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Biosignatures Show Potential For Predicting Cancer Risk in Non-Alcoholic Liver Disease Patients

NEW YORK – An international team led by investigators at the University of Texas Southwestern Medical Center has come up with tissue- and blood serum-based gene signatures for predicting hepatocellular carcinoma (HCC) risk in individuals with non-alcoholic fatty liver disease (NAFLD).

"[H]CC risk prediction is particularly critical in NAFLD to identify a subset of patients with elevated likelihood of developing HCC among the larger, mostly indolent NAFLD population," senior and corresponding author Yujin Hoshida, an internal medicine researcher at the University of Texas, and his colleagues explained.

In particular, the researchers saw signs that hepatic tissue transcriptome and blood serum secretome signatures — known as PLS-NAFLD and PLSec-NAFLD — could classify NAFLD patients into groups with high or very low HCC risk.

These and other results reported in Science Translational Medicine on Thursday suggested that such signatures could stem excessive screening for the liver cancer in those who are unlikely to develop it, while flagging higher-risk patients for follow-up and providing a clearer look at the molecular pathways that are altered in NAFLD patients who are most prone to cancer development.

Although similar signatures have been developed in the past, the authors noted that "there is still room for improvement, especially in identifying patients with negligible risk, who may not require HCC screening, and identifying those at highest risk to whom intensive screening efforts could be targeted."

For their analyses, the investigators began by developing the PLS-NAFLD signature using hepatic tissue gene expression profiles for four dozen NAFLD patients with a history of HCC — a group that included 28 patients with documented HCC recurrence.

From that discovery set, the team narrowed in on a 133-gene signature for HCC risk, turning to a computational pipeline known as TexSEC to translate findings from that PLS-NAFLD signature into a second PLSec-NAFLD signature focused on four blood serum protein markers.

From there, the investigators tested the signatures in several validation groups comprised of NAFLD patients who had or had not developed HCC when the study began.

On the PLS-NAFLD validation side, for example, the team followed 106 HCC "naïve" NAFLD patients, including six patients diagnosed with HCC over up to 12 years of follow-up. There, HCC occurred in almost 23 percent of individuals classified as high risk with the PLS-NAFLD signature. No patients in the PLS-NAFLD low-risk group had HCC diagnoses during the study's follow-up time of more than a decade.

In an NAFLD validation group that included patients with a history of the liver cancer, meanwhile, 32 of 59 individuals experienced HCC recurrence. In that cohort, the investigators documented recurrence in almost 72 percent of patients classified as high risk with the PLS-NAFLD signature compared with 42.9 percent of the low-risk patients.

Similarly, when they assessed a four protein PLSec-NAFLD serum secretome protein panel in 59 NAFLD patients with cirrhosis who were cancer-free when the study began, the researchers found that seven individuals went on to develop HCC — a group that represented 37.6 percent of the PLSec-NAFLD-classified high-risk individuals and none of the low-risk individuals.

Even so, the authors noted that the PLS-NAFLD risk score "was modified by bariatric surgery, lipophilic statin, and IDO inhibitor [use], suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials."