Source, co-occurrence, and prognostic value of PTEN mutations or loss in colorectal cancer

Somatic PTEN mutations are common and have driver function in some cancer types. However, in colorectal cancers (CRCs), somatic PTEN-inactivating mutations occur at a low frequency (similar to 8-9%), and whether these mutations are actively selected and promote tumor aggressiveness has been controversial. Analysis of genomic data from similar to 53,000 CRCs indicates that hotspot mutation patterns in PTEN partially reflect DNA-dependent selection pressures, but also suggests a strong selection pressure based on protein function. In microsatellite stable (MSS) tumors, PTEN alterations co-occur with mutations activating BRAF or PI3K, or with TP53 deletions, but not in CRC with microsatellite instability (MSI). Unexpectedly, PTEN deletions are associated with poor survival in MSS CRC, whereas PTEN mutations are associated with improved survival in MSI CRC. These and other data suggest use of PTEN as a prognostic marker is valid in CRC, but such use must consider driver mutation landscape, tumor subtype, and category of PTEN alteration.

Automated summary

Somatic PTEN mutations are less frequent in colorectal cancers and their relationship with tumor aggressiveness is controversial. PTEN alterations co-occur with certain other mutations in microsatellite stable tumors but not in microsatellite instability tumors. Interestingly, PTEN deletions are associated with poor survival in microsatellite stable colorectal cancers, while PTEN mutations are associated with improved survival in microsatellite instability colorectal cancers.