Genetic information collected from seemingly healthy tissue near lung tumors may be a better predictor of whether cancer will come back after treatment than analysis of the tumors themselves, according to new research led by NYU Langone Health and its Perlmutter Cancer Center.

The new study focuses on lung adenocarcinoma. This cancer, which forms in alveolar epithelial cells, accounts for about a third of all lung cancers in the United States, according to the U.S. Centers for Disease Control and Prevention. Most patients are cured if tumors are surgically removed early in the disease’s progression, but residual cancer cells regrow in about 30 percent of cases and can lead to death. Consequently, experts have long searched for biomarkers that are predictors of recurrence and whose presence might prompt more-aggressive initial treatment.

The study included 147 men and women treated for early-stage lung cancer. It explored the utility value of the transcriptome, the complete set of RNA molecules that tell cells what proteins to make. Analysis of RNA collected from apparently healthy tissue adjacent to tumor cells accurately predicted that cancer would recur 83 percent of the time, while RNA from tumors themselves was only informative 63 percent of the time.

“Our findings suggest that the pattern of gene expression in apparently healthy tissue might serve as an effective and until now elusive biomarker to help predict lung cancer recurrence in the earliest stages of the disease,” said study co-lead author Igor Dolgalev, PhD.

Published online November 8 in the journal Nature Communications, the investigation is the largest to date to compare genetic material from tumors and adjacent tissue for their ability to predict recurrence, says Dr. Dolgalev, an assistant professor in the Department of Medicine at NYU Grossman School of Medicine and a member of Perlmutter Cancer Center.

For the study, the research team collected almost 300 tumor and healthy tissue samples from patients with lung cancer. The study investigators then sequenced the RNA from each sample and fed these data, along with whether or not recurrence occurred within five years of surgery, into an artificial intelligence algorithm. Using machine learning, the program built mathematical models that estimated recurrence risk.

The findings revealed that the expression of genes associated with inflammation, or heightened immune-system activity, in adjacent, apparently normal lung tissue was especially useful for making predictions. This defensive reaction, the study authors say, ought not to be present in tissue that is truly healthy and may be an early warning sign of disease.

“Our results suggest that seemingly normal tissue that sits close to a tumor may not be healthy after all,” said study co-lead author Hua Zhou, PhD, a bioinformatician at NYU Grossman School of Medicine and a member of Perlmutter Cancer Center. “Instead, escaped tumor cells might be triggering this unexpected immune response in their neighbors.”

“Immunotherapy, which bolsters the body’s immune defenses, might therefore help combat tumor growth before it becomes visible to traditional methods of detection,” added study co-senior author and cancer biologist Aristotelis Tsirigos, PhD.

Dr. Tsirigos, a professor in the Department of Pathology and a member of Perlmutter Cancer Center, cautions that the investigation worked backward, training the computer program using cases already known to have had disease return.

As a result, the study team next plans to use the program to prospectively assess recurrence risk in patients newly treated for early-stage lung cancer, says Dr. Tsirigos, who is also director of NYU Langone’s Applied Bioinformatics Laboratories.

Funding for the study was provided by National Institutes of Health grants R37CA244775 and U01CA214195. Further support was provided by an American Association for Cancer Research grant and the Roche Access to Distinguished Scientists Programme.

NYU Langone has a patent pending (TSI03-02PRO) for diagnostic tools developed from this approach. Dr. Tsirigos, Dr. Dolgalev, Dr. Zhou, study co-senior investigators Harvey I. Pass, MD; Andre Da Luz Moreira, MD; and Leopoldo N. Segal, MD; and NYU Langone itself may benefit financially from this patent. The terms and conditions of these relationships are being managed in accordance with the policies of NYU Langone Health.

In addition to Dr. Dolgalev, Dr. Zhou, and Dr. Tsirigos and the co-senior investigators listed above, other NYU Langone researchers involved in the study are Hortense Le, MS; Theodore Sakellaropoulos, PhD; Nina Shenker-Tauris, MS; Nicolas Coudray, PhD; Varshini Vasudevaraja, MS; Kelsey Zhu, BS; Chandra Goparaju, PhD; Yonghua Li, MD, PhD; Imran Sulaiman, MD; Jun-Chieh J. Tsay, MD; Peter Meyn; Hussein Mohamed, PE; Iris Sydney, BA; Sitharam Ramaswami, PhD; Navneet Narula, MD; Luis A. Chiriboga, PhD; Adriana Heguy, PhD; Thales Y. Papagiannakopoulos, PhD; Matija Snuderl, MD; Salman R. Punekar, MD; Vamsidhar Velcheti, MD; John T. Poirier, PhD; Benjamin G. Neel, MD, PhD; and Kwok-Kin Wong, MD, PhD.

Additional co-authors are Anna Yeaton, BS, at the Broad Institute of MIT and Harvard University in Cambridge, Massachusetts; Ruth Kulicke, BS, Fred Davis, MD, Nicolas Stransky, PhD, and Gromoslaw Smolen, PhD, at Celsius Therapeutics, also in Cambridge; and Wei-Yi Cheng, PhD, and James Cai, PhD, at the Roche Innovation Center in New York City.

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