Retrotransposon Risks

Retrotransposons – gene sequences that can copy themselves within a genome – have been found in several types of epithelial cancer. Now, a team of researchers in Maryland are the first to demonstrate that an endogenous retrotransposon can initiate tumorigenesis (1).

The retrotransposon LINE-1 (L1) was thought to be confined to germline cells, and be silenced in somatic cells during maturation. However, the team have now shown that L1 can evade somatic repression in colon tissue to cause insertion mutations in the APC gene. These combine with a point mutation to deactivate APC’s tumor-suppressor function, which triggers colorectal cancer.

The researchers looked at the APC gene in 10 colorectal cancer patients, and found an L1 insertion in one patient with a strong family history of cancer. Further examination of samples from this patient revealed a number of L1 insertions in their tumor, which were not found in surrounding healthy tissue.

The researchers also investigated the origin of the L1 insertion (chromosome 17) and, after evaluating the mutation against 26 different populations, found that the chromosome 17 insertion via L1 is only found in African and African-derived populations. “We have begun screening other patients to further understand if L1 is associated with an increased novel cancer risk. If we determine that it is, we could screen patients to see if they have it and watch them more closely for cancer,” says Scott Devine, lead researcher and Associate Professor of Medicine at the University of Maryland School of Medicine.

As well as screening, the discovery could lead to new colorectal cancer therapeutic targets, and there’s a possibility that the retrotransposon’s oncogenic effect may be found in other tissues. “L1 will probably be found to initiate or drive other cancers, but it will take a lot more work to find out. It has been difficult to link its somatic insertions to cancers, but the techniques used to identify somatic L1 insertions often only recover a fraction of the insertion, so may represent an incomplete picture,” says Devine.

Speaking about his lab’s next steps and their future research goals, Devine says, “We would like to get a better idea of how often somatic L1 insertions can initiate or drive tumorigenesis. Most research to date has examined somatic L1 insertions in tumors, but it would make sense to look at L1s that are active in normal tissues, particularly for tissues like the colon where the APC gene is known to mutate and cause cancer.”