Abnormal PALB2 Gene Increases Breast Cancer Risk More Than Previously Thought

About 5% to 10% of breast cancers are thought to be hereditary, caused by abnormal genes passed from parent to child.

Genes are particles in cells, contained in chromosomes, and made of DNA (deoxyribonucleic acid). DNA contains the instructions for building proteins. And proteins control the structure and function of all the cells that make up your body.

Think of your genes as an instruction manual for cell growth and function. Abnormalities in the DNA are like typographic errors. They may provide the wrong set of instructions, leading to faulty cell growth or function. In any one person, if there is an error in a gene, that same mistake will appear in all the cells that contain the same gene. This is like having an instruction manual in which all the copies have the same typographical error.

Many inherited cases of breast cancer are associated with two abnormal genes: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two). But changes in other genes also are linked to breast cancer.

A study has found that another gene may be just as important in breast cancer risk as BRCA1 and BRCA2: an abnormal PALB2 gene was found to increase breast cancer risk 5 to 9 times higher than average.

The research was published in the Aug. 7, 2014 issue of the New England Journal of Medicine. Read the abstract of “Breast-Cancer Risk in Families with Mutations in PALB2.”

The PALB2 gene is called the partner and localizer of the BRCA2 gene. It provides instructions to make a protein that works with the BRCA2 protein to repair damaged DNA and stop tumor growth. Inheriting two abnormal PALB2 genes causes Fanconi anemia type N, which suppresses bone marrow function and leads to extremely low levels of red blood cells, white blood cells, and platelets.

In this study, researchers from 14 centers in eight countries looked at information from 362 family members from 154 families who had an abnormal PALB2 gene, but didn’t have an abnormal BRCA1 or BRCA2 gene. The people in the study were:

• 311 women with an abnormal PALB2 gene; 229 of these women had been diagnosed with breast cancer
• 51 men with an abnormal PALB2 gene; seven of these men had been diagnosed with breast cancer

The researchers compared the breast cancer risk of the people in the study to average breast cancer risk. They found that overall, women with an abnormal PALB2 gene had a risk of breast cancer that was 9.47 times higher than average.

Women with an abnormal PALB2 gene had a 14% risk of developing breast cancer by age 50 and a 35% risk of developing breast cancer by age 70.

In comparison, women with an abnormal BRCA1 gene have a 50%-70% risk of developing breast cancer by age 70. Women with an abnormal BRCA2 gene have a 40%-60% risk of developing breast cancer by age 70.

The average lifetime risk of breast cancer is about 12%.

Still, this increase in risk linked to an abnormal PALB2 gene was dependent on the women’s age and family history.

In women with an abnormal PALB2 gene, breast cancer risk was:

• 8 to 9 times higher than average in women ages 20 to 39
• 6 to 8 times higher than average in women ages 40 to 60
• 5 times higher than average in women older than 60

By age 70, women with an abnormal PALB2 gene:

• with no family history of breast cancer had a 33% risk of developing breast cancer
• with two or more first-degree relatives (sister, mother, daughter) with breast cancer had a 58% risk of developing the disease

“On the basis of our estimates, the breast-cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines," the researchers concluded. "This level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2."

A test has been developed for the abnormal PALB2 gene. The researchers said the test will soon be more widely available.

If you have a strong family history of breast cancer, yet you and your family members have tested negative for an abnormal BRCA1 or BRCA2 gene, you may want to talk to your doctor about this study and ask if having a PALB2 genetic test makes sense for you.

A strong family history of breast cancer usually means that you have a higher than average risk of breast cancer. The Gail score is a standard breast cancer risk assessment tool that assesses breast cancer risk based on a series of personal health questions that women and their doctors answer together. The questions ask about risk factors such as age, child-bearing history, family history of breast cancer, and breast biopsy results. The Gail score estimates the risk of developing invasive breast cancer in the next 5 years. If you think you may be at high risk for breast cancer, you might want to talk to your doctor about your personal and family medical history. You also may want to ask your doctor to consider calculating your Gail score and then talk about what it means.

For more information on genetics and breast cancer risk, visit the Genetics page in the Breastcancer.org Lower Your Risk section.