Double Risk: Combination of Two Genetic IBD Risk Variants Promotes Inflammation and Cancer

^{© Konrad Aden / Kiel university
Excerpt_TKO oncogenes}

Research team in Kiel identifies two genetic alterations that, when combined, may increase the risk of colorectal cancer in people with chronic inflammatory bowel diseases.

It is already known that chronic inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn’s disease, increase the risk of developing colorectal cancer. However, the specific inflammatory factors that drive cancer development have remained unclear. Now, a research team from the Cluster of Excellence PMI has discovered that a combination of two genetic variants, both previously known as risk genes for IBD, can also promote cancer development. This finding provides a better functional understanding of the underlying disease mechanisms. The team, led by Professor Konrad Aden from the Institute of Clinical Molecular Biology (IKMB) at the Faculty of Medicine of Kiel University (CAU) and the University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, has published its results in the journal Oncogene.

The focus is on two genes: Xbp1 and Atg16l1. The Xbp1 gene encodes proteins essential for maintaining the balance of the endoplasmic reticulum (ER), a cellular structure responsible for producing and folding proteins into their correct shapes. When the ER is under stress – such as during inflammation – it produces an excess of misfolded proteins. The second gene, Atg16l1, plays a key role in autophagy, the cell’s waste disposal system. Autophagy identifies and removes defective or unnecessary cellular components, including misfolded proteins. To some extent, autophagy can counterbalance the inflammatory processes triggered by protein misfolding.

A genetic variant is an alteration in a gene that disrupts its normal function. In this case, such variants impair the cell’s ability to manage ER stress and autophagy. Previous studies have shown that the interaction between the Xbp1 and Atg16l1 gene variants and the corresponding disturbances in ER stress and autophagy promote the development of IBD. “The disruption of ER balance combined with impaired autophagy causes chronic intestinal inflammation,” explains lead author Prof. Aden. “We wanted to investigate whether these two mechanisms also play a role in the development of colorectal cancer.”

To do this, the researchers used a specialized DNA repair model in mice. Healthy cells have mechanisms to quickly repair DNA damage and errors. If this repair fails, cells can become cancerous. In their study, the researchers used genetically modified mice in which a key part of this repair system no longer functions. They compared these mice with others that had additional alterations in either the Xbp1 or Atg16l1 genes, as well as mice with both genes altered. They then analyzed the extent of DNA damage and the occurrence of intestinal tumors.

They found that in cells with a defective DNA repair system, autophagy increased, which was a predictable response, as the cells attempt to repair damage through this mechanism. However, when autophagy was impaired due to the Atg16l1 variant, DNA damage increased, although tumors did not yet form. When both Atg16l1 and Xbp1 were altered, disrupting both autophagy and ER homeostasis, spontaneous intestinal tumors developed.

“Our observations suggest that a disturbed interaction between autophagy and ER stress not only promotes chronic inflammation but also drives cancer development,” says Aden. “This could help us pinpoint the cellular mechanisms that enable the transition from inflammation to cancer.”

“These findings enhance our understanding of the link between chronic intestinal inflammation and colorectal cancer,” adds senior author Prof. Philip Rosenstiel, Director of the IKMB and board member of the Cluster of Excellence PMI. “If these findings can be confirmed in humans, we may one day be able to identify IBD patients at elevated cancer risk based on specific genetic variants.”
“That would be a key step towards true precision medicine: using molecular markers to make accurate, individualized predictions about disease risks and progression.”

You can find the news here.