Kyoto, Japan — Colorectal cancer, or CRC, is the world’s second most lethal cancer based on the number of deaths, and is the third most prevalent malignant tumor. Doctors and patients have long been hoping for better diagnostics for prognosis, such as molecular subtyping, which uses data collected from cancer stem cells, or tumor-initiating cells, to further divide one type of cancer into subgroups. It may correlate with patient outcomes and enable better prognoses.
Though many CRC tissue samples have been analyzed and classified based on mRNA gene expression, currently the practical application of these studies in patient prognosis is limited for colorectal cancer. This motivated a team of researchers from Kyoto University to examine cancer stem cells for the molecular subtyping of CRC.
“We need more comprehensive and clinically useful markers and their signatures to help predict the outcome of each patient,” says first author Fumihiko Kakizaki.
To start, the team carefully selected markers from large public databases in both the United States and Europe that showed statistically significant differences between low- and high-risk populations. From this, the team established a library of CRC stem cells and normal colonic epithelial stem cells derived from more than 200 patients, and analyzed them in a culture as well as embedded in xenografts. They predicted this would allow them to identify dysregulated genes, which could indicate authentic changes in the cancer stem cell-specific gene expression levels that are potentially predictive of patient outcomes.
Based on their results, the team was able to identify five molecular subtypes of CRC stem cells. They then integrated these signatures to produce a practical prognostic indicator, designated as the general colorectal cancer signature, or GCS, and were then able to provide individualized predictive signatures for each patient. The team further validated the clinical significance of GCS with a novel orthotopic xenograft mouse model, which summarized patient outcomes.
“We empirically know that every study population is different and that regional demographics affect statistical data in various ways,” says team leader Makoto ‘Mark’ Taketo. “However, our analysis was very close to the normal distribution with similar cut-off parameters for public databases in quartile analyses, showing that our novel system is statistically ideal for clinical use.”
These findings provide a comprehensive overview of clinically relevant molecular subtypes of CRC stem cells, enabling the team to define new expression signatures that rapidly predict the prognosis of CRC. The prognostic markers and signatures that the team managed to obtain in this study are clinically useful in that they can help every patient regarding their prognostic outcomes, and they also work well with expression data from tumor tissues. This method is also less costly and much more efficient than other systems currently used in clinical practice because of the team’s careful selection of markers.
An example usage of General Colorectal Cancer Signature (GCS) (KyotoU / Makoto Taketo)
AloJapan.com