Study: Cancer risks of people with inherited PALB2 mutations

IN-DEPTH REVIEW OF RESEARCH

Study background

Inherited mutations in the PALB2 gene were first linked to an increased risk of breast cancer in 2007. The protein made by the PALB2 gene interacts with BRCA proteins to help cells repair DNA (thus its name: Partner And Localizer of BRCA2). A large international research group estimated the risk of breast cancer among women with a PALB2 mutation to be 14 percent by age 50 and 44 percent by age 80, based on a study of 154 families. Currently, PALB2 is included in genetic testing for inherited mutations that increase breast cancer risk.

Mutations in PALB2 have also been implicated in an increased risk of pancreatic and stomach cancers and possibly with ovarian and colorectal cancers as well. However, these previous studies were small and statistically unconvincing.

This study is the largest research of people with inherited PALB gene mutations to date. Because of the large number of participants, researchers could more accurately estimate the risk of multiple types of cancer for people with these mutations.
 

Researchers of this study wanted to know

Researchers wanted to estimate the risks of male and female breast cancer and ovarian, pancreatic, prostate and colorectal cancers for people with inherited PALB2 mutations.

Populations in this study

This study looks at cancer information from the largest group of people with PALB2 mutations in the PALB2 Interest Group. Participants included 524 families with inherited, deleterious PALB2 mutations from 44 study centers in 21 countries. Families had at least one living family member with a deleterious mutation. For this study, families with BRCA1 or BRCA2 mutations were excluded; only families with deleterious mutations that cause shorter or absent PALB2 proteins were included. Families with missense mutations were excluded (due to a less certain impact of these mutations on PALB2 protein function).

The family members included 8,830 women and 9,076 men. In this group, 852 women and 124 men had a PALB2 mutation. The remaining family members did not have PALB2 mutations. The makeup of this group allowed researchers to compare individuals with and without PALB2 mutations who were from similar environmental and genetic backgrounds.

Study design

A modeling test called “complex segregation analysis” was used to estimate relative risk. Family members were followed from birth until diagnosis with a first cancer (excluding non-melanoma skin cancer), age of death, age of the last follow-up, age of risk-reducing mastectomy (for breast cancer estimates), age of risk-reducing bilateral salpingo-oophorectomy (RRBSO for ovarian cancer estimates), or age 80, whichever happened first.

Study findings

Models

Several genetic models were considered. Risk estimates were reported for the model with the best fit, which was PALB2 plus some variable impact of additional family history for breast and ovarian cancer risk. This means that risk estimates may differ depending on whether there is no family history of that cancer or more family history.

For most cancer, the model reported was a constant lifetime risk. However, for breast and ovarian cancer, a model that varied by decade of life fit better or as well as a constant risk model.

Breast cancer risk in women

Women with an inherited PALB2 mutation had a 7-fold greater risk of breast cancer compared to women without a PALB2 mutation. This estimate assumes that a woman’s risk is constant over her lifetime.

A better fitting model varied risk by the decade of life. In these estimates, women with a PALB2 mutation had their highest risk of breast cancer at age 25—a 13-fold greater risk of breast cancer compared to women without a PALB2 mutation at the same age. The risk then declined by age 75, when women with a PALB2 mutation had a 4.7-fold greater risk of breast cancer compared to women without a PALB2 mutation at the same age.

The lifetime risk of breast cancer in women with a PALB2 mutation was:

• 17% by age 50
• 53% by age 80 (for a woman with no family history of breast cancer)
  • The breast cancer risk for a woman with a PALB2 mutation who has two close female relatives, e.g., mother and/or sisters who had breast cancer by age 50, is up to 76%.

Breast cancer risk in men

Men with an inherited PALB2 mutation had a 7-fold greater risk of breast cancer compared to men without a PALB2 mutation. This estimate assumes that their risk is constant over their lifetime.

The lifetime risk of breast cancer in men with a PALB2 mutation was:

• 1% by age 80

Ovarian cancer risk

Women with an inherited PALB2 mutation had a 3-fold greater risk of ovarian cancer compared to women without a PALB2 mutation. This estimate assumes that risk is constant over their lifetime.

In the model in which risk varied by the decade of life, a woman with a PALB2 mutation had a lower risk of ovarian cancer by age 50, 2-fold greater than women without a PALB2 mutation. Her risk increased to 4.7-fold by age 75 compared to women without a PALB2 mutation. The constant model and this age-specific model were likely to be statistically equal.

The lifetime risk of ovarian cancer for women with a PALB2 mutation was:

• 0.6% by age 50
• 5% by age 80 (for women with no family history of ovarian cancer)
  • The ovarian cancer risk for a woman with a PALB2 mutation who has two close female relatives with ovarian cancer e.g., mother and/or sisters with ovarian cancer by age 50, is up to 16%.

Pancreatic cancer risk

People with inherited PALB2 mutation had a 2.4-fold greater risk of pancreatic cancer compared to family members without a PALB2 mutation. This estimate assumes that their risk is constant over their lifetime.

The lifetime risk of pancreatic cancer for individuals with a PALB2 mutation was:

• 2.2% by age 80 for women
• 2.8% by age 80 for men

This study found no increase in the risk for prostate or colorectal cancer.

Strengths and limitations

Strengths

• This is the largest group of people with PALB2 mutations to be considered to date. The size of the group means that there is greater confidence that the findings are accurate.
• The models considered and the resulting range of risk estimates are clearly presented.
• By looking at only clearly deleterious PALB2 mutations, the findings are more robust and interpretable than prior studies that included missense mutations.

Limitations

• This is study relies on self-reporting of retrospective information (past events). Retrospective studies may be biased by participants’ recall of information.
• The risk of a second primary breast cancer in women with PALB2 mutations could not be determined.
• Only people with known deleterious mutations were included. The risk of cancer for people with missense mutations in PALB2 was not determined.
• The cancer risk of people who had a mutation in both a PALB2 and a BRCA gene was not determined. Because the BRCA proteins and the PALB2 protein work together to perform DNA repair, the combined effect of mutations in these genes is difficult to predict.
• No information is provided about participants’ race or ethnicity or whether any difference in risk varies by race or ethnicity.

Context

Prior studies involving 154 families estimated the risk of breast cancer in women with an inherited PALB2 mutation to be 14 percent by age 50 and 44 percent by age 80. As a result, genetic testing panels include PALB2 when testing for inherited breast cancer genes. This study's results agree with the smaller, less certain prior studies on breast cancer in both men and women.

Links to pancreatic and stomach cancer have been reported with less clear links to ovarian and colorectal cancers. Overall, not much information was available about these cancers among people with known PALB2 mutations. Prior studies of PALB2-related ovarian cancer risk produced inconsistent results. Some studies showed no increase, while others found substantial risk but these were small and not statistically significant. As the most extensive to date, this study included 524 families, nearly 18,000 individuals and provides more definitive results.

Although prior studies suggested that PALB2 mutations may be linked to increased prostate cancer risk, this study found no such increased risk.

Conclusions

PALB2 mutations substantially increase the risk of breast cancer in women and men. The risk of ovarian cancer and pancreatic cancer in men and women is also higher. Establishing the lifetime risk of cancer for people with inherited PALB2 mutations allows this information to be incorporated into risk models for healthcare decision-making.

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posted 7/1/21