Biomarker found that predicts a cancer’s ‘aggressiveness’

Novel technology enables discovery, which could help predict tumour recurrence

Researchers from the Fred Hutch Cancer Centre, Seattle, Washington and the University of Texas MD Anderson Cancer Centre, Houston, Texas have uncovered a biomarker capable of accurately predicting outcomes in meningioma brain tumours and breast cancers.

The technology uses a computational method which has discovered that the amount of a specific enzyme – RNA Polymerase II (RNAPII) – found on histone genes was associated with the aggressiveness of tumours and their recurrence.

Hyper-elevated levels of RNAPII on these histone genes indicate cancer over-proliferation and potentially contribute to chromosomal changes. These findings point to tools being developed in the field of genomic technology being potentially used as in cancer diagnosis  and establishing prognosis. It could also improve approaches in precision oncology therapies.

“Histone genes could be a rate-limiting factor in cell replication and, in turn, a strong indicator of tumour cell over-proliferation,” said Dr. Ye Zheng, co-first author and assistant professor of Bioinformatics and Computational Biology at MD Anderson.

“This is because current RNA sequencing methods are unable to detect histone RNAs meaning these [RNA] libraries have vastly underestimated their presence. Our novel approach – combining a new experimental technology and computational pipeline – establishes a comprehensive ecosystem that can leverage biopsy samples from multiple cancer types to enhance tumour diagnosis and prognosis.”

The results of the study were made possible by a new profiling technology developed in the lab of Dr. Steven Henikoff co-first author and professor in the Basic Sciences Division at Fred Hutch, which enables researchers to better study gene expression using formalin-fixed, paraffin-embedded (FFPE) samples.

Tissue biopsies are commonly stored for long-term use as FFPE samples, but the sample RNA degrades over time and becomes increasingly unstable which potentially leads to lower-quality gene expression data.

The new technology – Cleavage Under Targeted Accessible Chromatin (CUTAC) – focuses on small, fragmented DNA non-coding sequences where RNAPII fragments bind, located on the same chromosome as the gene they regulate, and allowing scientists to directly measure gene transcription activity from the DNA.

When examining clinical samples using CUTAC technology across various cancer types, the researchers found that the expression of histone genes was consistently and significantly higher in tumour samples compared to normal tissue samples.

Histone proteins provide essential structural support for DNA in chromosomes, acting as spools around which DNA strands wrap. These proteins have been well studied, but most current tools to study gene expression rely on RNA sequencing. Histone RNA is unique in that its structure prevents the RNA molecules from being detected by current methods.

Therefore, expression of histone genes may be significantly underestimated in tumour samples. The researchers hypothesised that the increased proliferation of cancer cells leads to a very elevated expression – or ‘hypertranscription’ – of histones to meet the added demands of cell replication and division.

To test their hypothesis, the researchers used CUTAC profiling to examine and map RNAPII, which transcribes DNA into precursors of messenger RNA. They studied 36 FFPE samples from patients with meningioma – a common and benign brain tumour – and used a novel computational approach to integrate this data with nearly 1,300 publicly available clinical data samples and corresponding clinical outcomes.

In tumour samples, the RNAPII enzyme signals found on histone genes were reliably able to distinguish between cancer and normal samples.

RNAPII signals on histone genes also correlated with clinical grades in meningiomas, accurately predicting rapid recurrence as well as the tendency of whole-arm chromosome losses. Using this technology on breast tumour FFPE samples from 13 patients with invasive breast cancer also predicted cancer aggressiveness.

“The technique we developed to examine preserved tumour samples now reveals a previously overlooked mechanism of cancer aggressiveness,” said Dr. Henikoff.

“Identifying this mechanism suggests it could be a new test to diagnose cancers and possibly treat them.”

Zheng and colleagues plan to use this technology on FFPE samples from multiple cancer types for further validation.

For further reading please visit: https://www.science.org/doi/10.1126/science.ads2169