PALB2

  • Partner and localizer of BRCA2 (PALB2)
  • Gene location: chromosome 16p12.2

Biology

  • The PALB2 gene, located on chromosome 16p12.2, encodes the PALB2 protein.1
  • PALB2 is a key member of the homologous recombination repair (HRR) protein family, which is characterized by an N-terminal coiled-coil domain essential for protein-protein interactions within the DNA repair complex.1
  • PALB2 functions as a central scaffold protein that bridges and stabilizes the interaction between BRCA1 and BRCA2 at sites of DNA double-strand breaks (DSBs). It facilitates recruitment of RAD51 recombinase, enabling accurate repair of DSBs through homologous recombination and maintaining genomic stability and preventing oncogenic transformation.2,3
  • Loss-of-function mutations in PALB2 compromise the HRR pathway, resulting in the accumulation of unrepaired DNA damage and genomic instability, thereby increasing the risk of cancer development.2,4
  • BRCA1 and BRCA2 both rely on PALB2 to mediate direct binding to areas of DNA repair, as BRCA2 is unable to efficiently react to DNA damage without PALB2 acting as a central docking station for all 3 components (BRCA1-BRCA2-RAD51).3

Etiology and Epidemiology

  • Germline PALB2 mutations are observed in approximately 1% to 3% of pancreatic cancer patients, making PALB2 the second most frequently mutated gene in hereditary PDAC after BRCA2.5,6 These mutations confer an estimated 2% to 5% lifetime risk for developing pancreatic cancer.6
  • Identification of PALB2 mutations in patients with PDAC has diagnostic, prognostic, and therapeutic significance. Carriers of the PALB2 mutation may benefit from targeted therapies (eg, PARP inhibitors and platinum-based chemotherapy) that exploit homologous recombination deficiency.6,7

Testing

When to Test:

  • Testing for PALB2 mutations is recommended in individuals with a family history of breast, pancreatic, or ovarian cancer, as these cancers are frequently associated with PALB2 pathogenic variants.8-10
  • PALB2 testing is also considered when BRCA1/2 testing is negative, but hereditary pancreatic cancer risk remains high based on family history. Testing is typically done as part of a broader multigene panel to assess other relevant genes.11

Available Testing Methods:

  • Next-generation sequencing (NGS) is the primary approach used for detecting PALB2 mutations. NGS allows simultaneous analysis of multiple genes and detects single nucleotide variants and small insertions/deletions efficiently and cost-effectively.12
  • Multiplex ligation-dependent probe amplification (MLPA) complements NGS by detecting large genomic deletions or duplications in PALB2 not identified by sequencing alone. MLPA uses synthetic probes and electrophoresis to compare gene dosage with reference samples.13
  • MLPA is typically a secondary test used if NGS does not detect pathogenic variants but clinical suspicion remains.13
  • After detecting PALB2 mutations, patients may be referred for pancreatic cancer screening via imaging modalities such as magnetic resonance cholangiopancreatography or endoscopic ultrasound, depending on personal and family cancer history.6

Guideline Recommendations:

  • NCCN Guidelines (version 2.2025) recommend genetic testing for PALB2 mutations in individuals with personal or family histories indicative of hereditary breast and pancreatic cancer syndromes.6
  • Patients identified as carriers of the mutation should receive comprehensive counseling regarding their elevated risk of PALB2-associated malignancies and appropriate cancer screening recommendations.6
  • For individuals with a significant family history suggestive of hereditary cancer predisposition, multigene panel testing—including PALB2, BRCA1, BRCA2, ATM, CHEK2, TP53, and other relevant genes—is strongly advised.6

Targeted Therapy

Investigational Agents/Strategies:

  • Platinum Chemotherapy (Cisplatin)14,15
    • Mechanism of action:
      • Cisplatin is a platinum-based chemotherapeutic that forms DNA intra- and interstrand crosslinks, interfering with DNA replication and transcription.
      • In tumors with HRR deficiencies (eg, mutations of BRCA1, BRCA2, or PALB2), impaired DNA repair mechanisms lead to the accumulation of DNA damage, resulting in increased tumor cell death.
    • Investigational studies:
      • PLATINUM study14
        • ClinicalTrials.gov: NCT06115499
        • Study design: Phase 2/3 trial evaluating the efficacy of a triplet chemotherapy regimen (nab-paclitaxel, gemcitabine, and cisplatin) compared to the standard doublet regimen of nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer harboring a germline or somatic mutation in BRCA1, BRCA2, or PALB2.
  • PARP Inhibitors16,17
    • Mechanism of action:
      • Olaparib is a potent oral inhibitor of PARP enzymes, including PARP1, PARP2, and PARP3, which are involved in DNA damage detection and repair.
      • In tumors with HRR deficiencies, PARP inhibition leads to accumulation of DNA damage, replication stress, and, ultimately, synthetic lethality, resulting in tumor cell death.
    • Investigational studies:
      • APOLLO study16
        • ClinicalTrials.gov: NCT04858334
        • Study design: Phase 2 trial investigating how well the addition of olaparib following completion of surgery and chemotherapy works in treating patients with pancreatic cancer that has been surgically removed (resected) and have a pathogenic mutation in BRCA1, BRCA2, or PALB2.

References

  1. Park JY, Singh TR, Nassar N, et al. PALB2: the hub of a network of tumor suppressors involved in DNA damage responses. Biochim Biophys Acta. 2019;1871(1):59-73. doi:10.1016/j.bbcan.2014.06.003
  2. Oliver AW, Swift S, Lord CJ, Ashworth A, Pearl LH. Structural basis for recruitment of BRCA2 by PALB2. EMBO Rep. 2020;10(9):990-996. doi:10.1038/embor.2009.126
  3. Buisson R, Niraj J, Rodrigue A, et al. Cooperation of BRCA1 and PALB2 in the DNA damage response. Proc NatlAcad Sci U S A. 2020;117(8):4322-4331. doi:10.1073/pnas.1919573117
  4. Zhang J, Powell SN. The role of the BRCA1-PALB2-BRCA2 axis in homologous recombination DNA repair and cancer susceptibility. J Mol Biol. 2021;433(9):166839. doi:10.1016/j.jmb.2021.166839
  5. Jones S, Hruban RH, Kamiyama M, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324(5924):217. doi:10.1126/science.1171202
  6. NCCN Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 2.2025. Accessed July 25, 2025. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  7. Golan T, Kanji ZS, Epelbaum R, et al. Overall survival and clinical characteristics of pancreatic cancer in patients with germline BRCA mutations. Br J Cancer. 2014;111(6):1132-1138. doi:10.1038/bjc.2014.418
  8. NCCN. Clinical Practice Guidelines in Oncology. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic; version 2.2025. Accessed July 25, 2025. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
  9. Hu C, Hart SN, Polley EC, et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA. 2018;319(23):2401-2409. doi:10.1001/jama.2018.7714
  10. Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. CancerDiscov. 2012;2(1):41-46. doi:10.1158/2159-8290.CD-11-0194
  11. Lindor NM, Guidugli L, Wang X, et al. Multigene panel testing in clinical cancer genetics: insights and practical considerations. Front Genet. 2021;12:724404. doi:10.3389/fgene.2021.724404
  12. Møller P, Knudsen LB, Andersen MK, et al. Overview of hereditary cancer genetics and recommendations for testing. Scand J Clin Lab Invest Suppl. 2020;80(247):39-50. doi:10.1080/00365513.2020.1758727
  13. Brouwer J, Vink GR, van Os NJH, et al. MLPA analysis to detect large rearrangements in cancer predisposition genes. HumMutat. 2019;40(8):1004-1016. doi:10.1002/humu.23790
  14. The PLATINUM trial: optimizing chemotherapy for the second-line treatment of metastatic BRCA1/​2 or PALB2-associated metastatic pancreatic cancer. ClinicalTrials.gov. Updated April 2, 2025. Accessed July 25, 2025. https://clinicaltrials.gov/study/NCT06115499
  15. Cisplatin. Prescribing information. Pfizer; 2024. Accessed July 30, 2025. https://labeling.pfizer.com/ShowLabeling.aspx?id=12139
  16. APOLLO: a randomized phase II double-blind study of olaparib versus placebo following curative intent therapy in patients with resected pancreatic cancer and a pathogenic BRCA1, BRCA2 or PALB2 mutation. ClinicalTrials.gov. Updated July 22, 2025. Accessed July 25, 2025. https://clinicaltrials.gov/study/NCT04858334
  17. Lymparza. Prescribing information. AstraZeneca; 2025. Accessed July 25, 2025. https://drd9vrdh9yh09.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/00997c3f-5912-486f-a7db-930b4639cd51/00997c3f-5912-486f-a7db-930b4639cd51_viewable_rendition__v.pdf