Why Can Liver Cancer Occur With a Normal AFP?

A normal alpha-fetoprotein (AFP) blood test can be reassuring—but it does not necessarily mean that liver cancer is absent.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is biologically diverse. Some HCC tumors produce enough AFP to raise its concentration in the blood, while others produce little or no measurable increase. As a result, patients can have HCC even when their AFP level remains within the normal range.

This is one reason researchers are investigating blood-based cancer signals that measure something fundamentally different from AFP.

What Is AFP?

AFP is a protein normally produced at high levels during fetal development. In healthy adults, blood levels are generally low.

AFP can become elevated in HCC, which is why it has been used for decades as a blood biomarker in liver cancer surveillance and clinical evaluation. However, AFP is not specific to HCC, and not every liver cancer produces elevated AFP.

Published studies have reported substantial variation in AFP performance depending on factors such as tumor size, patient population, and the cutoff used to define an abnormal result. The 2024 American Journal of Pathology study underlying the MoleculeDx scientific program noted reported AFP sensitivities of 49%–71% for HCC tumors smaller than 5 cm.

Therefore:

Normal AFP does not rule out hepatocellular carcinoma.

Why Can HCC Be Present When AFP Is Normal?

Cancer is not a single molecular disease. Even tumors arising in the same organ can differ substantially in their genetic alterations, gene expression, protein production, and other biological characteristics.

AFP reflects protein expression. If an HCC does not produce enough AFP to substantially increase its concentration in blood, AFP testing alone may not identify that cancer.

But the same tumor can contain other cancer-associated molecular abnormalities.

This distinction is important because it creates an opportunity to look for signals that represent different aspects of tumor biology.

Looking Beyond AFP to Fusion Transcripts:

One such class of molecular signals is fusion transcripts.

Cancer cells can undergo chromosomal rearrangements that join DNA from two different genes. These rearrangements can create fusion genes. When a fusion gene is expressed, it produces an abnormal RNA molecule called a fusion transcript.

Research underlying MoleculeDx technology has demonstrated that selected cancer-associated fusion transcripts can be detected as circulating cell-free RNA in the serum of patients with HCC. A 2019 study showed serum detection of fusion transcripts including MAN2A1-FER, CCNH-C5orf30, and SLC45A2-AMACR and found that serum-positive signals corresponded with fusion-positive HCC tissue in matched samples.

Fusion transcripts therefore provide biological information that is fundamentally different from AFP:

AFP measures a protein.

Fusion-transcript testing detects RNA signals associated with cancer-related genomic rearrangements.

What Happens in HCC Patients With Normal AFP?

This distinction becomes particularly important in patients whose HCC does not produce an elevated AFP level.

In the published studies underlying the MoleculeDx research program, more than 95% of HCC patients with normal AFP levels were positive for the evaluated fusion-transcript markers.

The finding does not mean that one fusion transcript identifies every liver cancer. Different tumors can contain different fusion events, and individual fusion transcripts vary in how frequently they occur and how readily they can be detected in serum.

Instead, it demonstrates an important principle:

A liver cancer that is not identified by an elevated AFP may still produce detectable cancer-associated fusion-transcript signals.

That is why AFP and fusion-transcript analysis should not be viewed simply as competing versions of the same test. They examine different biological features of HCC screening.

Why Use Multiple Fusion-Transcript Signals?

HCC is heterogeneous. No single molecular alteration is expected to characterize every tumor.

MoleculeDx therefore uses a multi-marker approach rather than relying on one fusion transcript.

The scientific program has investigated combinations of cancer-associated fusion transcripts in serum. In a 2024 study, nine fusion transcripts were analyzed in 61 patients with HCC and 75 individuals with non-HCC conditions. MAN2A1-FER was detected in the pretreatment serum of all 61 HCC patients in that study, while several other fusion transcripts occurred at varying frequencies.

Computational models were then used to evaluate combinations of the measured molecular signals. Study-specific models demonstrated that combining molecular information can improve classification compared with relying on a single signal.

These published performance results apply to the particular markers, models, cohorts, and analytical methods evaluated in those studies and should not be interpreted as universal performance estimates for every patient or every use of a current commercial test.

What Does This Mean for Liver Cancer Screening?

The limitations of AFP do not mean that AFP has no value. Rather, they demonstrate why liver cancer surveillance should not depend on AFP alone.

For people at increased risk of HCC, appropriate surveillance and clinical follow-up remain important even when AFP is normal.

Blood-based molecular testing offers an opportunity to obtain additional biological information that AFP cannot provide. The MoleculeDx Liver Cancer Fusion Predictor is based on this principle, using Fusion-detect™ technology to analyze multiple cancer-associated fusion-transcript signals in blood.

A blood-test result does not replace appropriate clinical evaluation or diagnostic imaging. Instead, molecular information can help identify cancer-associated signals that may warrant further evaluation.

Normal AFP Is Not the End of the Screening Conversation:

A normal AFP result answers one question: the concentration of AFP in the blood is not elevated.

It does not answer every question about whether HCC is present.

Advances in molecular diagnostics now allow researchers to look beyond conventional protein biomarkers and examine cancer-associated RNA signals arising from the molecular changes within tumor cells.

For patients at increased risk of HCC, that distinction matters.

Normal AFP does not necessarily mean no liver cancer—and fusion-transcript analysis provides a different molecular window into the disease.