations (4 BRCA1, 2 BRCA2, and 1 BRCA1/2). Mutations in non-BRCA HRR genes were found in ATM (1/15; 7%), BARD1 (1/15; 7%), and BRIP1 (1/19; 5%). Most HGSCs with SET features (17/19; 90%) were considered to be homologous recombination-deficient tumors. Three HGSCs with classic morphology (3/20; 15%) showed BRCA2 mutations. Mutations in non-BRCA HRR genes were found in CDK12 (2/14; 14%), FANCL (1/14; 7%), RAD51B (1/14; 7%), and RAD54L (1/14; 7%). Eleven HGSCs with classical morphology (11/20; 55%) were considered to be homologous recombination deficient. In contrast, all ovarian carcinoma control cases (5 endometrioid carcinomas, 1 clear cell carcinoma, 2 low-grade serous carcinomas, and 1 malignant Brenner tumor) were homologous recombination proficient and did not have BRCA mutations. Our results show that the majority of HGSCs with SET features are homologous recombination-deficient tumors independently of the BRCA status and highlight the importance of the HRR tumor testing, especially in BRCA wild-type tumors. Recognition of transitional cell variant of HGSCs may help to identify patients most likely to benefit from PARP inhibitors.

D'Angelo E ，Espinosa I ，Felicioni L ，Buttitta F ，Prat J ... -  《-》

Molecular characterization of high-grade serous ovarian cancers occurring in younger and older women.

To determine if the mutational landscapes and genomic features of homologous recombination DNA repair defects (HRD) vary between younger and older patients with high-grade serous ovarian cancer (HGSOC). Younger and older women were defined as bottom and top age quartiles, respectively. HGSOCs from 15 younger (median 49 years, range 35-53) and 15 older women (median 72 years, range 70-87) were subjected to whole-exome sequencing (WES). For validation, HGSOC WES data were obtained from The Cancer Genome Atlas (TCGA), including 38 younger (median 45 years, range 34-50) and 30 older women (median 74 years, range 68-84). Mutational profiles, BRCA1/2 status, genomic HRD features, and for TCGA cases RNA-sequencing-based HRD transcriptomic signatures were assessed. In the institutional cohort, pathogenic germline BRCA1/2 mutations were more frequent in younger (5/15) than older women (0/15, p = 0.042). No somatic BRCA1/2 mutations were identified. HGSOCs from older patients preferentially displayed aging-related mutational signatures and, in contrast to younger patients, harbored CCNE1 amplifications (3/15, 20%). In the TCGA cohort, pathogenic germline BRCA1 (younger 8/38, older 0/30, p = 0.007) but not BRCA2 mutations (young 3/38, older 4/30, p = 0.691) were more frequent in younger patients. Again, no somatic BRCA1/2 mutations were identified. HGSOCs from younger women more frequently displayed genomic features of HRD (all, p < 0.05), a significant HRD gene-signature enrichment, but less frequently CCNE1 amplification (p = 0.05). Immunoreactive CLOVAR subtypes were more common in HGSOCs from younger women, and proliferative subtypes in HGSOCs from older women (p = 0.041). HGSOC patients diagnosed at an older age less frequently harbor pathogenic BRCA1 germline mutations and genomic features of HRD than younger women. Individualized treatment options, particularly pertaining to use of PARP inhibitors, in older women may be warranted.

Filippova OT ，Selenica P ，Pareja F ，Vahdatinia M ，Zhu Y ，Pei X ，Riaz N ，Long Roche K ，Chi DS ，Abu-Rustum NR ，Ellenson LH ，Reis-Filho JS ，Zamarin D ，Weigelt B ... -  《-》

[Clinical significance and distribution of BRCA genes mutation in sporadic high grade serous ovarian cancer].

Liu WL ，Wang ZZ ，Zhao JZ ，Hou YY ，Wu XX ，Li W ，Dong B ，Tong TT ，Guo YJ ... -  《-》