FORCE has a strong commitment to promoting research to benefit our community. We advocate for more research funding, educate people about available studies, and report findings back to our community.
by Katrina Altersitz Wells and Lisa Rezende, PhD
Many families have multiple members with cancer who have all tested negative for BRCA1 or BRCA2 gene mutations. Some of these families have mutations in other genes that are also associated with increased cancer risk. Genetic testing is available for several of these mutations, either alone or as part of multi-gene panels. Because some of these genes are newly discovered, less is known about the exact risks associated with mutations in these genes. Consulting with a genetic counselor before and after genetic testing is important to ensure that people receive personalized information about their risk for cancer and the meaning of genetic test results.
PALB2, a gene that has previously been implicated in increased risk of pancreatic and breast cancer, has recently received media attention. A new study released in the New England Journal of Medicine1 estimates the lifetime risk for breast cancer for women with PALB2 mutations, information that may help guide decisions about cancer risk management in people who test positive for this mutation. The normal function of PALB2 is to work with BRCA1 and BRCA2 to repair DNA damage in cells. Like with BRCA1/2, mutations in PALB2 can disrupt this DNA repair process, making it more likely that cancer will develop.
Researchers studied 154 families that had at least one family member with breast cancer who tested negative for BRCA1 and BRCA2 mutations, but tested positive for a mutation in PALB2. Within the families, 311 women had PALB2 mutations, of whom 229 had breast cancer, and 51 men had PALB2 mutations, of whom 7 had breast cancer. When the researchers looked at the family history of women with PALB2 mutations, they found that the absolute breast cancer risk was higher for women with a stronger family history of cancer.
Based on these findings, the researchers estimated women with a PALB2 mutation have:
This study also confirmed previous studies showing that men with PALB2 mutations are also at increased risk for breast cancer, although the exact level of risk is not known.
PALB2 mutations are associated with an increased risk of developing pancreatic cancer, but the exact risk still needs to be determined. The researchers also noted a small but statistically insignificant increase in ovarian cancer risk associated with PALB2 mutations. Larger studies are needed to confirm whether or not increased ovarian cancer risk exists in families with PALB2 mutations.
Although this study is an important first step in understanding risks associated with PALB2 mutations, it was a relatively small study and every family in it had at least one relative with breast cancer. We still do not know the extent of cancer risk in all individuals with PALB2 mutations, or how the risks might affect risk management or treatment recommendations. An editorial that accompanied the article2 also suggests that because PALB2 works alongside BRCA1/2, it is possible that PALB2-associated cancers might also respond to PARP inhibitors,2 an idea that will require research to determine whether this is the case or not.
Genetic testing for PALB2 mutations is available from a number of laboratories. However, there are currently no national guidelines for the testing of individuals for PALB2 mutations or for management of cancer risk in patients with PALB2 mutations. In the absence of guidelines, expert recommendations for risk management are often based on the family history of cancer. In the absence of guidelines, testing may not be covered by health plans. FORCE has heard from members of our community who have tested positive for a PALB2 mutation, some asked for resources and support for high-risk screening and others indicated they are pursuing prophylactic surgery. Genetics experts can help people who have a strong family history of breast cancer but no known mutation in BRCA1 or BRCA2 to determine whether testing for mutations in PALB2 or other genes associated with increased cancer risk is right for them and help them make medical decisions based on the best available information about their risk.
FORCE will continue to support all people at high risk for hereditary cancer, review new research on cancer risk associated with PALB2 and other mutations, and provide expert-reviewed resources for families that carry mutations in genes associated with increased breast and/or ovarian cancer risk. For more information, our current Joining FORCEs Newsletter has articles on additional genetic testing for BRCA negative families. Visit our website section on finding specialists to locate a genetics expert in your area.