New method identifies genes that can predict prognoses of cancer patients

Approach could help in developing new diagnostics and therapies

2013-01-25

(Press-News.org) BOSTON – In recent years, it has been thought that select sets of genes might reveal cancer patients' prognoses. However, a study published last year examining breast cancer cases found that most of these "prognostic signatures" were no more accurate than random gene sets in determining cancer prognoses. While many saw this as a disappointment, investigators at Beth Israel Deaconess Medical Center (BIDMC), the Dana-Farber Cancer Institute, and the Institut de Recherches Cliniques de Montréal (IRCM) saw this as an opportunity to design a new method to identify gene sets that could yield more significant prognostic value.

Led by Andrew Beck, MD, Director of the Molecular Epidemiology Research Laboratory at BIDMC, the team has developed SAPS (Significance Analysis of Prognostic Signatures), a new algorithm that makes use of three specific criteria to more accurately identify prognostic signatures associated with patient survival.

Their results, the largest analysis of its kind ever performed, are reported in the January 24 on-line issue of the journal PLOS Computational Biology.

"SAPS makes use of three specific criteria," explains Beck, who is also an Assistant Professor of Pathology at Harvard Medical School. "First, the gene set must be enriched for genes that are associated with survival. In addition, the gene set must separate patients into groups that show survival differences. Lastly, it must also perform significantly better than sets of random genes at these tasks."

In the new study, the scientific team applied the SAPS algorithm to gene expression profiling data from the study's senior author Benjamin Haibe-Kains, PhD, Director of the Bioinformatics and Computational Genomics Laboratory at IRCM and an Assistant Research Professor at the University of Montreal. The first collection of data was obtained from 19 published breast cancer studies (including approximately 3800 patients), and the second included 12 published gene expression profiling studies in ovarian cancer (including data from approximately 1700 patients).

When the investigators used SAPS to analyze these previously identified prognostic signatures in breast and ovarian cancer, they found that only a small subset of the signatures that were considered statistically significant by standard measurements also achieved statistical significance when evaluated by SAPS.

"Our work shows that when using prognostic associations to identify biological signatures that drive cancer progression, it is important to not rely solely on a gene set's association with patient survival," says Beck. "A gene set may appear to be important based on its survival association, when in reality it does not perform significantly better than random genes. This can be a serious problem, as it can lead to false conclusions regarding the biological and clinical significance of a gene set."

By using SAPS, Beck and his colleagues found that they could overcome this problem. "The SAPS procedure ensures that a significant prognostic gene set is not only associated with patient survival but also performs significantly better than random gene sets," says Beck. His team revealed new prognostic signatures in subtypes of breast cancer and ovarian cancer and demonstrated a striking similarity between signatures in estrogen receptor negative breast cancer and ovarian cancer, suggesting new shared therapeutic targets for these aggressive malignancies.

The findings also indicate that the prognostic signatures identified with SAPS will not only help predict patient outcomes but might also help in the development of new anti-cancer drugs. "We hope that markers identified in our analysis will provide new insights into the biological pathways driving cancer progression in breast and ovarian cancer subtypes, and will one day lead to improvements in targeted diagnostics and therapeutics," says Beck. "We also hope the method proves widely useful to other researchers." To that end, the team would like to create a web-accessible tool to enable investigators with little knowledge of statistical software and programming to identify gene sets significantly associated with patient outcomes in different diseases.

"We also plan to soon release a software package, which includes all the code and corresponding documentation of our analysis pipeline," adds Haibe-Kains. "This will allow others to fully reproduce our results while enabling the bioinformatics and computational biology communities to take over and potentially adapt and improve our pipeline to address important new issues in biomedicine."

Beck and his collaborators are currently working to further validate the prognostic signatures they identified in breast and ovarian cancers, with the hopes of bringing them closer to the clinic through the development of new diagnostics and treatments. "We are also extending our approach to other common cancers that lack robust prognostic signatures," he notes.

### Study coauthors include BIDMC investigators Nicholas Knoblauch, Marco Hefti, Jennifer Kaplan, Stuart J. Schnitt; and Aedin Culhane, Markus Schroeder, Thomas Risch, and John Quackenbush, of the Dana-Farber Cancer Institute.

This work was supported by an award from the Klarman Family Foundation.

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and currently ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org. END

ELSE PRESS RELEASES FROM THIS DATE:

Monitoring and robust induction of nephrogenic intermediate mesoderm from human iPSCs

2013-01-25

The research group led by Associate Professor Kenji Osafune and his colleague Shin-ichi Mae, both from Center for iPS Cell Research and Application (CiRA), Kyoto University in Japan, has succeeded in developing a highly efficient method of inducing human induced pluripotent stem (iPS) cells to differentiate into intermediate mesoderm, the precursor of kidney, gonad, and other cell lineages. This represents a major step toward realizing renal regeneration. As nearly all kidney cells are derived through differentiation from intermediate mesoderm, to realize kidney regeneration ...

Dartmouth research offers new control strategies for bipolar bark beetles

2013-01-25

Population explosions of pine beetles, which have been decimating North American forests in recent decades, may be prevented by boosting competitor and predator beetle populations, a Dartmouth study suggests. Bark beetles are the most destructive forest pests worldwide. Management and climate change have resulted in younger, denser forests that are even more susceptible to attack. Though intensively studied for decades, until now an understanding of bark beetle population dynamics—extreme ups and downs—has remained elusive. The Dartmouth-led study, published in the ...

Gene mutation immortalizes malignant melanoma

2013-01-25

About ten percent of all cases of malignant melanoma are familial cases. The genome of affected families tells scientists a lot about how the disease develops. Prof. Dr. Rajiv Kumar of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) together with Prof. Dr. Dirk Schadendorf from Essen University Hospital studied a family where 14 family members were affected by malignant melanoma. The scientists analyzed the genomes of family members and found an identical mutation in the gene for telomerase, an enzyme often called 'immortality enzyme', in all ...

At least 1 in 5 were infected in flu pandemic, international study suggests

2013-01-25

The highest rates of infection were in children, with 47 per cent of those aged five to 19 showing signs of having caught the virus. Older people were affected less, with only 11 per cent of people aged 65 or older becoming infected. The findings come from an international collaboration led by the World Health Organization and Imperial College London, which analysed data from 19 countries, including the UK, US, China and India, to assess the global impact of the 2009 influenza pandemic. The results, published in the journal Influenza and Other Respiratory Viruses, showed ...

Global warming less extreme than feared?

2013-01-25

Internationally renowned climate researcher Caroline Leck of Stockholm University has evaluated the Norwegian project and is enthusiastic. "These results are truly sensational," says Dr Leck. "If confirmed by other studies, this could have far-reaching impacts on efforts to achieve the political targets for climate." Temperature rise is levelling off After Earth's mean surface temperature climbed sharply through the 1990s, the increase has levelled off nearly completely at its 2000 level. Ocean warming also appears to have stabilised somewhat, despite the fact that ...

Put me in, coach! How trained literacy coaches can improve student reading comprehension

2013-01-25

PITTSBURGH—The language and reading comprehension skills of low-income upper elementary-school students—especially English-language learners—can improve markedly if trained literacy coaches engage teachers in conducting interactive text discussions with students, according to a three-year University of Pittsburgh study. The Pitt researchers report in the journal Learning and Instruction that language and reading comprehension showed measurable improvement for young students when their teachers had worked "at-elbow" with content-specific literacy coaches to foster a more ...

Fighting back against citrus greening

2013-01-25

This press release is available in Spanish. U.S. Department of Agriculture (USDA) scientists in Fort Pierce, Fla. are helping citrus growers and juice processors address the threat posed by Huanglongbing (HLB), a disease that is costing the citrus industry millions of dollars each year. Citrus trees infected with HLB, also called citrus greening, usually die within five to 10 years. Fruit on infected trees often falls to the ground before harvest, and fruit that remains on trees may become misshapen and sometimes only partially ripen. Supervisory horticulturalist ...

Diet, parental behavior, and preschool can boost children's IQ

2013-01-25

Supplementing children's diets with fish oil, enrolling them in quality preschool, and engaging them in interactive reading all turn out to be effective ways to raise a young child's intelligence, according to a new report published in Perspectives on Psychological Science, a journal of the Association for Psychological Science. Using a technique called meta-analysis, a team led by John Protzko, a doctoral student at the NYU Steinhardt School of Culture, Education, and Human Development, combined the findings from existing studies to evaluate the overall effectiveness ...

Black silicon can take efficiency of solar cells to new levels

2013-01-25

This press release is available in German. Scientists at Aalto University, Finland, have demonstrated results that show a huge improvement in the light absorption and the surface passivation on highly absorbing silicon nanostructures. This has been achieved by applying atomic layer coating. The results advance the development of devices that require high sensitivity light response such as high efficiency solar cells. This method provides extremely good surface passivation. Simultaneously, it reduces the reflectance further at all wavelengths. These results are ...

DNA and quantum dots: All that glitters is not gold

2013-01-25

A team of researchers at the National Institute of Standards and Technology (NIST) has shown that by bringing gold nanoparticles close to the dots and using a DNA template to control the distances, the intensity of a quantum dot's fluorescence can be predictably increased or decreased.* This breakthrough opens a potential path to using quantum dots as a component in better photodetectors, chemical sensors and nanoscale lasers. Anyone who has tried to tune a radio knows that moving their hands toward or away from the antenna can improve or ruin the reception. Although ...

LAST 30 PRESS RELEASES:

ASTRO issues update to clinical guideline on radiation therapy for rectal cancer

Mount Sinai opens the Hamilton and Amabel James Center for Artificial Intelligence and Human Health to transform health care by spearheading the AI revolution