CTRB2 misfolding variant

The CTRB2 misfolding variant refers to a genetic alteration involving the deletion of exon 6 in the CTRB2 gene, which encodes a protein called chymotrypsinogen B2. This variant has been linked to an increased risk of pancreatic cancer due to its effects on protein folding and cellular stress. Research using a CRISPR/Cas9-engineered mouse model that mimics this human genetic variant has shown that the mutation causes the production of a truncated version of another related protein, CTRB1. This misfolded protein accumulates in the endoplasmic reticulum (ER), leading to ER stress and the formation of protein inclusions.

The resulting ER stress disrupts normal pancreatic cell function, reducing chymotrypsin enzyme activity, protein synthesis, and secretion of digestive enzymes like amylase. Additionally, it activates inflammatory pathways and impairs the pancreas's ability to recover from injury, creating a pro-inflammatory and pro-cancer environment in the pancreas. This microenvironment increases the risk of developing pancreatic ductal adenocarcinoma (PDAC), a highly aggressive form of cancer.

While this discovery highlights the potential of the CTRB2 variant as a marker for identifying individuals at higher risk of pancreatic cancer, routine genetic testing is not yet recommended. However, future strategies combining ER stress-relieving drugs and anti-inflammatory treatments may help mitigate this risk.