Anti-ERCC2 monoclonal antibody, clone FQS0785

Background: Perioperative treatment is standard of care in Western Europe for locally advanced gastroesophageal cancer (GEC) [gastric and gastroesophageal junction (GEJ) adenocarcinoma]. Predictive markers for toxicity and efficacy prior to start with chemotherapy are desirable, particularly when applying a prolonged neoadjuvant treatment. Here we analyse the impact of previously published SNPs involved in drug metabolism and DNA repair. Methods: Genomic DNA was isolated from 48 tumor samples of patients treated within the NeoFLOT-study. In this trial, FLOT (5-FU, leucovorin, oxaliplatin, docetaxel) was administered every two weeks for 6 cycles chemotherapy prior to surgery. Direct DNA sequencing was carried out for rs25487 [Excision Repair Cross-Complementation Group 1 (XRCC1], rs1805087 [5-methyltetrahydrofolate-homocysteine methyltransferase (MTR)], rs11615 and rs3212986 (both ERCC1), rs1799793 and rs13181 (both ERCC2), rs 1801019 [Orotate Phosphoribosyl Transferase (OPRT] and rs 16430del [thymidylate synthase: 6-bp-deletion in the in the 3' untranslated regulatory region (TS3utrdel)]. Furthermore, thymidylate synthase: 28-bp-tandem repeats in the 5' untranslated region (TS5utr tandem repeat) polymorphism was analysed by Restriction Fragment Length Polymorphism (RFLA). Toxicity was stated according to NCI-CTC version 4.0. For efficacy analysis overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and recurrence-free survival (RFS) were used. Results: ERCC2 rs1799793 was significantly associated with thrombocytopenia >= grade 3 (P=0.04) and overall hematotoxicity >= grade 3 (P=0.04) while rs13181 was significantly associated with leukopenia >= grade 3 (P=0.03). Rs11615 of ERCC1 had a predictive value for leukopenia (P=0.04) and thrombocytopenia (P=0.008). Rs1805087 of MTR and TS5utr tandem repeat polymorphism were both associated with anemia (P=0.04 and 0.04, respectively). Concerning non-hematological toxicity, rs1805087 of MTR was associated with diarrhea (P=0.004). Regarding treatment efficacy, patients harbouring the minor allele of C of OPRT rs1801019 obtained a higher ORR and showed a better but statically non-significant prolonged PFS and OS while rs3212986 of ERCC1 was associated with pCR rate (P=0.006). Conclusions: For single nucleotide polymorphism (SNPs) of ERCC1/2, MTR and TS tandem repeat we could demonstrate the predictive value for toxicity of FLOT in GEC. Furthermore, OPRT rs1801019 might be useful to predict response for neoadjuvant treatment.

Patent ductus arteriosus (PDA) is a common congenital cardiovascular malformation with both inherited and acquired causes. Several genes have been reported to be related to PDA, but the molecular pathogenesis is still unclear. Here, we screened a population matched cohort of 39 patients with PDA and 100 healthy children using whole exome sequencing (WES). And identified 10 copy number variants (CNVs) and 20 candidate genes using Gene ontology (GO) functional enrichment analysis. In gene network analysis, we screened 7 pathogenic CNVs of 10 candidate genes (MAP3K1, MYC, VAV2, WDR5, RXRA, APLNR, TJP1, ERCC2, FOSB, CHRNA4). Further analysis of transcriptome array showed that 7 candidate genes (MAP3K1, MYC, VAV2, APLNR, TJP1, FOSB, CHRNA4) were indeed significantly expressed in human embryonic heart. Moreover, CHRNA4 was observed the most important genes. Our data provided rare CNVs as potential genetic cause of PDA in humans and also advance understanding of the genetic components of PDA.