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Biomarkers in Saliva Help Detect Early-Stage Pancreatic Cancer
By David T.W. Wong, DMD, DMSc
The onset and presence of a distal systemic disease being reflected in saliva is enormously significant and highly impactful. The implications are, amongst others, that saliva and its constituent biomarkers can be used for early detection, monitoring disease progression, and predicting therapeutic outcomes. The translational and clinical utilizations of salivary biomarkers for personalized individual medicine applications are here. There is no need to replace blood chemistries for clinical assays. However, salivary biomarkers for disease detection (eg, oral and systemic), particularly for molecular oncology, is emerging where blood markers are still elusive.
For example, pancreatic ductal adenocarcinoma is the most common pancreatic cancer and considered the most deadly of all cancers, effecting more than 42,000 people and resulting in more than 35,000 deaths per year. We have found that salivary diagnostics may be helpful in the fight against this form of pancreatic cancer.
In our study published in Gastroenterology, we connected changes in the molecular signatures found in human saliva to the presence of early-stage pancreatic cancer. By analyzing the altered gene expression, we identified biomarkers in saliva that distinguish pancreatic cancer patients and non-cancer patients.
The most surprising finding is that every systemic disease that we have studied (eg, pancreatic cancer, breast cancer, lung cancer, gastric cancer, ovarian cancer) has yielded highly discriminatory salivary biomarkers. This either could be due to our choice of diseases, which all happened to reflect in saliva, or investigators never looking into saliva before, particularly using the diagnostics tools that we have developed (ie, proteome, transcriptome, micro-RNA, metabolome, and microbiome).
The scientists hope that salivary diagnostics may facilitate the fight against pancreatic cancer in the near future. However, further studies are still needed to confirm the ability of salivary biomarkers to identify very early-stage and/or pre-invasive pancreatic cancer.
But the implications for furthering the understanding of the association between oral and systemic health are immense. The notion that the onset, progression, and therapeutic responsiveness of oral and systemic disease can be assessed by salivary biomarkers carries significant translation and clinical values. Coupled with the non-invasive, non-painful, and non-embarrassing nature of saliva collection, it is an ideal biofluid for diagnostics. In April 2010, President Obama’s Office of Science and Technology issued 14 Grant Challenges for the biomedical research communities. First is to sequence the DNA of every human cancer; second is to develop therapeutics that will only target tumor cells but spare normal cells; and third is to detect dozens of diseases in a sample of saliva.1 Our data support this goal and is making significant progress toward it.
1. National Economic Council. Grand Challenges of the 21st Century. Available at: www. whitehouse.gov/blog/2010/02/04/grand-challenges-21st-century. Accessed August 21, 2011.
Salivary Transcriptomic Biomarkers for Detection of Resectable Pancreatic Cancer
Zhang L, Farrell JJ, Zhou H, Elashoff D, Akin D, Park NH, Chia D, Wong DT.
Featured in Gastroenterology.
2010;138(3):949-957.e1-7. Epub 2009 Nov 18.
Background & Aims: Lack of detection technology for early pancreatic cancer invariably leads to a typical clinical presentation of incurable disease at initial diagnosis. New strategies and biomarkers for early detection are sorely needed. In this study, we have conducted a prospective sample collection and retrospective blinded validation to evaluate the performance and translational utilities of salivary transcriptomic biomarkers for the noninvasive detection of resectable pancreatic cancer.
Methods: The Affymetrix HG U133 Plus 2.0 Array (Affymetrix, Santa Clara, CA) was used to profile transcriptomes and discover altered gene expression in saliva supernatant. Biomarkers discovered from the microarray study were subjected to clinical validation using an independent sample set of 30 pancreatic cancer patients, 30 chronic pancreatitis patients, and 30 healthy controls.
Results: Twelve messenger RNA biomarkers were discovered and validated. The logistic regression model with the combination of 4 messenger RNA biomarkers (KRAS, MBD3L2, ACRV1, and DPM1) could differentiate pancreatic cancer patients from noncancer subjects (chronic pancreatitis and healthy control), yielding a receiver operating characteristic plot, area under the curve value of 0.971 with 90.0% sensitivity and 95.0% specificity.
Conclusions: The salivary biomarkers possess discriminatory power for the detection of resectable pancreatic cancer, with high specificity and sensitivity. This report provides the proof of concept of salivary biomarkers for the noninvasive detection of a systemic cancer and paves the way for prediction model validation study followed by pivotal clinical validation.
About the Author
David T.W. Wong, DMD, DMSc
Felix and Mildred Yip Endowed Professor
Division of Oral Biology and Medicine
UCLA School of Dentistry
Associate Dean for Research
UCLA School of Dentistry
Director, Dental Research Institute
UCLA School of Dentistry
Los Angeles, California