Wu Shijie, Qi Lina, Chen Huihui, Zhang Kun, He Jiapan, Guo Xianan, Shen Lu, Zhou Yunxiang, Zhong Xi, Zheng Shu, Zhou Jiaojiao, Chen Yiding
Department of Breast Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
NPJ Breast Cancer. 2022 Jul 19;8(1):86. doi: 10.1038/s41523-022-00454-6.
Germline PALB2 pathogenic variants are associated with an increased lifetime risk for breast, pancreatic, and ovarian cancer. However, the interpretation of the pathogenicity of numerous PALB2 missense variants of uncertain significance (VUSs) identified in germline genetic testing remains a challenge. Here we selected ten potentially pathogenic PALB2 VUSs identified in 2279 Chinese patients with breast cancer and evaluated their impacts on PALB2 function by systematic functional assays. We showed that three PALB2 VUSs p.K16M [c.47 A > T], p.L24F [c.72 G > C], and p.L35F [c.103 C > T] in the coiled-coil domain impaired PALB2-mediated homologous recombination. The p.L24F and p.L35F variants partially disrupted BRCA1-PALB2 interactions, reduced RAD51 foci formation in response to DNA damage, abrogated ionizing radiation-induced G2/M checkpoint maintenance, and conferred increased sensitivity to olaparib and cisplatin. The p.K16M variant presented mild effects on BRCA1-PALB2 interactions and RAD51 foci formation. Altogether, we identify two novel PALB2 VUSs, p.L24F and p.L35F, that compromise PALB2 function and may increase cancer risk. These two variants display marked olaparib and cisplatin sensitivity and may help predict response to targeted therapy in the clinical treatment of patients with these variants.
种系 PALB2 致病变异与乳腺癌、胰腺癌和卵巢癌的终身风险增加相关。然而，在种系基因检测中鉴定出的众多意义未明的 PALB2 错义变异（VUS）的致病性解释仍然是一项挑战。在此，我们选择了在 2279 例中国乳腺癌患者中鉴定出的 10 个潜在致病性 PALB2 VUS，并通过系统的功能分析评估了它们对 PALB2 功能的影响。我们发现，卷曲螺旋结构域中的 3 个 PALB2 VUS，即 p.K16M [c.47 A > T]、p.L24F [c.72 G > C] 和 p.L35F [c.103 C > T]，损害了 PALB2 介导的同源重组。p.L24F 和 p.L35F 变异部分破坏了 BRCA1-PALB2 相互作用，减少了 DNA 损伤后 RAD51 焦点的形成，消除了电离辐射诱导的 G2/M 检查点维持，并增加了对奥拉帕尼和顺铂的敏感性。p.K16M 变异对 BRCA1-PALB2 相互作用和 RAD51 焦点形成呈现轻微影响。总之，我们鉴定出两个新的 PALB2 VUS，即 p.L24F 和 p.L35F，它们损害 PALB2 功能并可能增加癌症风险。这两个变异显示出明显的奥拉帕尼和顺铂敏感性，可能有助于预测携带这些变异的患者在临床治疗中对靶向治疗的反应。
