POLE and POLD1 and the Polymerase Proofreading–Associated syndrome (PPAP)
POLE and POLD1 are polymerase proof-reading genes. Their role is to fix mismatches that occur in DNA. When they are damaged (mutated) there is an increased risk of polyps and colon (bowel) cancer as well as uterine cancer.
POLE (pronounced POL eee, standing for polymerase epsilon) and POLD1 (pronounced POL dee one, polymerase delta) are a very rare cause of hereditary polyposis and hereditary colon cancer. Even in individuals with colon cancers attending familial cancer clinics, germline (hereditary) pathogenic (disease causing) variants (changes in the DNA) in POLE or POLD1 are detected in <1% of all families.
As always, the type of mutation and where it is located in the gene matters.
Unusually, truncating mutations (mistakes in the DNA that mean the POLE or POLD1 protein is not made) don't cause problems - the cell just used the other, working copy. Instead, it is missense mutations that increase polyp and cancer risk. That's because the proof-reading protein is made, it just does a bad job. Specifically, the mistake has to affect the amino acids in the "endonuclease functional domain" of the protein. That is, amino acids numbered 268 to 471 in POLE and and those numbered 304 to 533 in POLD1.
Read more about mutations and what they mean on our What is genetic testing? FAQ page.
If the protein doesn't function properly as a proof-reader, many, many mistakes slip through. This results in polyps that can become cancers and is why the syndrome is called the Polymerase-Proofreading Associated Polyposis syndrome (PPAP). The cancers, if they occur are said to have a "hypermutated phenotype" due to all the mistakes present.
Management for individuals with germline POLE and POLD1 mutations
This is still an area of research. Current guidelines recommend colonoscopy screening every 3 years from age 25, or as directed by polyp load.
For individuals with significant polyps (3 before 30 or more than 10 lifetime), recommendations are based on other hereditary polyposis syndromes such as attenuated Familial Adenomatous Polyposis syndrome and usually include annual screening.
Perhaps surprisingly, the cancers are usually associated with a very good prognosis. The abnormal proteins (called neopeptides) are highly immunogenic. This means the immune system quickly spots and destroys the cancer cells. These cancers also show good response to the new class of cancer treatments called immune checkpoint inhibitors