BRCA1 (Phospho-Ser1524) ELISA Kit

Pathogenic variants (PVs) in theBRCA1andBRCA2genes are associated with an increased lifetime risk of pancreatic ductal adenocarcinoma (PDAC), and more recently have been associated with increased risk of biliary tract cancers (BTC). This study assessed the prevalence, age and gender distribution of PDAC/BTC cases in families known to carry aBRCA1/2PV compared to those of the Irish population. A review of all families referred to a national genetics clinic from 09/11/1997 to 01/06/2018 was performed. The BOADICEA algorithm was used to estimate the probability that an untested relative of a knownBRCA1/2PV carrier with PDAC was a carrier. We reviewed 3252 family pedigrees, 1193 contained a proband who underwent testing forBRCA1/2based on Manchester score >= 15. Among 128BRCA2PV-positive families, 27 (21%) contained a 1st/2nd/3rd-degree relative with PDAC, while of 116BRCA1PV-positive families, 11 (9%) contained a 1st/2nd/3rd-degree relative with PDAC. Within these 38 families, 25 patients with PDAC had >= 50% likelihood of being aBRCA1/2PV carrier. This cohort had a median age at diagnosis of 55 years (range 33-75), with a mean (55 years) lower than 8364 patients with PDAC identified through the National Cancer Registry of Ireland (71 years, p < 0.0001). SixBRCA2positive (5%) and 2BRCA1positive pedigrees (2%) included an individual with BTC; median age at diagnosis was 65 years (range 33-99). PDAC and BTC are prevalent in Irish families harbouring aBRCA2PV and are associated with early-onset malignancy. This supports current guidelines recommending universal germline testing for PDAC patients.

Objective:Mutations in TP53 lead to loss of function (LOF) or gain of function (GOF) of the corresponding protein p53 and produce a different effect on the tumor. Our goal was to determine the spectrum of somaticTP53variants inBRCA1/2associated high-grade serous ovarian cancer (HGSOC). Methods:The population under study comprised of HGSOCs with pathogenic variants inBRCA1(n= 78) orBRCA2(n= 21). Only chemo-naive and platinum-sensitive patients were included in this study. The case group of the IARC database (n= 1249) with HGSOC not stratified by BRCA status was used as a reference. A custom NGS panel was used for sequencingTP53and mutational hot-spots of other genes, and p53 expression was evaluated by immunohistochemistry for 68 cases of HGSOCs. Results:SomaticTP53variants (95) or inhibition of wild-type p53 expression (3) were observed in 98 cases. The sample with normal p53 hadCDKNA1variants. The frequency of truncating variants was significantly higher than in the reference cohort (30.3 vs. 21.0%,p= 0.01). Most of the samples (41/68) demonstrated low (or absent) expression of p53, and 17 samples overexpressed p53. LOH was typical for TP53 nonsense variants (14/15). In total, 68/95 samples were LOH positive and showed LOH in all tumorous cells, thus indicating the driver effect ofTP53mutations. Three specimens hadKRAS, BAX, APC, andCTNNB1subclones variants. Conclusion:High frequency ofTP53truncating variants, the low expression of mutant p53, and low incidence of oncogene mutations show potential GOF properties of p53 to be poorly represented in BRCA1/2 associated HGSOC.