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Posts Tagged ‘Fred Hutchinson Cancer Research Center’


Genomics of Incident Ischemic Stroke Events, Stroke and Cardiovascular Disease

Reporter: Aviva Lev-Ari, PhD, RN

 

Associations Between Incident Ischemic Stroke Events and Stroke and Cardiovascular Disease-Related Genome-Wide Association Studies Single Nucleotide Polymorphisms in the Population Architecture Using Genomics and Epidemiology Study

Cara L. Carty, PhD, Petra Bůžková, PhD, Myriam Fornage, PhD, Nora Franceschini, MD, Shelley Cole, PhD, Gerardo Heiss, MD, PhD, Lucia A. Hindorff, PhD, MPH, Barbara V. Howard, PhD, Sue Mann, MPH, Lisa W. Martin, MD, Ying Zhang, PhD, Tara C. Matise, PhD, Ross Prentice, PhD, Alexander P. Reiner, MD, MS and Charles Kooperberg, PhD

Author Affiliations

From the Public Health Sciences, Fred Hutchinson Cancer Research Center (C.L.C., S.M., R.P., C.K.); Department of Biostatistics, University of Washington, Seattle, WA (P.B.); Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX (M.F.); Division of Epidemiology, School of Public Health, University of Texas Health Sciences Center, Houston, TX (M.F.); Department of Epidemiology, University of North Carolina, Chapel Hill, NC (N.F., G.H.); Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX (S.C.); Office of Population Genomics, National Human Genome Research Institute, Bethesda, MD (L.A.H.); Medstar Health Research Institute, Washington, DC (B.V.H.); George Washington University School of Medicine, Washington, DC (B.V.H., L.W.M.); University of Oklahoma Health Sciences Center, Oklahoma City, OK (Y.Z.); Department of Genetics, Rutgers University, Piscataway, NJ (T.C.M.); Department of Epidemiology, University of Washington, Seattle, WA (A.P.R.).

Correspondence to Dr Cara L. Carty, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N./M3-A410, Seattle, WA 98109. E-mail ccarty@fhcrc.org

Abstract

Background—Genome-wide association studies (GWAS) have identified loci associated with ischemic stroke (IS) and cardiovascular disease (CVD) in European-descent individuals, but their replication in different populations has been largely unexplored.

Methods and Results—Nine single nucleotide polymorphisms (SNPs) selected from GWAS and meta-analyses of stroke, and 86 SNPs previously associated with myocardial infarction and CVD risk factors, including blood lipids (high density lipoprotein [HDL], low density lipoprotein [LDL], and triglycerides), type 2 diabetes, and body mass index (BMI), were investigated for associations with incident IS in European Americans (EA) N=26 276, African-Americans (AA) N=8970, and American Indians (AI) N=3570 from the Population Architecture using Genomicsand Epidemiology Study. Ancestry-specific fixed effects meta-analysis with inverse variance weighting was used to combine study-specific log hazard ratios from Cox proportional hazards models. Two of 9 stroke SNPs (rs783396 and rs1804689) were associated with increased IS hazard in AA; none were significant in this large EA cohort. Of 73 CVD risk factor SNPs tested in EA, 2 (HDL and triglycerides SNPs) were associated with IS. In AA, SNPs associated with LDL, HDL, and BMI were significantly associated with IS (3 of 86 SNPs tested). Out of 58 SNPs tested in AI, 1 LDL SNP was significantly associated with IS.

Conclusions—Our analyses showing lack of replication in spite of reasonable power for many stroke SNPs and differing results by ancestry highlight the need to follow up on GWAS findings and conduct genetic association studies in diverse populations. We found modest IS associations with BMI and lipids SNPs, though these findings require confirmation.

SOURCE:

Circulation: Cardiovascular Genetics.2012; 5: 210-216

 

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Reporter: Aviva Lev-Ari, PhD, RN

Head and Neck Cancer Studies Suggest Alternative Markers More Prognostically Useful than HPV DNA Testing

September 18, 2012

NEW YORK (GenomeWeb News) – The presence or absence of human papillomavirus DNA on its own in an individual’s head or neck cancer does not provide enough information to help predict a patient’s survival, according to a pair of new papers in the journal Cancer Research.

Two research teams — headed by investigators at Brown University and Heidelberg University, respectively — looked at the reliability of using PCR-based HPV testing to determine which head and neck squamous cell carcinomas were HPV-related and, thus, more apt to respond to treatment.

Previous studies have shown that individuals with HPV-associated head and neck cancers tend to have more favorable outcomes than individuals whose head and neck cancers that are not related to HPV infection.

“Everybody who has studied it has shown that people with virally associated disease do better,” Brown University pathology researcher Karl Kelsey, a senior author on one of the new studies, explained in a statement.

“There are now clinical trials underway to determine if they should be treated differently,” he added. “The problem is that you need to appropriately diagnose virally related disease, and our data suggests that people need to take a close look at that.”

For their part, Kelsey and his co-authors from the US and Germany assessed the utility of testing for the presence of HPV by various means in individuals with head and neck cancer. This included PCR-based tests for HPV DNA in the tumor itself, tests aimed at detecting infection-associated antibodies in an individual’s blood, and tests for elevated levels of an HPV-related tumor suppressor protein.

For 488 individuals with HNSCC, researchers did blood-based testing for antibodies targeting HPV16 in general, as well as testing for antibodies that target the viral proteins E6 and E7.

For a subset of patients, the team assessed the tumors themselves for the presence of HPV DNA and/or for elevated levels of the host tumor suppressor protein p16.

Based on patterns in the samples, the group determined that the presence of viral E6 and E7 proteins in the blood was linked to increased survival for individuals with an oropharyngeal form of HNSCC, which affects part of the throat known as the oropharynx.

A positive test for HPV DNA alone was not significantly linked to head and neck cancer outcomes. On the other hand, when found in combination with E6 and E7 expression, a positive HPV16 test did coincide with improved oropharyngeal cancer outcomes.

Likewise, elevated levels of p16 in a tumor were not especially informative on their own, though they did correspond to better oropharyngeal cancer survival when found together with positive blood tests for E6 and E7.

Based on these findings, Kelsey and his team concluded that “[a] stronger association of HPV presence with prognosis (assessed by all-cause survival) is observed when ‘HPV-associated’ HNSCC is defined using tumor status (HPV DNA or P16) and HPV E6/E7 serology in combination rather [than] using tumor HPV status alone.”

In a second study, meanwhile, a German group that focused on the oropharyngeal form of the disease found its own evidence arguing against the use of HPV DNA as a solo marker for HPV-associated head and neck cancer.

For that analysis, researchers assessed 199 fresh-frozen oropharyngeal squamous cell carcinoma samples, testing the tumors for HPV DNA and p16. They also considered the viral load in the tumors and looked for gene expression profiles resembling those described in cervical carcinoma — another cancer associated with HPV infection.

Again, the presence of HPV DNA appeared to be a poor indicator of HPV-associated cancers or predictor of cancer outcomes. Whereas nearly half of the tumors tested positive for HPV16 DNA, just 16 percent and 20 percent had high viral loads and cervical cancer-like expression profiles, respectively.

The researchers found that a subset of HPV DNA-positive tumors with high viral load or HPV-associated expression patterns belonged to individuals with better outcomes. In particular, they found that cervical cancer-like expression profiles in oropharyngeal tumors coincided with the most favorable outcomes, while high viral load in the tumors came a close second.

“We showed that high viral load and a cancer-specific pattern of viral gene expression are most suited to identify patients with HPV-driven tumors among patients with oropharyngeal cancer,” Dana Holzinger, that study’s corresponding author, said in a statement.

“Once standardized assays for these markers, applicable in routine clinical laboratories, are established, they will allow precise identification of patients with oropharyngeal cancer with or without HPV-driven cancers and, thus, will influence prognosis and potentially treatment decisions,” added Holzinger, who is affiliated with the German Cancer Research Center and Heidelberg University.

In a commentary article online today in Cancer Research, Eduardo Méndez, a head and neck surgery specialist with the University of Washington and Fred Hutchinson Cancer Research Centerdiscussed the significance of the two studies and their potential impact on oropharyngeal squamous cell carcinoma prognoses and treatment.

But he also cautioned that more research is needed to understand whether the patterns described in the new studies hold in other populations and to tease apart the prognostic importance of HPV infection in relation to additional prognostic markers.

 

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