eLife: Gene interactions can classify intestinal tumors

This new classification of bowel cancer will help people understand the disease and may eventually be used by doctors in precision medicine – helping them tailor the best treatment
for individual patients.

"Currently, disease staging is used to guide the clinical management of bowel cancer patients, but this is not enough, because there may be significant differences between tumors at similar stages," explains
first author Lu Zaoqu from the First Affiliated Hospital of Zhengzhou University.
"A more detailed molecular classification of bowel cancer is more effective, but it is still based on a snapshot of the level of gene activity at a point within the tumor (e.
g.
, at the time of biopsy) and does not reflect the dynamics of change in gene activity and how genes interact
with each other.
"

In contrast, biological interaction networks — that is, maps of how genes typically interact with each other — remain relatively stable at all times and can more reliably describe tissues
.
In addition, gene interactions are highly conserved in normal tissues but extensively altered
in disease.
By quantifying the "interaction changes" of different gene pairs, it is possible to compare the overall change in gene interaction in diseased tissue with the change
in background levels in normal tissue.

Using this gene interaction network (GIN) approach, the team used more than 2,000 bowel cancer tissue samples and 308 normal intestinal tissue samples to construct a large-scale network
of gene interaction changes.
Using this network, they were able to classify bowel cancer into six subtypes, each with different clinical and molecular characteristics
.
These features include important tumor characteristics, such as the ratio of cancer cells to other types of cells, and whether cancer cells are similar to stem cells, which can affect the likelihood of
tumor growth and spread.

GIN classification also identifies populations with different immunogenicity — that is, how likely it is that intestinal tumor tissue will stimulate an immune response, which is critical
to determining whether a patient is likely to respond to immunotherapy.
Other useful features include a possible prognosis, resistance to radiation and immunotherapy, and sensitivity to different chemotherapy drugs – all of which help adjust treatment
.
When the GIN method was tested on 19 further bowel cancer datasets, the same 6 subtypes were consistently identified
.

The first GIN was based on more than 2,000 interactions between nearly 1,400 genes and generated a classifier based on 289 genes
.
This is impossible to test in a clinical setting, so to provide a quick and accessible clinical tool, the team simplified the classifier to a randomly selected mini-classifier of 14 genes
.
When they used a mini-classifier on a subset of 214 bowel cancer samples, they found that it was as stable
as the full classifier when identifying 6 bowel cancer subtypes.

"Our study has identified and validated a high-resolution classification system that can be used as a tool to optimize treatment decisions for bowel cancer patients," said
Professor Han Xinwei, director of the Department of Interventional Radiology at the First Affiliated Hospital of Zhengzhou University in China.
"The next step will be to confirm the biological and clinical explainability of the six bowel cancer subtypes in prospective clinical trials, but we believe this new taxonomy can facilitate more effective personalized treatment
for bowel cancer patients.
"