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. These data empower us in many ways. For example, using our ability to impute sequence data, we can multiply by 100 times the amount of information generated by sequencing one individual. We can use these tools to discover and integrate rarer variants into our tests and scans, identify drug targets for licensing, and put our know-how at the disposal of our service customers. We believe that this is an important advantage for conducting large-scale whole sequence studies over the next couple of years,” said Kari Stefansson, CEO of deCODE.

Because the risk is inherited and varies in this way, the SNP, located on chromsome 11, had never been linked to T2D even though it had been genotyped in large, traditional genome-wide association studies (GWAS). These do not distinguish between paternally and maternally inherited SNPs. But deCODE can track the parental origin of virtually any SNP in the genome of the tens of thousands of Icelandic participants in the company’s gene discovery work. In this study, deCODE used its population-wide genealogy database and proprietary statistical tools to determine the parent of origin of a number of SNPs in some 40,000 Icelandic participants in the company’s gene discovery programs. Some of these SNPs had previously been associated with different diseases and are located near “imprinted” genes – genes in which only the maternally or paternally inherited copy is “switched-on” to encode a protein. Five of these, one each in breast and skin cancer and three in T2D, showed that the parental origin of the variants affects the risk they confer.

The paper, “Parental origin of sequence variants associated with complex diseases,” is published online at www.nature.com, and will appear in the December 17 print edition.

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.

The key to fighting breast cancer, like all cancers, is early detection, which is why the medical field is buzzing over deCODE’s new breast cancer test.

“This test helps define individual prevention which is what so many of my patients want,” says Owen Winsett, MD, founder and director of the Breast Center of Austin.

Dr. Winsett, who has already ordered the test for 25 of his patients, can’t hide his enthusiasm over how the decode breast cancer test is changing the way he screens for the disease.

“I’m excited to be able to extend my screening and prevention practice. I plan to make this test a standard tool for helping me decide which of my patients may benefit from screening at an earlier age, or benefit from more intensive screening, including breast MRI’s. And then if my patients don’t have breast cancer, to motivate them to begin healthy preventive strategies.”

The test is not offered directly to individual women, but rather ordered by doctors on the request of their patients. deCODE advises that the test-which scans a woman’s genome for seven widely replicated single-letter variations (SNPs) in the human genome that are linked to increased risk of breast cancer-is a way to better connect doctor and patient.

Dr. Winsett agrees. He recommends that before taking this test women should consult their general practitioner, and if their doctor is uncertain about how to use the results of the test, to seek out a breast cancer specialist.

Like all new technologies – particularly those that may change accepted clinical practice – this type of risk screening has raised concerns in some quarters. Some critics have argued that the test is not accurate enough because it’s not based on a large enough sample of women to predict risk of breast cancer. However, the evidence tells a different story. According to Dr. Winsett, epidemiological studies on breast cancer present a fairly straightforward argument that deCODE’s genetic test does indeed give a picture of a patient’s baseline risk. The evidence shows that the seven SNPs in the human genome that the decode test scans for are linked to an estimated 60 percent of all breast cancer cases. These findings are derived from integrated data from discovery and replication studies published in major peer-reviewed journals and involving nearly 100,000 breast cancer patients.

“I remind patients this test is one peice of the puzzle,” says Dr. Winsett. “The test won’t tell patients if they will get breast cancer or if they won’t. It shows the average risk, and then says where a woman stands in relation to that average and then what her absolute risk is. As a doctor, deCODE’s breast cancer test helps me evaluate a patient and make a future plan for prevention and testing.”

Still, some non-clinicians feel genetic testing only benefits women who have a strong family history of breast cancer. One bioethicist recently wrote on an MSNBC blog that “the tests Decode and other companies are offering are more likely to empty family pocketbooks and leave women with a false sense of security than they are to prevent breast cancer.”

Dr. Winsett finds this argument muddled. There are already tests to pick up genetic risk factors for highly familial forms of the disease, and neither those tests nor deCODE’s for measuring risk will cure or prevent breast cancer. Dr. Winsett notes that mammograms, ultrasounds and breast MRIs don’t prevent women from getting breast cancer either, but doctors still use them because they are tools to help detect breast cancer.

“Sometimes a patient will say, ‘I’ve had a mammogram regularly, so how can I get breast cancer?’ It’s easy to think that. But neither mammograms nor the deCODE test can on their own prevent breast cancer. It’s how you use the information from the genetic test to shape a patient’s care that leads to prevention or early detection.”

Genetic risk screening for breast cancer might sound like cutting-edge medicine, but doctors have been using genetics to assess risk of developing breast cancer for years. There are genetic tests that look for mutations of the BRCA 1 and BRCA 2 genes. Variations in these genes are linked to the rare and essentially purely genetic forms of breast cancer.

While detecting the BRCA variants is considered very valuable information to women with a family history of the disease, doctors and researchers knew genetics would one day play a bigger role in the remaining 95 percent of breast cancers. The deCODE BreastCancer^TM test is aimed squarely at filling this gap, and to broadening the use of genetics in fight against breast cancer.

When a woman’s genome is scanned with deCODE BreastCancer, deCODE’s CLIA-registered laboratory checks for certain versions of seven single-letter variations in the genome, called SNPs. According to which versions are detected, that woman’s risk is then tallied, adding together the risk of each of the seven SNPs, to yield a score in relation to average risk, which is about 12% for American women of European origin. By multiplying the relative risk by the average, the results also provide a score of a woman’s absolute risk of developing breast cancer in her lifetime.

Depending upon a woman’s assessed risk, her doctor may suggest that she receive regular mammograms earlier than age 40, the standard starting age in the United States. If the test reveals a high risk, clinicians like Dr. Winsett might order a more advanced breast MRI or an ultrasound test for his patient. In some cases, high-risk patients with other contributing risk factors might start on a course of treatment to reduce the risk of tumors.

Decode’s breast cancer test is not a silver bullet. It won’t cure cancer. It measures risk and will be used in conjunction with other diagnostic tools and treatments to reduce the impact of the disease. But by using deCODE’s genetic test to find out which patients have a higher risk for the disease, says Dr. Winsett, earlier detection of breast cancer is possible.

“With the advent of deCODE’s breast cancer test we can intervene before the cancer happens. My hope is that we’ll see fewer breast cancers. I’m in business of dealing with breast lumps. I’m hoping this test can help reduce the breast lumps that I see.”