You may have heard about this gene on the radio or in a news article lately. What’s all the fuss about? On August 7, 2014, the New England Journal of Medicine (NEJM) published an article discussing breast cancer risk in families with mutations in PALB2.1 Although this is a recent article, the increased risk of breast cancer in individuals with a mutation in PALB2 has been known for a few years. Similar to many inherited genes that result in an increased cancer risk, testing routinely for these genes was cost and time prohibitive prior to the availability of next-generation sequencing. This was particularly the case for PALB2, as these mutations were believed to be rare and their associated cancer risks were unclear. PALB2 is a gene located on chromosome 16. It stands for “partner and localizer of BRCA2.” The name reflects initial findings that it encodes a protein involved in the BRCA2-related pathway. However, subsequent studies have demonstrated it also interacts with BRCA1 and RAD51.2 Similar to other genes in the BRCA2 pathway, biallelic inactivation of PALB2 (ie, mutation in both copies of the gene) results in Fanconi anemia, whereas a heterozygous germline mutation (ie, mutation in one copy of the gene) increases an individual’s risk for cancer. The first PALB2 truncating mutations in familial breast cancer families were identified in 2007,3,4 and mutations have been identified in individuals of various descents, including African American, Australian, Chinese, Finnish, French-Canadian, German, Italian, Polish, Russian, South African, and Spanish.5-16 Most studies have focused on mutations found in familial and early-onset breast cancer cases in which mutation prevalence has ranged from 0.4% to 3.4%17 and risk of breast cancer has ranged from 2- to 4-fold.3,8 An association with pancreatic cancer has also been observed in both men and women, but risk estimates are poorly defined.18,19 With the exception of a few particular mutations in PALB2, previous studies have primarily provided risk in terms of relative risk. It is important to recall that “fold” is usually a measure of relative risk—it is the ratio of the probabilities of 2 absolute risks. For example, a 2-fold risk may imply that a group with the PALB2 mutation has twice as great a chance of developing breast cancer as the group without the mutation in the population studied.20 How often does a woman present to genetic counseling inquiring about relative risk? The typical question is a variation of: “What is my chance of developing breast cancer and/or a second breast cancer?” This question is one of absolute risk. The NEJM article is the first article to broadly address the absolute risk of breast cancer conferred by PALB2 mutations. The researchers behind this article found that the risk of breast cancer for PALB2 female mutation carriers by age 70 ranges from 33% to 58%, depending on family history, and provide a table depicting breast cancer risk by age and family history.1 When age 80 is used as lifetime risk, the range is 41% to 67%. Furthermore, this same article estimated the risk of breast cancer in men with PALB2 mutations at just over 8-fold. The availability of absolute risk data for PALB2 provides useful information for genetic counseling. For one, the upper risk range of PALB2 overlaps with the risk range of the well-described gene BRCA2. Thus, it is reasonable to consider PALB2 testing whenever BRCA2 testing is indicated. Additionally, the lower risk range to age 70 is at the risk level for which guidelines suggest annual surveillance via breast magnetic resonance imaging (MRI). Therefore, even in the absence of extensive family history, a female with a PALB2 mutation may be a candidate for breast MRI.21 However, as with any genetic counseling session, other factors, such as mutation-specific information, must be taken into account when presenting risk and management options. There are data suggesting that certain mutations in PALB2 may have a more aggressive phenotype and lower associated survival.22 For women with these particular mutations, it may be important to consider risk-reducing mastectomies if these findings are confirmed. Additionally, the penetrance of certain mutations may be higher. For example, in 2010, an Australian study reported that a mutation in PALB2 conferred a breast cancer risk of 91% to age 70.6 PALB2 mutations may also have therapeutic significance, as it has been demonstrated that PALB2-deficient cells are sensitive to PARP inhibitors.23 All of these findings could have an impact on a PALB2 carrier’s surveillance and management options. However, to translate these findings into clinical practice, prospective studies of PALB2 mutation carriers are needed to refine the clinical phenotype and determine optimal cancer risk management and treatment options to improve patient outcomes. Take-Home Messages
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Drs Steven Narod, Kelly Metcalfe, and Tuya Pal, together with the ICARE study team, are in the process of recruiting 500 PALB2 mutation carriers to determine breast cancer characteristics and outcomes. Only through these types of research efforts will we be able to learn more about this important gene and figure out how to help those with mutations. Please contact us through our website (inheritedcancer.net), email (ICARE@inheritedcancer.net), or phone (813-745-6446) if you have a patient with a PALB2 mutation who may be interested in participating in this effort.
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