We used integrated molecular characterization of oviductal HGSCs arising in the context of Brca1, Trp53, Rb1, and Nf1 (BPRN) inactivation to determine whether the mouse tumors recapitulate human HGSCs across multiple domains of molecular features.
We used integrated molecular characterization of oviductal HGSCs arising in the context of Brca1, Trp53, Rb1, and Nf1 (BPRN) inactivation to determine whether the mouse tumors recapitulate human HGSCs across multiple domains of molecular features.
Carriers of BRCA1 and BRCA2 mutations are at increased risk of high grade serous carcinoma and are therefore offered risk-reducing salpingo-oophorectomy (RRSO) by 40-45 years.
In one of the four women with co-existing ovarian HGSC and tubal precursor lesion we found non-identical TP53 mutations and a lack of common mutations shared between her precursor lesion and carcinoma.
Intraepithelial fallopian tube neoplasia is thought to be a precursor lesion to high-grade serous carcinoma of the Müllerian adnexae, particularly in women with BRCA1 or BRCA2 mutations.
Recent work predominantly carried out in tubo-ovarian high-grade serous carcinoma has revealed 4 main patterns of p53 staining (normal/wild-type, complete absence, overexpression, and cytoplasmic); the latter 3 patterns are variably termed abnormal/aberrant/mutation-type and are strongly predictive of an underlying TP53 mutation.
We conducted a retrospective study on the prevalence of high grade serous carcinoma and STIC in BRCA1/2 carriers presenting for RRSO, and their follow-up.
Novel TP53 in-frame deletion mutations c.719_727delGTTCCTGCA (p53 p.Ser240_Cys242del) and c.634_642delTTTCGACAT (p53 p.F212_H214del) were detected in a single case of HGSC each.
Targeted next-generation sequencing confirmed the presence of TP53 mutations in fimbrial brushings from HGSC, but not in benign samples, and demonstrated concordance with the immunostaining pattern.
Sequencing was successful in 3 of the 4 cases, and an identical Tp53 mutation was detected in the HGSC and bilateral STINs in 2 of these 3 cases.One STIN was morphologically a STIL.
The goal of the study is to report the frequency of subsequent BC and high-grade serous carcinoma (HGSC) following RRSO in BRCA1 and BRCA2 mutation carriers and in patients with personal history of BC with or without BRCA mutation.
Understanding of the genomics of HGSC has led to the routine introduction of germline and somatic BRCA1/2 testing, as well as testing of mutations in other homologous recombination genes, widening the range of patients who may benefit from PARP inhibitors.
The goal of the study is to report the frequency of subsequent BC and high-grade serous carcinoma (HGSC) following RRSO in BRCA1 and BRCA2 mutation carriers and in patients with personal history of BC with or without BRCA mutation.
Because the putative precursors of the other p53 immunophenotypical HGSC are not proposed, we presume γ-H2AX-expressing cells without p53 overexpression may be a potent candidate of null-type TP53-mutated tubal cells, which are named "γ-H2AX responsive foci."
Here we have used one ID8 Trp53 <sup>-/-</sup> clone to generate further mutants, with additional mutations in Brca1, Pten and Nf1, all of which are frequently mutated or deleted in HGSC.
High expression levels of HER2 and PD-L1 were more commonly observed in CCC patients (12.6% vs 2.7%, 21.1% vs 11.6%, P = 0.006, 0.064, respectively), while loss of BRCA1 and BRCA2 expression were more frequently occurred in HGSC patients (72.6% vs 54.3%, 89.4% vs 79.8%, P = 0.007, 0.054, respectively).
We employed Ovgp1-iCreER<sup>T2</sup> mice to show that FTE-specific inactivation of several different combinations of tumour suppressor genes that are recurrently mutated in human HGSCs - namely Brca1, Trp53, Rb1, and Nf1 - results in serous tubal intraepithelial carcinomas (STICs) that progress to HGSC or carcinosarcoma, and to widespread metastatic disease in a subset of mice.