PALB2

Overview

PALB2 (Partner And Localizer of BRCA2) encodes a protein that links BRCA1 and BRCA2 in the DNA double-strand break repair by homologous recombination. Germline pathogenic variants in PALB2 confer an intermediate-to-high lifetime risk of breast cancer and a significantly elevated risk of pancreatic ductal adenocarcinoma. Biallelic inactivation produces homologous recombination deficiency (HRD), which is the mechanistic basis for sensitivity to PARP inhibitors.

Alterations observed in the corpus

  • Germline pathogenic PALB2 variants detected in 0.5% (approximately 12/2,336) of PDAC patients in the MSK 2,336-patient cohort; listed among high/moderate-penetrance germline genes (BRCA2 3.7%, BRCA1 1.8%, ATM 1.8%, PALB2 0.5%). At least 1 PALB2-variant patient received durable PARPi benefit, indicating biallelic inactivation and HRD susceptibility. PALB2 included in the ~10% of PDAC patients with OncoKB level 1 or 2 actionable biomarkers. PMID:39753968
  • PALB2 assessed in gallbladder carcinoma (GBC) genomic landscape study as part of HRD gene panel PMID:36228155
  • Germline splice-site variant plus somatic missense mutation in 2 neuroblastoma patients; BRCA complex member; identified in Broad WES/WGS cohort of 240 high-risk neuroblastoma tumors PMID:23334666
  • Somatic mutation in 1/23 (4%) pancreatic acinar cell carcinomas; identified as a Fanconi-anemia-pathway member, flagging potential sensitivity to DNA cross-linking agents and PARP inhibitors PMID:24293293
  • Single frameshift mutation (suspected germline) identified in the sinonasal adenoid cystic carcinoma cohort; PALB2 is a known BRCA2-interacting genome stability gene PMID:24418857
  • Germline PALB2 mutations confer HBOC-spectrum risk including elevated gastric cancer susceptibility; must be ruled out before FNHGC labeling; included in standard multigene GC panel alongside BRCA1, BRCA2, ATM, and BRIP1 PMID:24816255
  • Part of the Fanconi anaemia (FA) pathway; homozygous deleterious events used as a DNA-repair-defect classifier for carboplatin sensitivity analysis in mCRPC; siRNA knockdown of FA genes (including PALB2) reduced proliferation in prostate cancer cell lines. PMID:26928463
  • Somatic mutations in 4% of metastatic breast cancer (mBC) vs 0.1% of early breast cancer (eBC) (FDR=0.006); authors propose PALB2-deficient mBC may be sensitive to PARP inhibitors such as olaparib PMID:28027327
  • TRMT10A expression correlated positively with PALB2 (along with BRCA1, BRCA2, RAD51) in TCGA prostate samples, linking PALB2 to the TRMT10A-dependent HR repair scaffold PMID:28068672
  • Less frequent DDR alteration in non-muscle-invasive bladder cancer (NMIBC; n=105), contributing to the 30% high-grade NMIBC DDR-altered fraction; markedly elevated mutational burden associated with DDR-altered tumors supports checkpoint immunotherapy trials PMID:28583311
  • Somatic HR pathway gene; CDK12, FANCA, PALB2, and RAD50 identified as additional somatic HR-deficiency contributors in advanced prostate cancer across locoregional, metastatic noncastrate, and mCRPC disease states; CDK12 loss hypothesized to confer PARP inhibitor sensitivity PMID:28825054
  • Nominated as a novel prostate-cancer-specific DNA-repair SMG in a WES meta-analysis of 1,013 primary and metastatic prostate tumors (prad_p1000); DNA-repair pathway altered in 16% of cases overall PMID:29610475.

Cancer types (linked)

  • PAAD: Germline PALB2 pathogenic variants in 0.5% of PDAC; constitutes an actionable HRD subgroup with potential PARPi benefit. PMID:39753968

Co-occurrence and mutual exclusivity

  • In PDAC, PALB2 carriers overlap with the broader HRD germline carrier landscape (BRCA1/2, ATM); biallelic inactivation is a prerequisite for PARPi sensitivity (parallel to the BRCA2 findings in the same cohort where biallelic loss was necessary but not sufficient for durable PARPi response). PMID:39753968

Therapeutic relevance

  • Germline PALB2 pathogenic variants with somatic second-hit (biallelic inactivation) in PDAC support PARP inhibitor eligibility; at least one patient in the MSK PDAC cohort achieved durable PARPi benefit. Better predictive biomarkers beyond biallelic inactivation status are still needed (6/16 biallelic BRCA2 PDAC patients did not respond to PARPi, suggesting the full HRD phenotype picture is incomplete). PMID:39753968

Open questions

  • Frequency of biallelic somatic inactivation in germline PALB2 carriers in PDAC, and whether this mirrors the BRCA2 pattern (strong selection for biallelic LOH), is not specifically reported in this cohort due to small numbers. PMID:39753968

Sources

This page was processed by entity-page-writer on 2026-05-15. - PMID:29610475

This page was processed by wiki-cli on 2026-05-15.