Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer

Abstract

Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk

Updates and Critical Evaluation on Novel Biomarkers for the Malignant Progression of Intraductal Papillary Mucinous Neoplasms of the Pancreas

“…It is located on chromosome arm 19p (51). STK11 mutation is associated with IPMN and pancreatic ductal adenocarcinoma (52).…”

Systems-guided forward genetic screen reveals a critical role of the replication stress response protein ETAA1 in T cell clonal expansion

“…For anti-CD3/CD28 stimulation, CTV-labeled CD45.1 + Etaa1 +/+ and CD45.2 + Etaa1 ΔEx2/ΔEx2 splenocytes were mixed in a 50:50 ratio, and 5 × 10 5 cells/well were stimulated in 0.1-10 μg/mL soluble anti-CD3 (clone 500A2; BD Biosciences) with or without 2 μg/mL anti-CD28 (clone 37.15; BD Biosciences) in a flat-bottom 96-well plate. For in vitro P14 stimulation, 2 × 10 6 P14 total splenocytes per well were cultured in a flat-bottom 24-well plate with 10 ng/mL LCMV GP [33][34][35][36][37][38][39][40][41] peptide (Biomolecular Resource Facility of the John Curtin School of Medical Research, Australian National University) and 10 ng/mL recombinant human IL-2 (Peprotech). Daily cell counts were normalized via expression as fold change over the starting number of CD8 + Vα2 + P14 cells.…”

“…Flow cytometry staining with tetramers enabled enumeration of CD8 + T cells specific for two immunodominant epitopes of the virus, GP [33][34][35][36][37][38][39][40][41] and NP [396][397][398][399][400][401][402][403][404] , and CD4 + T cells specific for the immunodominant GP 66-77 virus epitope. Compared with wild-type controls, there were 10-fold fewer antigen-specific CD8 + and CD4 + T cells in LCMV-infected homozygotes for either the exon 2 deleted or the C166X null allele, although there was still a detectable effector T-cell response in both strains (Fig.…”

“…To track CD8 + T cells bearing a defined T-cell receptor (TCR) for virus antigen, we crossed the Etaa1 ΔEx2 allele to congenically marked (CD45.1 + ) P14 TCR transgenic C57BL/6 mice, which express a TCR specific for LCMV GP [33][34][35][36][37][38][39][40][41] antigen. Naïve CD8 + T cells expressing the P14 TCR developed and accumulated normally despite ETAA1 deficiency.…”

“…6C). To test in vitro proliferative capacity following antigen-specific stimulation, we stimulated Etaa1 +/+ or Etaa1-ΔEx2/ΔEx2 P14 CD8 + T cells with GP [33][34][35][36][37][38][39][40][41] peptide and IL-2 in vitro and analyzed them daily for 5 d. ETAA1-deficient P14 cells acquired the Ki67 cell cycle marker and increased in number comparably to their wild-type counterparts, and also exhibited a comparable percentage of viable cells at each time point (Fig. 6D), demonstrating that ETAA1 is dispensable for clonal expansion in vitro.…”