Genetic testing for PALB2 gene mutations in breast cancer

The Angelina Jolie effect refers to the increase in genetic testing for mutations in genes (e.g. BRCA1 and BRCA2) that confer a greater probability of breast cancer. As I posted earlier, Ms Jolie publicly announced that she possesses a particularly dangerous BRCA1 mutation, and that she elected to undergo a preventive double mastectomy. Raising awareness, especially for women with a family history of breast and/or ovarian cancer, is a good thing.

In the future, genetic testing for breast cancer will become more accurate and comprehensive as more mutations and genes are found that affect breast cancer risk. Indeed a recent article in the New England Journal of Medicine (NEJM) estimated the risk for people carrying mutations in the PALB2 gene, which is not currently used in the genetic tests. The PALB2 protein binds to the BRCA2 protein to form a complex that repairs damaged DNA. Interestingly, the cumulative risk for PALB2 loss-of-function mutations approached that of the BRCA mutations:

"Over all, the researchers found, a PALB2 mutation carrier had a 35 percent chance of developing cancer by age 70. By comparison, women with BRCA1 mutations have a 50 percent to 70 percent chance of developing breast cancer by that age, and those with BRCA2 have a 40 percent to 60 percent chance. The lifetime risk for breast cancer in the general population is about 12 percent."

This risk depended on the age of the individual with the relative risk increasing for younger women:

"The breast cancer risk for women younger than 40 with PALB2 mutation was eight to nine times as high as that of the general population. The risk was six to eight times as high among women 40 to 60 with these mutations, and five times as high among women older than 60."

The risk also increased for those with a family history of breast cancer, and especially those with first-degree relatives (i.e. parents, siblings, children) with breast cancer:

"The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age."

Although the number of people who possess a mutant PALB2 gene is low (only 0.08% of population), these mutations are estimated to account for 2.4% of families with a history of breast cancer (depending on the population). By comparison, 2.5% of all breast cancer patients possess a BRCA mutation.

Thus in terms of both risk and prevalence, the PALB2 mutations approach that of the BRCA1 and BRCA2 mutations. This makes PALB2 a good candidate for future genetic testing for breast cancer. The authors of the NEJM article conclude:

"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. This level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2. We expect new diagnostics to incorporate the PALB2 gene."

Adding PALB2 the panel of genes (i.e. BRCA1 and BRCA2) to be screened in genetic diagnostics for breast cancer will help to make the genetic tests more accurate and comprehensive. However it is important to appreciate the limitations of this testing; namely "90% of women diagnosed with breast cancer don't have a hereditary type" i.e. mutations in BRCA1, BRCA2, PALB2, etc. As the genetics of breast improves this 90% number may decrease slightly, but that does not obscure the dominant role of environment and chance interacting with one's genes to give rise to cancer.

Thus, PALB2 gene mutations and genetic screening in general are important advances but they are not panaceas in terms of assessing risk and determining treatment:

"The problem is that many patients think genetic testing can tell us far more than it does. Despite the exaggerated claims of some entrepreneurs and lab owners, we can’t predict patients’ cancer risk and advise them appropriately just by sequencing their genome. At least not yet.

We have to have patience with the pace of research. We can now use genetic information to prevent breast, ovarian and colon cancer in many patients, and we will get better at this. In the meantime, most people should focus less on the high-tech future of genetic testing and more on the low-tech history of their family trees. Those who don’t know their own family histories, because of adoption, secrecy, loss or estrangement, should take comfort in the fact that we are one big family. Data in aggregate from many families, gathered together in studies like Dr. Tischkowitz’s, will eventually teach us how to manage our risks, how to treat disease and how to save lives."

Thus, it is important for women to be vigilant and perform breast self-exams and have their annual mammograms as recommended by their doctors and the American Cancer Society even if they don't possess BRCA1, BRCA2, or PALB2 mutations.

Figure 1. Genetic testing is an important part of preventing and treating breast cancer, but it is only part of the total picture.