COLUMBUS, Ohio -- A multi-institutional team of researchers co-led by The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) has demonstrated a way to identify and understand early progression of genetic events leading to cancer in a type of head and neck cancer for which this previously was not possible – an advance that could hold significant clinical importance. Reported in the journal Nature Cancer, the researchers, including scientists at the Broad Institute of MIT and Harvard and at Massachusetts General Hospital Cancer Center, say that analysis of precancerous tissue has often identified the typical order of genetic changes leading to invasive tumors in several cancer types, helping clinicians determine better targeted treatments. However, premalignant tissue is unobtainable for some cancers, leaving genetic progression unknown and effective treatments less likely. In this study – co-led by James Rocco, MD, PhD, chair of the Department of Otolaryngology – Head and Neck Surgery at Ohio State; Ed Mroz, PhD, of the same department; and by Gad Getz, PhD, and Ignaty Leshchiner, PhD, of the Broad Institute – researchers used a computational method called PhylogicNDT to infer genetic progression in primary tumors by sequencing the exome, or the protein-coding region of the human genome, in the absence of premalignant tissue. The researchers first showed that PhylogicNDT could match and substantially extend the progression of genetic events in head and neck squamous cell carcinoma (HNSCC) that is not associated with the human papillomavirus, or HPV-negative (HPV-), that had been previously determined from premalignant tissue. They then used PhylogicNDT to evaluate HPV-positive (HPV+) HNSCC, which lacks premalignant tissue, via exome sequencing and uncovered its previously unknown progression, including early drivers of the disease. They surmise that this approach could be applied to other cancers for which premalignant tissue is not available.  “Our approach can establish previously unknown early genetic progression of cancers with unobtainable precanerous tissue, supporting development of experimental models and methods for early detection, interception and prognostication,” they write in Nature Cancer.  Dr. Rocco says results of this study should have an impact on the understanding of HNSCC tumor initiation and subsequent tumor evolution for both types of HNSCC (HPV- and HPV+). He points out that deciphering the order of genetic mutational events throughout cancer progression has long been a goal of cancer research. “That order can provide clues to the biologic history and cellular mechanisms of tumor formation, helping us understand how normal tissue becomes a tumor,” he explains.  “It can also provide ways to detect and treat early disease stages and identify early genetic events as promising targets for treating later invasive tumors, or cancer metastasis.” Dr. Rocco says analysis of cancers with well-defined pathologic progression from normal or premalignant tissue has provided helpful genetic progression models. “However,” he adds, “there are many cancer types, such as HPV-positive HNSCC, with poorly defined, undetectable or difficult-to-biopsy premalignant lesions whose genetic progression remains speculative. But now we’ve shown how to infer the typical order of genetic events in HPV-positive HNSCC from exome sequencing of primary tumor samples taken long after cancer initiation.” In their Nature Cancer article, the researchers write that their analysis of HPV+ HNSCC “fills a major gap in knowledge about the progression of genetic events in this increasingly prevalent and clinically significant disease, a cancer whose lack of premalignant tissue frustrated prior attempts at (determining genetic progression).” They also believe that applying their approach to other cancers whose premalignant tissue is seldom or never obtainable, including multiple rare tumor types, could be clinically invaluable.  “Establishment of progression trajectories, early drivers and similarity of progression to other cancer types can lead to development of improved disease models, better treatment strategies and clinical management, and more accurate prediction of disease course,” they write. To learn more about head and neck treatment and research at the OSUCCC – James, visit cancer.osu.edu/headandneck or call 1-800-293-5066. -30- *news release written by Bob Hecker   MEDIA CONTACT: Amanda Harper OSUCCC – James Media Relations 614-685-5420 | Amanda.Harper2@osumc.edu