Compugen Discovers Possible Lung Cancer Biomarker
Compugen this week stated that it has discovered and tested a potential blood-based small-cell lung cancer biomarker that it has named CGEN-438.
The proposed biomarker is a splice variant of the delta-like protein 3 precursor, DLL3. Previous observations suggest that DLL3 mutations and over-expression are associated with cancer. But CGEN-438 shares no sequence similarity to the membrane protein DLL3. And, unlike DLL3, CGEN-438 is reportedly secreted into the bloodstream.
CGEN-438 is one of a group of possible cancer and cardiovascular biomarkers predicted by Compugen’s immunoassay computational discovery platform. The company has developed a test to detect CGEN-438 and has filed a patent application covering the prospective biomarker.
To test the validity of CGEN-438 as a biomarker, Compugen scientists measured the serum levels of CGEN-438 in 40 lung cancer patients and controls. They reportedly found that serum CGEN-438 levels were higher in small-cell lung cancer patients than in control individuals. They noted that CGEN-438 expression also appears to be higher in some of those with non-small cell lung cancer.
Based on these results, Compugen said CGEN-438 may ultimately become a useful biomarker for diagnosing small-cell lung cancer and for helping to diagnose non-small cell lung cancer in conjunction with other tests.
Global Consortium Forms to Advance Cancer Genomics
A group of research organizations from 10 nations is pooling its resources, infrastructure, and expertise in a collaboration aimed at generating “high quality genomic data on up to 50 types of cancer,” the National Institutes of Health said this week.
Each member institute involved in the International Cancer Genome Consortium will conduct high-resolution analysis of the range of genomic changes in at least one specific type or subtype of cancer, NIH said.
Each of the projects will use specimens from roughly 500 patients and is expected to cost around $20 million, NIH said.
“Clearly, there is an urgent need to reduce cancer’s terrible toll,” said ICGC Secretariat Thomas Hudson. “To help meet that need, the consortium will use new genome analysis technologies to produce comprehensive catalogs of the genetic mutations involved in the world’s major types of cancer.”
In addition to NIH, the ICGC members include Australia’s National Health and Medical Research Council; Canada’s Genome Canada and the Ontario Institute for Cancer Research; the Chinese Cancer Genome Consortium; the European Commission; France’s National Cancer Institute; India’s Department of Biotechnology in the Ministry of Science and Technology; RIKEN’s National Cancer Center in Japan; the Genome Institute of Singapore; and the UK’s Wellcome Trust Sanger Institute.
The ICGC suggested that its members involved in producing genomic catalogues consider several key factors, including “comprehensiveness, which involves detecting all cancer-related genetic mutations that occur in at least three percent of tumor samples; resolution, which involves generating data at the level of individual DNA bases; quality, which involves monitoring based on common standards for pathology and technology; and controls, which involves comparisons of data from matched, non-tumor tissue.”
The member nations of the ICGC plan to agree to common standards covering consent and ethics issues, while the consortium plans to make data from the studies publicly available to qualified investigators.
The ICGC is made up of Funding Members and Research Members, the ICGC said in a white paper outlining its structure and plans, each of which is an individual or allied group that will provide a level of funding or scientific expertise needed to undertake a Cancer Genome Project.
The Funding Members will be required to provide the equivalent of a minimum of $20 million on a project to cover operations, salaries, consumables, and other sundries over a period of five years.
Research Members will be nominated by Funding Members, and must have the demonstrated capability and capacity to support a Cancer Genome Project according to a set of ICGC’s regulations.
ACMG Says Consumer Genetics Requires Informed, Counseled Customers
The American College of Medical Genetics last week issued an advisory statement to the public and the health care community about direct-to-consumer genetic tests, saying in a policy paper that consumers need to be counselled on the utility and meaning of these new technologies.
“Just because a genetic test exists, does not mean it is right for everyone or even right for anyone,” ACMG Executive Director Michael Watson said in a statement.
The group advises greater involvement from counsellors and doctors with consumers when it comes to making choices about these tests, and for increased oversight and regulation for the nascent consumer genetics industry.
The group proposed five recommendations for health care providers, businesses, regulators, and consumers to consider.
According to the ACMG, because genetic testing is “highly technical and complex, a knowledgeable professional should be involved in the process of ordering and interpreting a genetic test.” This can help reduce certain risks involved in genetic testing, which include issues of consent, “inappropriate testing, misinterpretation of results, testing that is inaccurate or not clinically valid, lack of follow-up care, misinformation, and other adverse consequences.”
“The consumer should be fully informed regarding what the test can and cannot say about his or her health,” the group contended. Because interpretation of results is “highly nuanced … such information needs to be communicated to the consumer in the appropriate context and in an understandable fashion,” ACMG advised.
The group also asserted that the “scientific evidence on which a test is based should be clearly stated.”
In addition, ACMG said that labs involved in offering these genetic testing services “must be accredited by CLIA, the state and/or other applicable accrediting agencies,” and this accreditation should be shared with the consumer with test results.
Finally, privacy concerns also must be addressed, the group said. Consumers should be informed about what will happen to their results, who will have access to them, and how they may find out information about privacy breaches that may occur, ACMG said. Other privacy matters that should be discussed with consumers include employment and insurance discrimination issues and the potential impact the results of tests may have on family members.
“The potential benefits to mankind are tremendous but there are a great many questions still to be answered and more research to be done to better understand how genetics affects many conditions,” ACMG President Joe Leigh Simpson said in a statement.
Third Wave Submits HPV Tests to FDA
Third Wave Technologies said this week that it has submitted to the US Food and Drug Administration applications for clearance of two molecular tests for human papillomavirus.
The Madison, Wis.-based firm submitted data from trials on its 14-type high-risk HPV and 16/18 genotyping tests. The submissions come after last month’s announcement that the clinical trials on the two tests met their primary endpoints.
Third Wave intends to have an instrument on the market next year for the HPV tests, it said in a statement.
Third Wave said the global HPV testing market is projected to be $250 million in 2008. But the firm, and Qiagen, which sells the only FDA-cleared molecular test for HPV, believe the market is highly underpenetrated and could be valued at around $1 billion.
NIH Offering $10M to Advance Gene-Variant Science
The National Institutes of Health will provide $10 million over two years for studies relating genetic variations to biological mechanisms or disease causality.
The National Institute on Drug Abuse, on behalf of the NIH Genes, Environment and Health Initiative, will spread the money out over as many as 13 awards, NIH said.
NIDA said it is interested in funding studies using relatively low-throughput approaches, such as transgenic mouse research, to test promising variants for changes in function or for studies using high-throughput tests to study different aspects of variant function.
Direct costs for the studies are limited to $300,000 per year, with no more than $600,000 over the entire two-year grant period.
The GEI is a four-year initiative across the NIH focused on supporting efforts to identify major genetic susceptibility factors for common diseases.
A critical challenge in functional genomics research is establishing that a particular genetic variant is contributing to or causing a disease. The integration of genomics and other ‘omics technologies with high-throughput technologies into pathway-driven approaches will be necessary, NIH said, in order to understand the involvement of environment, development, and genetics in complex human diseases.
Biomax Joins Austrian Personalized Medicine Consortium
Biomax Informatics said last week that it has been selected as a consortium partner in Austria’s OncoTyrol project Center for Personalized Cancer Medicine.
The four-year, €28 million ($43.7 million) OncoTyrol initiative focuses on “translating genomic, proteomic and metabolomic research into innovative, individualized, and cost-effective approaches for cancer diagnosis and treatment,” Biomax said.
The company will provide its BioXM knowledge-management platform for the project.
"After an in-depth evaluation we concluded that the BioXM system, with its highly visual approach and outstanding data integration capabilities, is the backbone we need” for the project, Armin Graber, head of the institute for bioinformatics at the University for Health Sciences, Medical Informatics and Technology, and head of bioinformatics and system biology for the OncoTyrol initiative, said in a statement.
OncoTyrol comprises a consortium of researchers at the Biomedical Campus Innsbruck, the University Hospital Innsbruck, and other academic and industrial partners.
Brd4 Protein Linked to Breast Cancer Survival Gene Signature
New research is pinpointing a gene that seems to govern a gene signature associated with better breast cancer survival.
The gene-expression pattern — first identified in mice and later verified in humans — apparently influences tumor growth and metastasis. In research published online last week in the Proceedings of the National Academy of Sciences, investigators from the National Cancer Institute and elsewhere demonstrated that the signature is influenced by one gene coding for a nuclear protein called bromodomain 4 or Brd4.
“For the first time in mice, we have a candidate gene for what drives an entire gene signature,” NCI geneticist Kent Hunter, who was senior author on the paper, said in a statement. “This should allow a better understanding of the mechanisms underlying cancer progression in humans.”
In typically growing cells, Brd4 is a nuclear protein that’s associated with chromatin. It apparently influences DNA replication and cell cycle progression. Because of its previously identified physical interaction with an invasiveness-suppressing GTPase activating protein called Sipa1, Hunter and his colleagues decided to delve into Brd4’s role in breast cancer.
First, the researchers examined Brd4’s potential role in invasiveness. They generated highly metastatic mouse mammary tumor cells transected with a control vector or with a vector expressing Brd4. When Brd4 was present, the cells were less invasive than control cells even though their growth rate remained the same.
To determine whether the same was true in an animal model, the researchers implanted both Brd4 expressing and non-expressing tumor cells into female mice and tracked their tumor progression and size after a month. Consistent with the cell line results, the Brd4-expressing mice had fewer metastatic tumors. But unlike the cell lines, they also had smaller tumors overall. The authors speculated that this difference in tumor size in vivo may reflect Brd4’s influence on the tumor microenvironment.
In mice Brd4 seemed to regulate the expression of a group of extracellular matrix genes previously classified as a potential metastasis-predictive gene signature. For instance, when they used qPCR to measure gene expression, the team found that five of twelve extracellular-matrix genes showed altered expression in cells expressing vector-borne Brd4.
Using Affymetrix GeneChip Mouse Genome 430 2.0 arrays, Hunter and his team also found a Brd4-mediated gene expression profile or signature in mice. Nearly 150 classes of genes seem to be influenced by Brd4 expression — including some related to cellular processes such as cell-cycle progression, chromatin structure, cytoskeletal remodeling, cell adhesion, and extracellular matrix functions.
They mapped these onto human Affymetrix datasets in the National Center for Biotechnology Information Gene Expression Omnibus and the Dutch Rosetta cohort, which used a different microarray platform. Several hundred human genes had expression profiles that were similar to those in Brd4 expressing mouse models. In addition, the level of Brd4 activation could predict survival for all five data sets.
It also provided clues about survival in other patient populations such as those whose cancer had not spread to their lymph nodes and those with estrogen-receptor-positive tumors.
Still, when the researchers looked at the Brd4 gene signatures associated with improved survival they found overlapping patterns of gene expression. But the patterns weren’t identical. The authors speculate that such differences may exist because of variables such as patient population and microarray platform. Still, they say, the overall Brd4 signature is consistent — and a promising prognostic tool.
Though the results are still preliminary, they suggest that this work may help doctors better predict each patient’s breast cancer progression. In addition, the authors noted that they are currently assessing SNP data to determine whether Brd4 polymorphisms also influence breast cancer progression and prognosis.
“The results of this study and other work in our laboratory suggests that people with inherited differences in Brd4 and the proteins that it induces have a genetic predisposition for developing cancer metastasis,” Hunter said. “A better understanding of this gene may lead to improved methods of diagnosing and treating cancer.”