PALB2-Related Cancer Risk
The PALB2 gene is classified as a “moderate risk” gene, meaning that there is a modestly increased risk for certain types of cancers. For example, women who have one PALB2 pathogenic gene mutation likely have approximately a 5-fold increased risk for breast cancer as compared to the general population. The risk for a woman to develop contralateral breast cancer (i.e. a second cancer diagnosis, but in the opposite breast) in the setting of a PALB2 gene mutation is not yet defined. PALB2 gene mutations may also be potentially linked to an increased risk for pancreatic, ovarian, and prostate cancer, but the lifetime risks for these types of cancer are not yet clearly defined. Further research is needed to understand the interactions of moderate risk genes and family history on lifetime cancer risk.
Rarely, an individual will inherit two PALB2 gene mutations – one from each parent. When this happens, the child has a severe disease called Fanconi Anemia (FA). Children who have FA have blood problems, developmental issues, and increased risk of cancers such as leukemia and lymphoma.
PALB2 cancer screening and risk-reducing options
The best long-term medical management for individuals who carry a mutation in the PALB2 gene is a topic of on-going research. Healthcare providers oftentimes rely on an individual’s personal and family history to guide medical care.
- Breast: Depending upon personal and family history, in addition to standard clinical breast exams, women may consider mammography and breast MRI starting at a younger age (approximately 30 years).
PALB2 associated therapeutic/ treatment implications
Individuals who have a cancer diagnosis and an identified PALB2 pathogenic mutation should speak with their treating physician about the availability of targeted/ personalized treatment options.
Clinical trials evaluating different medications in individuals who have pathogenic mutations in PALB2 and/or other related genes might be available now or in the future.
PALB2 testing in other family members
At this point in time, testing adult family members for a moderate risk gene mutation does NOT provide the same clarity or guidance that testing for a high risk gene mutation does. This is because moderate risk gene mutations should not be assumed to be the sole explanation for a particular family’s history of cancer. For example, a family could have additional unidentified genetic and/or non-genetic risk factors contributing to the development of cancer seen in family members. It is recommended that family members discuss risks, benefits and limitations of genetic testing with their physician and/or genetic counselor. If an adult family member were to test positive for the familial PALB2 gene mutation, increased cancer screening might be considered. However, given the current lack of data regarding PALB2 gene mutations, if an adult family member were to test negative for a familial PALB2 gene mutation, that individual may still be at increased risk for cancer depending upon the family history and possibility for other genes to be playing a role. Cancer screening should be performed in accordance with the family history until further data is available.
Because of the potential risk for children to be affected with Fanconi Anemia if both of their parents have PALB2 gene mutations, family members who are considering having children should speak with a genetic counselor to discuss risks and the possibility of having their partner tested before conceiving. Genetic test results may be used by some individuals for reproductive decision-making including the use of pre-implantation genetic diagnosis (PGD), donor gametes, or adoption.
As research and data on cancer risk estimates continue to evolve, physicians and researchers will gain a better understanding of how a PALB2 gene mutation influences medical care. Because the information provided to patients will almost certainly change, those with a PALB2 gene mutation are encouraged to keep in touch with their medical providers in order to receive updates.
- Tung N, Domchek SM, Stadler Z, Nathanson KL, Couch F, Garber JE, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol. 2016;13(9):581-8. doi: 10.1038/nrclinonc.2016.90. PubMed PMID: 27296296.
- Pritchard CC, Mateo J, Walsh MF, et al: Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 375:443-53, 2016
- Salo-Mullen EE, O’Reilly EM, Kelsen DP, et al: Identification of germline genetic mutations in patients with pancreatic cancer. Cancer 121:4382-8, 2015
- Grant RC, Selander I, Connor AA, et al: Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology 148:556-64, 2015
- Thompson ER, Rowley SM, Li N, et al. Panel testing for familial breast cancer: calibrating the tension between research and clinical care. J Clin Oncol 2016;34:1455–1459.
- Casadei S, Norquist BM, Walsh T, et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res 2011;71:2222–2229.
- Couch FJ, Hart SN, Sharma P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 2015;33:304–311.
- Cybulski C, Kluzniak W, Huzarski T, et al. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol 2015;16:638–644.
- Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014;371:497–506.
- Kanchi KL, Johnson KJ, Lu C, et al. Integrated analysis of germline and somatic variants in ovarian cancer. Nat Commun 2014;5:3156.
- Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res 2010;70:7353–7359