Genome profiling of pancreatic adenocarcinoma

Abstract

Pancreatic adenocarcinoma is one of the most aggressive human cancers. It displays many different chromosomal abnormalities and mutations. By using 244 K high-resolution array-comparative genomic hybridization (aCGH) we studied the genome alterations of 39 fine-needle aspirations from pancreatic adenocarcinoma and eight human adenocarcinoma pancreatic cell lines. Using both visual inspection and GISTIC analysis, recurrent losses were observed on 1p, 3p, 4p, 6, 8p, 9, 10, 11q, 15q, 17, 18, 19p, 20p, 21, and 22 and comprised several known or suspected tumor suppressor genes such as ARHGEF10, ARID1A, CDKN2A/B, FHIT, PTEN, RB1, RUNX1-3, SMAD4, STK11/LKB1, TP53, and TUSC3. Heterozygous deletion of the 1p35-p36 chromosomal region was identified in one-third of the tumors and three of the cell lines. This region, commonly deleted in human cancers, contains several tumor suppressor genes including ARID1A and RUNX3. We identified frequent genetic gains on chromosome arms 1q, 3q, 5p, 6p, 7q, 8q, 12q, 15q, 18q, 19q, and 20q. Amplifications were observed in 16 tumors. AKT2, CCND3, CDK4, FOXA2, GATA6, MDM2, MYC, and SMURF1 genes were gained or amplified. The most obvious amplification was located at 18q11.2 and targeted the GATA6 gene, which plays a predominant role in the initial specification of the pancreas and in pancreatic cell type differentiation. In conclusion, we have identified novel biomarkers and potential therapeutic targets in pancreatic adenocarcinoma.

Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

“…Mutations in this tumor suppressor gene have not been identified in pancreatic cancer, although the chromosomal region in which it lies on 10q23 does undergo loss of heterozygosity (48)(49)(50). Inactivation of Pten in the mouse, recently shown to cooperate with oncogenic Kras to drive pancreatic adenocarcinoma (51), may be the easiest way to deregulate Akt signaling in the mouse.…”

The emerging role of the TGFβ tumor suppressor pathway in pancreatic cancer

“…As in several other types of cancer, breaks and deletions in common fragile sites (FRA) such as FHIT/ FRA3B, MACROD2 and PARK2/FRA6E are observed. 3,5 Frequent mutations of the chromatin remodeling gene ARID1A have been found in gynecologic cancers.…”

Ubiquitination of Tumor Necrosis Factor Receptor-associated Factor 4 (TRAF4) by Smad Ubiquitination Regulatory Factor 1 (Smurf1) Regulates Motility of Breast Epithelial and Cancer Cells

“…In addition to their essential roles during development and normal physiological functions, several reports indicate that Smurf1 and Smurf2 expression are dysregulated in cancer cells (21)(22)(23)(24). Elevated Smurf expression in breast cancer tissues was shown exclusively in the cytoplasm (22), whereas siRNA knockdown of Smurf1 or Smurf2 led to cell rounding and retardation of cell migration (22,25).…”