A team of investigators at Beth Israel Deaconess Medical Center (BIDMC) recently published data that identified and validated an accurate 5-gene classifier for discriminating early pancreatic cancer from nonmalignant tissue—a finding that is a promising advance for the fourth leading cause of cancer death in the United States.
“Pancreatic cancer is a devastating disease with a death rate close to the incidence rate,” explained co-senior study author Towia Libermann, Ph.D., director of the Genomics, Proteomics, Bioinformatics, and Systems Biology Center at BIDMC and associate professor of medicine at Harvard Medical School (HMS). “Because more than 90 percent of pancreatic cancer cases are diagnosed at the metastatic stage, when there are only limited therapeutic options, earlier diagnosis is anticipated to have a major impact on extending life expectancy for patients. There has been a lack of reliable markers, early indicators and risk factors associated with pancreatic cancer, but this new way of differentiating between healthy and malignant tissue offers hope for earlier diagnosis and treatment.”
Using an array of publicly available gene-expression datasets for pancreatic cancer, the BIDMC researchers developed a strategy to reanalyze these datasets, applying rigorous statistical criteria for comparison of the varying data strings. The team then selected a subset of data for developing a panel for differentiating between pancreatic cancer and healthy pancreas tissue and thereafter applied this “Pancreatic Cancer Predictor” to the remaining datasets for independent validation to confirm the accuracy of the markers.
The findings from this study were published online recently in Oncotarget through an article entitled “Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier.”
Once the markers were independently validated, the researchers applied the predictor to datasets that also included benign lesions of the pancreas, including pancreatitis and early-stage cancer. The predictor accurately differentiated pancreatic cancer, benign pancreatic lesions, early-stage pancreatic cancer, and healthy tissue.
Additionally, the predictor achieved on average 95% sensitivity and 89% specificity in discriminating pancreatic cancer from nontumor samples in four training sets and similar performance (94% sensitivity, 90% specificity) in five independent validation datasets.
“Using innovative data normalization and gene selection approaches, we combined the statistical power of multiple genomic studies and masked their variability and batch effects to identify robust early diagnostic biomarkers of pancreatic cancer,” noted lead author Manoj Bhasin, Ph.D., co-director of BIDMC's Genomics, Proteomics, Bioinformatics, and Systems Biology Center and assistant professor of medicine at HMS.
Co-senior study author Roya Khosravi-Far, Ph.D., associate professor of pathology at BIDMC, added that “the identification and initial validation of a highly accurate 5-gene pancreatic cancer biomarker panel that can discriminate late and early stages of pancreatic cancer from normal pancreas and benign pancreatic lesions could facilitate early diagnosis of pancreatic cancer. Our findings may open a window of opportunity for earlier diagnosis and, consequently, earlier intervention and more effective treatment of this deadly cancer, leading to higher survival rates.”
In addition to providing a new tool for diagnoses, the research may also result in new insights into how pancreatic cancer arises.
“Because these five genes are 'turned on' so early in the development of pancreatic cancer, they may play roles as drivers of this disease and may be exciting targets for therapies,” stated Dr. Libermann.
Many of the five genes the team identified—named TMPRSS4, AHNAK2, POSTN, ECT2 and SERPINB5—have been linked to migration, invasion, adhesion, and metastasis of pancreatic or other cancers.
The researchers were excited by their findings and plan to evaluate the precise roles of the five genes and to validate the accuracy of their diagnostic assay in a prospective clinical study. “Moving forward, we will explore the potential to convert this tissue-based diagnostic into a noninvasive blood or urine test,” Dr. Libermann said.
“To further enhance the diagnostic power of this biomarker, we plan to expand it by including noncoding RNAs, proteins, metabolites, and mutations associated with pancreatic cancer,” Dr. Bhasin added. “This will result in the development of the first of its kind biomarker that gauges pancreatic cancer alterations from multiple genomic angles for making highly accurate diagnoses.”