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.

中文翻译：

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在家族性胰腺癌患者中发现的 PALB2 的 p.Ser64Leu 和 p.Pro104Leu 错义变体损害 DNA 损伤反应

PALB2已被鉴定为乳腺癌和胰腺癌易感基因。利用靶向测序方法，我们发现了两个新的种系错义PALB2变异 c.191C>T 和 c.311C>T，分别在胰腺癌登记中的个体中编码 p.Ser64Leu 和 p.Pro104Leu。没有来自家族性胰腺癌患者的错义 PALB2 变体，并且总体上很少有 PALB2 变体具有功能特征。鉴于 PALB2 的已知作用，我们测试了 p.Ser64Leu 和 p.Pro104Leu 变体对 DNA 损伤反应的影响。p.Ser64Leu 和 p.Pro104Leu 对与 BRCA1 和 KEAP1 的相互作用都没有明显的影响，这是由 PALB2 中的相邻基序介导的。然而，这两种变异都与 PALB2 和下游 RAD51 重组酶向 DNA 损伤灶的募集缺陷有关。此外，p.Ser64Leu 和 p.Pro104Leu 都在很大程度上损害了 DNA 双链断裂引发的同源重组，并赋予细胞对电离辐射 (IR) 和聚 (ADP-核糖) 聚合酶 (PARP) 抑制剂奥拉帕尼的敏感性增加。总之，我们的结果首次证明了与家族性胰腺癌相关的功能性有害 PALB2 错义变异以及卷曲螺旋结构域外 N 末端的有害变异。此外，我们的研究结果表明，使用 IR 或 PARP 抑制剂对胰腺癌和其他携带有害物质的癌症进行个性化治疗的可能性PALB2变体。