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Pathways underlying pancreatic tumorigenesis and an hereditary pancreatic cancer gene

A pancreatic cancer, gene technology, applied in the field of pancreatic cancer

Inactive Publication Date: 2011-09-28
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Identifies that the individual is at higher risk of developing pancreatic cancer when the mutation is present and at average risk when the mutation is absent

Method used

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  • Pathways underlying pancreatic tumorigenesis and an hereditary pancreatic cancer gene
  • Pathways underlying pancreatic tumorigenesis and an hereditary pancreatic cancer gene
  • Pathways underlying pancreatic tumorigenesis and an hereditary pancreatic cancer gene

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Embodiment 1

[0045] Sample selection. As with all cancer genomics studies, sample selection is critical. For the present study, we selected 24 advanced adenocarcinomas, each from a different and unrelated patient (Table S1). Advanced pancreatic cancers were chosen because they are expected to contain all of the genetic alterations that lead to tumor initiation and progression, whereas early cancers may contain only a subset. 24 cancers were passaged in vitro as cell lines or xenografts in nude mice to facilitate detection of mutations. Studies have shown that this passaging method provides a better DNA template for Sanger sequencing or copy number analysis than the primary tumor because it removes contaminating non-cancerous cells originally present in the tumor (12). Studies have also shown that clonal mutations in cell lines and xenografts are rare, if any, during ex vivo culture (12-14).

Embodiment 2

[0047] Sequencing protocol. Exon sequences encoding proteins found in Conserved Coding Sequences (Release No. 1), Reference Sequences (Release No. 16) and Ensembl Database (Release No. 31) were extracted and used to design primers for genomic DNA amplification (Fig. .S1). The same primers were used if primers designed in our past breast and colorectal cancer studies proved successful (75, 16). New primer sets were designed for 11,579 exons that had not been previously studied and for those exons for which primers had previously been designed but proved suboptimal (see below) (17). Each of the resulting exons was sequenced in 24 pancreatic cancers using dye-terminated sequencing and the 416,622 primers listed in Table S2. Exons containing variant sequences were reamplified from tumor DNA and resequenced to confirm the observed alterations. Additional testing was performed on DNA from normal tissue from patients with mutations in each case. This method determines whether the...

Embodiment 3

[0050] Somatic mutation. Among the 1562 somatic mutations, 25.5% were synonymous (synonymous), 62.4% were missense (missense), 3.8% were nonsense (nonsense), 5.0% were small insertions and deletions, and 3.3% were in Splice sites (splice sites) or in the untranslated region (UTR) (Table 1). Somatic mutation profiles can provide insights into potential carcinogens and other environmental exposures. Table 1 presents the mutational spectrum observed after a large-scale sequencing analysis of most of the protein-coding genes in the four tumors. Clearly, breast cancer has a unique somatic mutation spectrum, with 5′-TpC mutations predominating and 5′-CpG mutations relatively rare. However, the mutational profiles of colorectal, brain (18) and pancreatic tumors are similar, suggesting that mammary epithelial cells are exposed to different levels or classes of carcinogens compared with cells that develop into other tumors (19, 20) , or use a different repair system. Given that gas...

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Abstract

There are currently few therapeutic options for patients with pancreatic cancers and new insights into the pathogenesis of this lethal disease are urgently needed. To this end, we performed a comprehensive analysis of the genes altered in 24 pancreatic tumors. First, we determined the sequences of 23,781 transcripts, representing 20,583 protein-encoding genes, in DNA from these tumors. Second, we searched for homozygous deletions and amplifications using microarrays querying ~one million single nucleotide polymorphisms in each sample. Third, we analyzed the transcriptomes of the same samples using SAGE and next-generation sequencing-by-synthesis technologies. We found that pancreatic cancers contain an average of 63 genetic alterations, of which 49 are point mutations, 8 are homozygous deletions, and 6 are amplifications.; Further analyses revealed a core set of 12 regulatory processes or pathways that were each genetically altered in 70 % to 100 % of the samples. The data suggest that dysregulation of this core set of pathways is responsible for the major features of pancreatic tumorigenesis.

Description

[0001] This invention was made with US Government funding. Certain rights in this invention are reserved by the US Government under NIH grant terms CA43460, CA57345, CA62924, RO1CA97075, and CA121113. technical field [0002] The present invention relates to the field of pancreatic cancer. In particular, the invention relates to the diagnosis, treatment, identification, monitoring, detection and stratification of pancreatic cancer. Background of the invention [0003] In 2008, pancreatic cancer will affect 213,000 patients worldwide and nearly all of them will die from the disease (1). Part of the reason the death rate is so high is that the disease is usually not detected until it spreads locally or metastasizes to the liver, peritoneum or other organs. The tumor strikes men and women relatively evenly, and even when treated with aggressive therapies in the Western world, the overall survival rate is less than 5% (2, 3). Despite modest associations with smoking, long-sta...

Claims

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Application Information

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IPC IPC(8): C12Q1/68
CPCC12Q2600/156G01N2800/50C12Q1/6886G01N33/57438
Inventor B·沃格斯坦K·W·金兹勒D·W·帕森斯S·琼斯张晓松J·C·林R·J·利里P·安格嫩特N·帕帕多普洛斯V·韦尔库列斯库G·帕玛强尼R·卡新S·克恩R·赫鲁班J·R·埃什尔曼M·戈金斯A·克莱因
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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