deCODE You

Scientists at deCODE Genetics and academic collaborators from Iceland, The Netherlands, Spain, Denmark, Germany, Sweden, the USA, the UK and Romania today report the discovery of a variant in the sequence of the human genome associated with risk of developing basal cell carcinoma of the skin (BCC), as well as prostate cancer and glioma, the most serious form of brain cancer.  The study was done in collaboration with Illumina, Inc., and is published today in the online edition of Nature Genetics.

Using Illumina sequencing technology, deCODE scientists determined the sequences of the entire genomes of 457 Icelanders, and identified 16 million single nucleotide polymorphisms (SNPs). Through a combination of SNP genotyping and computational techniques utilizing the extensive Icelandic genealogy, they were able to propagate those 16 million variants into over 40,000 Icelanders for use in this study.

The researchers discovered a single letter variant located in TP53, a gene known to play a central role in tumor biology and for accumulating so called somatic mutations, during the development of cancer in patients.  Until now, however, individuals who are born with defective copies of the gene (germline variants) have been found extremely rarely, only in families with cancer predisposition syndromes, Li Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL). The variant found in the present study is an unusual type of mutation that appears to affect the way the gene’s messenger RNA is processed; the messenger RNA in patients with the mutant TP53 gene appears to lack proper termination and polyadenylation.

This is the first evidence of a germline variant in TP53 associated with cancer predisposition beyond LFS and LFL. While the mutations causing LFS and LFL syndromes are very rare (occuring 1:5,000 to 1:20,000 births), the variant described in this paper occurs in ~ 1 in 25 individuals in Iceland, and at comparable frequencies in US and UK populations.

“This mutation is one of a growing number of deCODE discoveries of relatively low frequency sequence variants with large effect,” said Kari Stefansson, deCODE’s CEO and senior author of the study.  “The discovery of such variants is made possible through the breadth and quality of the data that the Icelandic population provides.”

Dr. Stefansson emphasized, “We will, together with our collaborators, including Illumina, extend ourselves to turn this discovery into benefit for patients and those at risk of cancer.”

BCC is the most common cancer in people of European ancestry. Sun exposure is the primary risk factor for BCC, but genetic predisposition also plays a substantial role.   Until now, no mechanistic causal connection between cancers as diverse as BCC, prostate cancer, glioma, and colorectal adenoma was known.

The paper, “A Germline Variant in the TP53 Polyadenylation Signal Confers Cancer Susceptibility” is published online in Nature Genetics at www.nature.com/ng and will appear in an upcoming print edition of the journal.

Analysis of four SNPs, in tandem with genetic risk factors detected by the deCODE ProstateCancer™ test, yields substantial improvement in efficacy of PSA screening

Scientists from deCODE genetics and academic colleagues from Iceland, the UK, US, Netherlands, Spain and Romania today report the discovery of a set of single-letter variations in the sequence of the human genome (SNPs) that impact individual baseline levels of prostate specific antigen, or PSA. Testing for PSA levels is the most commonly used screening tool for the detection of prostate cancer. A prostate biopsy is routinely recommended for men with PSA above a certain threshold. However, PSA levels can rise for reasons unrelated to prostate cancer and baseline healthy levels vary substantially between individuals, resulting in many men without cancer being biopsied while cancer in others is not detected. The paper published today demonstrates that analysis of four SNPs can be used to derive a personalized PSA threshold that more accurately identifies those men who are more likely to have a positive biopsy and for whom one should therefore be recommended.

“This is straighforward genetics with direct clinical utility. Detected early, prostate cancer can be treated with near total success. The challenge is to more effectively risk stratify the population, identifying and biopsying those at high risk and with aggressive disease while minimizing the number of negative biopsies we perform. And using the genetics we are improving the sensitivity and specificity of PSA testing. Like virtually every protein in the body, PSA levels vary between individuals according to SNPs that regulate gene expression. The SNPs reported today enable us to personalize PSA thresholds, thereby changing the recommendation on whether to biopsy for a substantial proportion of men. Moreover, the discriminatory power of testing for these SNPs is highest when done in tandem with the SNPs associated directly with risk of the disease measured by our deCODE ProstateCancer™ test. We are working to swiftly incorporate these PSA markers into our testing portfolio,” said Kari Stefansson, CEO of deCODE and senior author on the study.

The paper, entitled “Genetic correction of PSA values using sequence variants associated with PSA levels,” is published today online in Science Translational Medicine and will appear in an upcoming print edition of the journal. The study was conducted in several stages and involved tens of thousands of men with and without prostate cancer. First, more than 300,000 SNPs were analyzed in 16,000 Icelandic men with PSA measurements but who had never been diagnosed with prostate cancer. SNPs that correlated with PSA levels were identified and then validated in a cohort from the UK. These SNPs were then studied in large case-control cohorts from Iceland, the Netherlands, Spain, Romania and the US to establish the association with PSA levels independent of risk of prostate cancer itself. The authors then demonstrated how measuring four SNPs correlated with PSA levels can be used to obtain a personalized threshold for when to biopsy, and that using such thresholds improves the ratio of positive to negative biopsies. The greatest improvement in prediction accuracy was seen when men were tested both for the PSA correction SNPs as well as a panel of prostate cancer risk SNPs detected by the deCODE ProstateCancer™ test.

deCODE and the authors wish to thank the thousands of participants who took part in this study. It was funded in part by grant 202059 (PROMARK) and grant 218071 (CancerGene), both from the 7^th Framework Program of the European Union.

deCODE scientists have discovered a single SNP that confers increased risk if inherited from the father, but is protective if inherited from the mother

Scientists at deCODE genetics, Inc. publish in the journal Nature the discovery of a version of a common single-letter variant in the sequence of the human genome (SNP) with a major impact on susceptibility to type 2 diabetes (T2D). The impact of the T2D variant is not only large, but unusual: if an individual inherits it from their father, the variant increases risk of T2D by more than 30% compared to those who inherit the non T2D-linked version; if inherited maternally, the variant  lowers risk by more than 10% compared to the non T2D-linked version. Nearly one quarter of those studied have the highest risk combination of the versions of this SNP, putting them at a roughly 50% greater lifetime risk of T2D than the quarter with the protective combination. This is the second largest effect of any genetic variant for T2D apart from SNPs in TCF7L2, discovered by deCODE in 2006.

“We could make this discovery beacause we are in the unique position of being able to distinguish what is inherited from the mother from what is inherited from the father. This we can do because of the large amount of data we have assembled on the Icelandic population. Read the rest of this entry »

A new genetic test assessing a woman's risk of developing the most common forms of breast cancer has arrived. Can the test, developed by the biopharmaceutical company deCODE, improve the way doctors screen for breast cancer?

Breast cancer kills 40,000 people a year in the U.S. This is about the population of Atlantic City, New Jersey. Imagine, each year an entire city wiped out by breast cancer.

To help fight breast cancer, a new test assessing individual risk has just become available. For women without a clear family history of the disease, the deCODE BreastCancer^TM test assesses their personal risk of developing the most common forms of breast cancer. The DNA test, launched by the biopharmaceutical company deCODE, makes it possible to identify those women at significantly higher than average risk, helping doctors use new screening technologies and treatments in a more targeted, personalized and effective manner.

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