Gut | Zhou Zongguang/Xu Heng of Sichuan University reveals the genome evolution of colorectal cancer and various models of systemic metastasis, laying the foundation for treatment

The systemic spread of iNature colorectal cancer (CRC) is dominated by the portal system, and it exhibits multiple metastasis patterns without systematic genomic research.

On February 24, 2021, Zhou Zongguang and Xu Heng of Sichuan University jointly published a research paper entitled "Genomic evolution and diverse models of systemic metastases in colorectal cancer" in Gut (IF=19.
82).
The study was conducted on 6 people The matched primary tumors, adjacent non-cancerous mucosa, liver metastases, and multiple areas of lung metastases (n = 74) of CRC patients were sequenced with whole exomes.

Phylogenetic reconstruction and evolutionary analysis are used to investigate the dissemination mode of metastasis and the origin of cloning.

The study found that three models (sequential model, branching model and diaspora model) were revealed based on the migration pattern and clonal origin, which not only supported the anatomical hypothesis that CRC cells cloned in the liver and spread to the lungs, but also outside the liver.
The metastasis is independent of the primary tumor.

Unlike other types of cancer, CRC has spread in multiple lines, which may lead to late metastasis of metastatic driver gene heterogeneity.

In the case of rapid dissemination, the study found that ZFP36L2 has repeated loss-of-function mutations and is associated with poor overall survival.

CRISPR/Cas9-mediated knockout of ZFP36L2 can enhance the metastatic potential of CRC cells.

In summary, the results of this study provide genomic evidence of metastatic evolution, and indicate that for patients with multiple organ failure or late postoperative metastasis, biopsy/sequencing of metastases can be considered.

Distant metastasis is the fatal result of cancer progression in patients with colorectal cancer (CRC) and accounts for most cancer-related deaths.

The presence of clinically obvious metastases in distant organs not only indicates advanced disease, but also rarely flows into the liver through the portal venous system.
Therefore, the metastasis of CRC is considered to be gradual.
Regional lymph nodes (RLN) are the first stop, followed by the liver.
, Subsequent extrahepatic organs (such as lungs).

These findings support the notion that metastasis depends not only on external factors (for example, physical accessibility), but also on the internal characteristics of cancer cells.

Cancer cells have metastatic potential due to random mutation, genetic drift and non-random selection.

Therefore, primary and metastatic cancer cells are genetically heterogeneous.

However, although cancer metastasis is known as a systemic disease involving multiple organs, so far, genome analysis of distant metastasis has mainly focused on a single pair of primary tumor/metastatic organs.

Therefore, there is still a lack of direct genomic evidence to prove the systematic metastatic evolution of CRC.

Since metastasis affects the effectiveness of clinical treatment, clarifying the pathway and origin of metastasis may optimize treatment decisions for CRC patients.

For example, if extrahepatic metastases originate from liver metastases, timely resection will be very important.
If multiple organ metastases originate from different tumor clones, the treatment of metastatic CRC will be more complicated.

So far, the phylogenetic evolution of CRC from the primary site to the liver and extrahepatic organs has almost no characteristics.

Therefore, it is not clear whether the treatment strategy needs to be changed according to different models of CRC systemic metastasis.

The study performed whole-exome sequencing on multiple regions (n ​​= 74) of matched primary tumors, adjacent non-cancerous mucosa, liver metastases, and lung metastases of 6 CRC patients.

Phylogenetic reconstruction and evolutionary analysis are used to investigate the dissemination mode of metastasis and the origin of cloning.

The study found that three models (sequential model, branching model and diaspora model) were revealed based on the migration pattern and clonal origin, which not only supported the anatomical hypothesis that CRC cells cloned in the liver and spread to the lungs, but also outside the liver.
The metastasis is independent of the primary tumor.

Unlike other types of cancer, CRC has spread in multiple lines, which may lead to late metastasis of metastatic driver gene heterogeneity.

In the case of rapid dissemination, the study found that ZFP36L2 has repeated loss-of-function mutations and is associated with poor overall survival.

CRISPR/Cas9-mediated knockout of ZFP36L2 can enhance the metastatic potential of CRC cells.

In summary, the results of this study provide genomic evidence of metastatic evolution, and indicate that for patients with multiple organ failure or late postoperative metastasis, biopsy/sequencing of metastases can be considered.

Reference message: https://gut.
bmj.
com/content/early/2021/02/24/gutjnl-2020-323703