PALB2 Study: Researchers and Patients Must 'Pal' for Progress

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Judy E. Garber, MD, MPH

Only rigorous and careful study will provide reliable data on which we can base recommendations for management of our patients found to carry [PALB2] mutations.

—Judy E. Garber, MD, MPH

The recent publication by Antoniou et al on risk of breast cancer in PALB2 carriers,1 reviewed in this issue of The ASCO Post (page 47), is a contribution to the interesting history of the PALB2 gene, and an important milestone in the expansion of hereditary cancer susceptibility testing in the post-BRCA1/2 era.

PALB2 (partner and localizer of BRCA2, aka “pal of B2”) was identified by functional studies in the Livingston lab in 2006.2 It encodes a BRCA2 binding protein that serves as a critical DNA repair gene in the homologous recombination repair pathway. Soon after, PALB2 was shown to be a Fanconi anemia gene (FANCN)3 and was reported as a susceptibility gene in BRCA1/2-negative hereditary breast cancer families4 with a founder mutation in the Finnish population,5 setting the standard for criteria for the identification of new breast cancer susceptibility genes.

In another pioneering study, the Vogelstein group identified PALB2 by complete exomic sequencing of the germ lines of probands from hereditary pancreatic cancer families.6 It has been disappointing that the prevalence of PALB2 mutations among both breast/pancreatic and pancreatic cancer families is low.

International Collaboration

In the study by Antoniou and colleagues, PALB2 is again leading the way. The study represents an international collaboration of breast cancer geneticists who contributed their PALB2 families. The analysis provides important data on which to base genetic counseling for individuals and families found to carry germline PALB2 mutations.

Despite the identification of PALB2 families in 2007, commercial testing for PALB2 mutations only recently became widely available with the introduction of breast cancer susceptibility gene panels. These include genes beyond the initial higher penetrance group, BRCA1, BRCA2, TP53, PTEN, CDH1, and STK11, for which lifetime breast cancer risks were approximately 40% or greater. Concerns have been raised about the use of these panels, which include increasing numbers of so-called “moderate penetrance” genes for which epidemiology studies have not yet provided clear penetrance estimates.7,8

The lack of stable cancer risk estimates often leaves patients and their health-care providers in the unsettling position of trying to extrapolate risk management options from data gathered over 20 years from the thousands of BRCA1- and ­BRCA2-mutation carriers in epidemiologic and clinical studies for these very high-penetrance genes. This should be unsettling in the era of data-driven care.

Research Paradigm

The Antoniou et al paper allows PALB2 to emerge from the pack, and again provides a paradigm for the genes to come after. The investigators used modern modified segregation analysis in 311 women and 51 men with mutations to account for family aggregation, and included only definitive mutations. They estimated that cumulative breast cancer risks among female mutation carriers were 14% by age 50 and 35% by age 70, considerably higher than U.S. risks (2% by age 50 and 12% by age 90 years).

Most relevant for clinical counseling, they estimated a 33% (95% confidence interval [CI] = 25%–44%) absolute risk of breast cancer by age 70 in those without family breast cancer history, but 58% (95% CI = 50%–66%) in those with two or more first-degree relatives with breast cancer diagnosed by age 50 years. Examination of breast cancer subtypes was limited to 129 cases, showing a small excess of triple-negative breast cancers (30%), with the remainder being hormone receptor–positive.

An excess of ovarian cancer could not be documented, and no pancreatic cancer data were provided. The authors are careful to say that ovarian cancer risk may still be increased, but the excess may not be high enough to have been observed in this relatively small cohort.

Essential Data Contribution

In addition to important data for counseling individuals with PALB2 mutations, what should we take away from the Antoniou publication? First, valuable data came from the pooled study of only 311 probands. It is going to be absolutely essential for individuals found to carry mutations in the even less prevalent genes included in current and future panels to contribute their data to such efforts, so that we can provide reliable estimates of cancer risk as quickly as possible.

The cancer genetics research communities have long collaborated on studies of cancer risk, screening, prevention, and, most recently, treatment of these relatively rare populations would otherwise be impossible. Given that many of the genes in the panels are only rarely mutated, and since panel testing in the United States is increasingly used by physicians and genetic counselors outside of academic centers, many of the individuals who can contribute important data to these studies will not be coming through the usual paths to research.

Challenges may be different outside of the United States, where genetic testing is generally performed within specialized health-care settings linked to research, but the decisions about which genes to include may be more complex. In the US, at least, it will be more important than ever for physicians and genetic counselors to encourage their patients to contribute to research on their genes, and for the academic community to find creative ways to expand its reach and provide easier ways for individuals and families tested in the broader community to contribute their data to these efforts.

The City of Hope network, the ENIGMA consortium, and the PROMPT project will provide essential early routes. The testing laboratories must also contribute to these efforts, sharing their data on mutations and variants and providing other support as appropriate.

Penetrance Estimates

It is also interesting that the penetrance estimates for PALB2 are high enough to place it above the “moderate penetrance” group. It is difficult to predict what the cancer risks will be for the other genes yet to be more fully evaluated, and we cannot and should not guess the numbers, the range of tumors, or the implications for management of the cancer risks.

Only rigorous and careful study will provide reliable data on which we can base recommendations for management of our patients found to carry these mutations. Those studies will require the same kind of meticulous data collection and follow-up that have been devoted to BRCA1/2 mutations, even though these mutations will be less prevalent. Our patients and their families deserve no less. ■

Disclosure: Dr. Garber has received research funding from Myriad Genetics Laboratories, Ambry Genetics, Novartis Pharmaceuticals, and Astra Zeneca and is a consultant for Pfizer.


1. Antoniou AC, Casadei S, Heikkinen T, et al: Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497-506, 2014.

2. Xia B, Sheng Q, Nakanishi K, et al: Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell 22:719-729, 2006.

3. Xia B, Dorsman JC, Ameziane N, et al: Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet 29:159-161, 2007.

4. Tischkowitz M, Xia B, Sabbaghian N, et al: Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci USA 104:6788-6793, 2007.

5. Erkko H, Xia B, Nikkilä J, et al: A recurrent mutation in PALB2 in Finnish cancer families. Nature 446:316-319, 2007.

6. Jones S, Hruban RH, Kamiyama M, et al: Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324:217, 2009.

7. Domchek SM, Bradbury A, Garber JE, et al: Multiplex genetic testing for cancer susceptibility. J Clin Oncol 31:1267-1270, 2013.

8. Robson M: Multigene panel testing: Planning the next generation of research studies in clinical cancer genetics. J Clin Oncol 32:1987-1989, 2014.


Dr. Garber is Director, Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, and Professor of Medicine, Harvard Medical School, Boston.

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