The p.Ser64Leu and p.Pro104Leu missense variants of PALB2 identified in familial pancreatic cancer patients compromise the DNA damage response Journal Article


Authors: Zhang, Y.; Park, J. Y.; Zhang, F.; Olson, S. H.; Orlow, I.; Li, Y.; Kurtz, R. C.; Ladanyi, M.; Chen, J.; Toland, A. E.; Zhang, L.; Andreassen, P. R.
Article Title: The p.Ser64Leu and p.Pro104Leu missense variants of PALB2 identified in familial pancreatic cancer patients compromise the DNA damage response
Abstract: 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. © 2020 Wiley Periodicals LLC
Keywords: homologous recombination; pancreatic cancer; palb2; variant of uncertain significance; functional studies; missense variants
Journal Title: Human Mutation
Volume: 42
Issue: 2
ISSN: 1059-7794
Publisher: Wiley Liss  
Date Published: 2021-02-01
Start Page: 150
End Page: 163
Language: English
DOI: 10.1002/humu.24133
PUBMED: 33169439
PROVIDER: scopus
PMCID: PMC7997419
DOI/URL:
Notes: Article -- Export Date: 1 March 2021 -- Source: Scopus
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MSK Authors
  1. Sara H Olson
    229 Olson
  2. Liying Zhang
    121 Zhang
  3. Irene Orlow
    221 Orlow
  4. Marc Ladanyi
    1140 Ladanyi
  5. Robert C Kurtz
    177 Kurtz
  6. Yirong Li
    11 Li