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.
- Depending on family history, women with a PALB2 mutation have a 41% to 67% risk of breast cancer to age 80. There is also an 8-fold risk of breast cancer in men as well as a reported association with pancreatic cancer in both men and women.
- Although previous studies suggest mutations in PALB2 are rare, the mutation prevalence remains unclear; regardless, this new article suggests that the impact to individuals carrying a PALB2 mutation is high. Identifying PALB2 carriers may lead to tailored surveillance and medical management.
- As the lifetime breast cancer risk for PALB2 carriers overlaps BRCA2, it is reasonable to consider testing for PALB2 mutations when BRCA2 testing is offered or in individuals who previously tested negative for BRCA mutations.
- It is important to conduct large-scale prospective studies of PALB2 carriers to further define cancer risks and optimize cancer risk management and treatment options.
- Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497-506.
- Zhang F, Ma J, Wu J, et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol. 2009;19(6):524-529.
- Rahman N, Seal S, Thompson D, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39(2):165-167.
- Foulkes WD, Ghadirian P, Akbari MR, et al. Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res. 2007;9(6):R83.
- Ding YC, Steele L, Chu LH, et al. Germline mutations in PALB2 in African-American breast cancer cases. Breast Cancer Res Treat. 2011;126(1):227-230.
- Southey MC, Teo ZL, Dowty JG, et al; kConFab for the Breast Cancer Family Registry. A PALB2 mutation associated with high risk of breast cancer. Breast Cancer Res. 2010;12(6):R109.
- Cao AY, Huang J, Hu Z, et al. The prevalence of PALB2 germline mutations in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives. Breast Cancer Res Treat. 2009;114(3):457-462.
- Erkko H, Xia B, Nikkilä J, et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007;446(7133):316-319.
- Kuusisto KM, Bebel A, Vihinen M, et al. Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1,
RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals. Breast Cancer Res. 2011;13(1):R20.
- Pern F, Bogdanova N, Schürmann P, et al. Mutation analysis of BRCA1, BRCA2, PALB2 and BRD7 in a hospital-based series of German patients with triple-negative breast cancer. PLoS One. 2012;7(10):e47993.
- Ghadirian P, Robidoux A, Zhang P, et al. The contribution of founder mutations to early-onset breast cancer in French-Canadian women. Clin Genet. 2009;76(5):421-426.
- Bogdanova N, Sokolenko AP, Iyevleva AG, et al. PALB2 mutations in German and Russian patients with bilateral breast cancer. Breast Cancer Res Treat. 2011;126(2):545-550.
- Balia C, Sensi E, Lombardi G, et al. PALB2: a novel inactivating mutation in a Italian breast cancer family. Fam Cancer. 2010;9(4):531-536.
- Dansonka-Mieszkowska A, Kluska A, Moes J, et al. A novel germline PALB2 deletion in Polish breast and ovarian cancer patients. BMC Med Genet. 2010;11:20.
- Sluiter M, Mew S, van Rensburg EJ. PALB2 sequence variants in young South African breast cancer patients. Fam Cancer. 2009;8(4):347-353.
- García MJ, Fernández V, Osorio A, et al. Analysis of FANCB and FANCN/PALB2 fanconi anemia genes in BRCA1/2-negative Spanish breast cancer families. Breast Cancer Res Treat. 2009;113(3):545-551.
- National Cancer Institute. Genetics of Breast and Ovarian Cancer PDQ. http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional/page3#Section_1322. Modified July 11, 2014. Accessed August 25, 2014.
- Tischkowitz MD, Sabbaghian N, Hamel N, et
al. Analysis of the gene coding for the BRCA2-interacting protein PALB2 in familial and sporadic pancreatic cancer. Gastroenterology. 2009;137(3):1183-1186.
- Jones S, Hruban RH, Kamiyama M, et al. Exomic sequencing identified PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324(5924):217.
- Radford C. Inherited cancer risk statistics: absolute risk versus relative risk. The Oncology Nurse-APN/PA. 2012;5(11):1, 28.
- Murphy CD, Lee JM, Drohan B, et al. The American Cancer Society guidelines for breast screening with magnetic resonance imaging: an argument for genetic testing. Cancer. 2008;113(11):3116-3120.
- Heikkinen T, Kärkkäinen H, Aaltonen K, et al. The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype. Clin Cancer Res. 2009;15(9):3214-3222.
- Buisson R, Dion-Côté AM, Coulombe Y, et al. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat Struct Mol Biol. 2010;17(10):1247-1254.
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.