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Ref Type Journal Article
PMID (33169439)
Authors Zhang Y, Park JY, Zhang F, Olson SH, Orlow I, Li Y, Kurtz RC, Ladanyi M, Chen J, Toland AE, Zhang L, Andreassen PR
Title The p.Ser64Leu and p.Pro104Leu missense variants of PALB2 identified in familial pancreatic cancer patients compromise the DNA damage response.
Journal Vol Issue Date Pages Journal Short Title
Human mutation 2020 Nov 10 150-163 Hum Mutat
URL
Abstract Text PALB2 has been identified as a breast and pancreatic cancer susceptibility gene. Utilizing a targeted sequencing approach, we discovered two novel germline missense PALB2 variants c.191C>T and c.311C>T, encoding p.Ser64Leu and p.Pro104Leu, respectively, in individuals in a pancreatic cancer registry. No missense PALB2 variants from familial pancreatic cancer patients, and few PALB2 variants overall, have been functionally characterized. Given the known role of PALB2, we tested the impact of p.Ser64Leu and p.Pro104Leu variants on DNA damage responses. Neither p.Ser64Leu nor p.Pro104Leu have clear effects on interactions with BRCA1 and KEAP1, which are mediated by adjacent motifs in PALB2. However, both variants are associated with defective recruitment of PALB2, and the RAD51 recombinase downstream, to DNA damage foci. Furthermore, p.Ser64Leu and p.Pro104Leu both largely compromise DNA double-strand break-initiated homologous recombination, and confer increased cellular sensitivity to ionizing radiation (IR) and the poly (ADP-ribose) polymerase (PARP) inhibitor Olaparib. Taken together, our results represent the first demonstration of functionally deleterious PALB2 missense variants associated with familial pancreatic cancer and of deleterious variants in the N-terminus outside of the coiled-coil domain. Furthermore, our results suggest the possibility of personalized treatments, using IR or PARP inhibitor, of pancreatic and other cancers that carry a deleterious PALB2 variant.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
PALB2 D134N missense no effect - predicted PALB2 D134N lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). D134N results in levels of homologous recombination (PMID: 33169439) and DNA damage-induced cell cycle checkpoint maintenance similar to wild-type protein, and does not demonstrate reduced homology-directed DNA repair activity in cultured cells lacking Tp53 (PMID: 31757951), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 E837* nonsense loss of function - predicted PALB2 E837* results in a premature truncation of the Palb2 protein at amino acid 837 of 1186 (UniProt.org). E837* results in impaired homologous recombination in cultured cells (PMID: 33169439), and therefore, is predicted to lead to a loss of Palb2 protein function.
PALB2 L337S missense no effect - predicted PALB2 L337S lies within the DNA-binding region of the Palb2 protein (UniProt.org). L337S does not demonstrate reduced homology-directed DNA repair activity compared to wild-type Palb2 in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951) and results in homologous recombination activity similar to wild-type in culture (PMID: 33169439), and therefore, is predicted to have no effect on Palb2 protein function.
PALB2 P104L missense loss of function PALB2 P104L lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). P104L retains the association with Brca1, Keap1, Rad51, and Rad51ap1, but results in decreased recruitment of Palb2 and Rad51 to nuclear foci, impaired homologous recombination, and failure to rescue PARP inhibitor sensitivity in PALB2-deficient cells in culture (PMID: 33169439).
PALB2 Q559R missense no effect PALB2 Q559R lies within the DNA-binding region of the Palb2 protein (UniProt.org). Q559R is a common Palb2 polymorphism (PMID: 23977390, PMID: 21165770), results in homologous recombination similar to wild-type Palb2 (PMID: 33169439, PMID: 33964450) and does not demonstrate reduced homology-directed DNA repair activity in cultured cells lacking Tp53 (PMID: 31636395, PMID: 31757951).
PALB2 R1086* nonsense loss of function - predicted PALB2 R1086* indicates a premature truncation of the Palb2 protein at amino acid 1086 of 1186 (UniProt.org). R1086* results in impaired homologous recombination in cultured cells (PMID: 33169439), and therefore, is predicted to lead to a loss of Palb2 protein function.
PALB2 R753* nonsense loss of function - predicted PALB2 R753* indicates a premature truncation of the Palb2 protein at amino acid 753 of 1186 (UniProt.org). R753* results in impaired homologous recombination in cultured cells (PMID: 33169439), and therefore, is predicted to lead to a loss of Palb2 protein function.
PALB2 S64L missense loss of function PALB2 S64L lies within the DNA-binding, and BRCA1 and RAD51-interacting regions of the Palb2 protein (UniProt.org). S64L retains the association with Brca1, Keap1, Rad51, and Rad51ap1, but results in decreased recruitment of Palb2 and Rad51 to nuclear foci, impaired homologous recombination, and failure to rescue PARP inhibitor sensitivity in PALB2-deficient cells in culture (PMID: 33169439).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PALB2 S64L Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment decreased viability of cells expressing PALB2 S64L in culture (PMID: 33169439). 33169439
PALB2 P104L Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment decreased viability of cells expressing PALB2 P104L in culture (PMID: 33169439). 33169439