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Posts Tagged ‘Disease and Conditions’


Reporter: Aviva Lev-Ari, PhD, RN

 

 

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

 

Nature (2012) 

doi:10.1038/nature11547 Received 09 January 2012  Accepted 04 September 2012 

Published online 24 October 2012

 

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRASTP53CDKN2A, SMAD4MLL3TGFBR2, ARID1A andSF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2,MAP2K4NALCNSLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Figures at a glance

Contributions

The research network comprising the Australian Pancreatic Cancer Genome Initiative, the Baylor College of Medicine Cancer Genome Project and the Ontario Institute for Cancer Research Pancreatic Cancer Genome Study (ABO collaboration) contributed collectively to this study as part of the International Cancer Genome Consortium. Biospecimens were collected at affiliated hospitals and processed at each biospecimen core resource centre. Data generation and analyses were performed by the genome sequencing centres, cancer genome characterization centres and genome data analysis centres. Investigator contributions are as follows: S.M.G., A.V.B., J.V.P., R.L.S., R.A.G., D.A.W., M.-C.G., J.D.M., L.D.S and T.J.H. (project leaders); A.V.B., S.M.G. and R.L.S. (writing team); A.L.J., J.V.P., P.J.W., J.L.F., C.L., M.A., O.H., J.G.R., D.T., C.X., S.Wo., F.N., S.So., G.K. and W.K. (bioinformatics/databases); D.K.M., I.H., S.I., C.N., S.M., A.Chr., T.Br., S.Wa., E.N., B.B.G., D.M.M., Y.Q.W., Y.H., L.R.L., H.D., R. E. D., R.S.M. and M.W. (sequencing); N.W., K.S.K., J.V.P., A.-M.P., K.N., N.C., M.G., P.J.W., M.J.C., M.P., J.W., N.K., F.Z., J.D., K.C., C.J.B., L.B.M., D.P., R.E.D., R.D.B., T.Be. and C.K.Y. (mutation, copy number and gene expression analysis); A.L.J., D.K.C., M.D.J., M.P., C.J.S., E.K.C., C.T., A.M.N., E.S.H., V.T.C., L.A.C., E.N., J.S.S., J.L.H., C.T., N.B. and M.Sc. (sample processing and quality control); A.J.G., J.G.K., R.H.H., C.A.I.-D., A.Cho., A.Mai., J.R.E., P.C. and A.S. (pathology assessment); J.W., M.J.C., M.P., C.K.Y. and mutation analysis team (network/pathway analysis and functional data integration); K.M.M., N.A.J., N.G.C., P.A.P.-M., D.J.A., D.A.L., L.F.A.W., A.G.R., D.A.T., R.J.D., I.R., A.V.P., E.A.M., R.L.S., R.H.H. and A.Maw. (functional screens); E.N., A.L.J., J.S.S., A.J.G., J.G.K., N.D.M., A.B., K.E., N.Q.N., N.Z., W.E.F., F.C.B., S.E.H., G.E.A., L.M., L.T., M.Sam., K.B., A.B., D.P., A.P., N.B., R.D.B., R.E.D., C.Y., S.Se., N.O., D.M., M-S.T., P.A.S., G.M.P., S.G., L.D.S., C.A.I.-D., R.D.S., C.L.W., R.A.M., R.T.L., S.B., V.C., M.Sca., C.B., M.A.T., G.T., A.S. and J.R.E. (sample collection and clinical annotation); D.K.C., M.P., C.J.S., E.S.H., J.A.L., R.J.D., A.V.P. and I.R. (preclinical models).

Competing financial interests

The authors declare no competing financial interests.

International Team Reports on Large-Scale Pancreatic Cancer Analysis

October 24, 2012

NEW YORK (GenomeWeb News) – A whole-exome sequencing and copy number variation study of pancreatic cancer published online today in Nature suggests that the disease sometimes involves alterations to genes and pathways best known for their role in axon guidance during embryonic development.

The work was conducted as part of the International Cancer Genome Consortium effort by researchers with the BCM Cancer Genome Project, the Australian Pancreatic Cancer Genome Initiative, and the Ontario Institute for Cancer Research Pancreatic Cancer Genome Study.

As they reported today, the investigators identified thousands of somatic mutations and copy number alterations in pancreatic ductal adenocarcinoma cancer, the most common form of pancreatic cancer. Some of the mutations affected known cancer genes and/or pathways implicated in pancreatic cancer in the past. Other genetic glitches pointed to processes not previously linked to the disease including mutations to axon guidance genes such as SLIT2, ROBO1, and ROBO2.

“This is a category of genes not previously linked to pancreatic cancer,” Baylor College of Medicine researcher William Fisher, a co-author on the new paper, said in a statement. “We are poised to jump on this gene list and do some exciting things.”

Pancreatic cancer is among the deadliest types of cancer, he and his colleagues explained, with a grim five-year survival rate of less than 5 percent. But despite its clinical importance, direct genomic studies of primary tumors had been stymied in the past due to difficulties obtaining large enough samples for such analyses.

“Genomic characterization of pancreatic ductal adenocarcinoma, which accounts for over 90 [percent] of pancreatic cancer, has so far focused on targeted polymerase chain reaction-based exome sequencing of primary and metastatic lesions propagated as xenografts or cell lines,” the study authors noted.

“A deeper understanding of the underlying molecular pathophysiology of the clinical disease is needed to advance the development of effective therapeutic and early detection strategies,” they added.

For the current study, researchers started with a set of tumor-normal samples from 142 individuals with stage I or stage II sporadic pancreatic ductal adenocarcinoma. Following a series of experiments to assess tumor cellularity and other features that can impact tumor analyses, they selected 99 patients whose samples were assessed in detail.

For whole-exome sequencing experiments, the investigators nabbed coding sequences from matched tumor and normal samples using either Agilent SureSelectII or Nimblegen capture kits before sequencing the exomes on SOLiD 4 or Illumina sequencing platforms. They also used Ion Torrent and Roche 454 platforms to validate apparent somatic mutations in the samples.

For its copy number analyses, meanwhile, the team tested the pancreatic cancer and normal tissue samples using Illumina HumanOmni1 Quad genotyping arrays.

When they sifted through data for the 99 most completely characterized pancreatic tumors, researchers uncovered 1,628 CNVs and roughly 2,000 non-silent, somatic coding mutations. More than 1,500 of the non-silent mutations were subsequently verified through additional sequencing experiments.

On average, each of the tumors contained 26 coding mutations. And despite the variability in mutations present from one tumor to the next, researchers identified 16 genes that were mutated in multiple tumor samples.

Some were well-known cancer players such as KRAS, which was mutated in more than 90 percent of the 142 pancreatic tumors considered initially. Several other genes belonged to cell cycle checkpoint, apoptosis, blood vessel formation, and cell signaling pathways, researchers reported, or to pathways involved in chromatin remodeling or DNA damage repair.

For example, some 8 percent of tumors contained mutations to ATM, a gene participating in a DNA damage repair pathway that includes the ovarian/breast cancer risk gene BRCA1.

Genes falling within axon guidance pathways turned up as well. That pattern was supported by the researchers analyses of data from published pancreatic cancer studies — including two studies based on mutagenesis screens in mouse models of the disease — and by their own gene expression experiments in mice.

The team also tracked down a few more pancreatic ductal adenocarcinoma cases involving mutations to axon guidance genes such as ROBO1, ROBO2, and SLIT2 through targeted testing on 30 more pancreatic cancer patients.

The findings are consistent with those found in some other cancer types, according to the study’s authors, who noted that there is evidence indicating that some axon guidance components feed into signaling pathways related to cancer development, such as the WNT signaling pathway. If so, they explained, it’s possible that mutations to axon guidance genes might influence the effectiveness of therapies targeting such downstream pathways or serve as potential treatment targets themselves.

Still, those involved in the study cautioned that more research is needed not only to explore such possibilities but also to distinguish between driver and passenger mutations in pancreatic cancer.

“The potential therapeutic strategies identified will … require testing in appropriate clinical trials that are specifically designed to target subsets of patients stratified according to well-defined molecular markers,” the study’s authors concluded.

 

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Reporter: Aviva Lev-Ari, PhD, RN

 

Van Andel, Emory to Develop Early Pancreatic Cancer Dx

October 19, 2012
 

NEW YORK (GenomeWeb News) – Van Andel Institute and Emory University researchers will use a $2.3 million grant from the National Cancer Institute to fund an effort to develop new biomarker tools that can aid in the early diagnosis of pancreatic cancer.

The Van Andel and Emory team plan to use gene expression studies and a shotgun glycomics approach to try to develop useful diagnostic tests for a certain carbohydrate structure that is prevalent in most, but not all, pancreatic cancer tumors.

In a shotgun glycomics approach, all of the glycans from a sample are tagged with a fluorescent tag and separated from each other to create a tagged glycolipid library. This library will be developed through gene expression studies on the tumor tissue.

“One of the most common features of pancreatic cancers is the increased abundance of a carbohydrate structure called the CA 19-9 antigen,” Brian Haab, head of Van Andel’s Laboratory of Cancer Immunodiagnostics, said in a statement.

Because CA 19-9 is attached to many different proteins that the tumor secretes into the blood it is used to confirm diagnosis of and to manage disease progression of pancreatic cancer. Tests for this structure have not yet been useful for early detection or diagnosis, however, because around 20 to 30 percent off incipient tumors produce low levels of CA 19-9.

“The low levels are usually due to inherited genetic mutations in the genes responsible for the synthesis of CA 19-9,” Haab explained. “However, patients who produce low CA 19-9 produce alternate carbohydrate structures that are abnormally elevated in cancer.”

This study aims to characterize and identify these glycans to improve the ability to detect cancer in patients with low CA 19-9 levels.

The research will integrate the use affinity reagents, a type of proteins called lectins, as well as shotgun glycomics, to detect these glycan structures and develop a diagnostic test for pancreatic cancer.

Because pancreatic cancer tends to spread before it is diagnosed and because of its resistance to chemotherapy, it has one of the lowest survival rates of any major cancer. It will affect more than 43,000 Americans in 2012 and will kill more than 37,000, according to NCI.

“We anticipate these new approaches advancing pancreatic cancer diagnostics as well as benefiting other glycobiology research in cancer,” Haab said.

Researchers from the Fred Hutchinson Cancer Research Center, Palo Alto Research Center, the University of Georgia, and the University of Pittsburgh Medical Center also are participating in the project.

 

 

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