POLD1

POLD1 is a gene that provides instructions for making a protein called DNA polymerase delta. This protein works together with other DNA polymerases, including POLE, to copy DNA when cells divide. Like POLE, POLD1 has a proofreading function that helps correct mistakes during DNA replication. This proofreading keeps the genetic code accurate and prevents harmful mutations from building up.

What happens when POLD1 is mutated?

Mutations in the proofreading part of the POLD1 gene reduce the protein’s ability to correct errors in DNA. As a result, DNA mistakes accumulate, leading to a hypermutated state. This means that cells develop many mutations, which can increase the risk of cancer.

Inherited mutations in POLD1 can cause a rare condition called polymerase proofreading–associated polyposis (PPAP). People with PPAP may develop many colon polyps and have an increased risk of colorectal cancer and endometrial cancer.

Like POLE mutations, POLD1 mutations can also occur in tumor cells that were not inherited. These tumor-specific mutations can also lead to ultramutated cancers.

What types of cancer are associated with POLD1 mutations?

Mutations in POLD1 have been linked to several cancers, including:

• Colorectal cancer.

• Endometrial cancer.

• Breast cancer.

• Less commonly, tumors in the pancreas and other organs.

POLD1-mutated tumors are usually microsatellite stable, but they may still be highly mutated and behave differently from other cancers.

How is POLD1 tested?

Doctors test for POLD1 mutations using molecular testing, most often through next-generation sequencing (NGS), which checks many genes at once. Polymerase chain reaction (PCR) can also be used to test for known mutations.

Testing may be recommended if:

• A person develops colorectal cancer or endometrial cancer at a young age.

• A person has many colon polyps.

• There is a strong family history of colorectal or endometrial cancer.

Your pathology report may describe POLD1 test results as pathogenic (disease-causing), likely pathogenic, or negative if no mutation is found.

Why is POLD1 testing important?

Finding a POLD1 mutation can help in several ways:

• It can explain why someone developed colorectal or endometrial cancer at a young age.

• It can guide treatment choices, since POLD1-mutated cancers may respond well to immunotherapy.

• It can provide prognostic information, as some POLD1-mutated tumors behave more aggressively, while others respond better to certain therapies.

• It can identify inherited conditions such as PPAP, which may affect other family members.

How are POLD1 and POLE similar and different?

Both POLD1 and POLE are genes that make proteins responsible for copying DNA when cells divide. They also perform a proofreading function, which means they check for mistakes in DNA and correct them. This proofreading is very important for preventing harmful mutations that could lead to cancer.

When either gene is mutated, the proofreading system does not work properly. This causes DNA errors to build up, leading to hypermutated or ultramutated tumors. These tumors often behave differently from cancers without these mutations and may respond better to treatments like immunotherapy.

The main differences between the two are:

• POLE mutations are most often linked to endometrial cancer and colorectal cancer, though they can appear in other cancers as well.

• POLD1 mutations are also linked to colorectal cancer and endometrial cancer, but are more often seen in some cases of breast cancer.

• People who inherit mutations in either gene can develop a condition called polymerase proofreading–associated polyposis (PPAP), which causes many colon polyps and increases cancer risk.

Questions to ask your doctor

• Was my tumor tested for POLD1 mutations?

• If I have a POLD1 mutation, is it inherited or only in my tumor?

• Do I have polymerase proofreading–associated polyposis (PPAP)?

• Does this mutation make me eligible for immunotherapy?

• Should my family members be tested for POLD1 mutations?