Wei Christina Hsiao, Wang Edward Wenge, Ma Lingzi, Zhou Yajing, Zheng Li, Hampel Heather, Shehayeb Susan, Lee Stephen, Cohen Joshua, Kohut Adrian, Fan Fang, Rosen Steven, Wu Xiwei, Shen Binghui, Zhao Yuqi
Department of Pathology, City of Hope Medical Center (COHNMC), Duarte, CA 91010, USA.
Department of Oncology & Therapeutics Research, City of Hope Medical Center (COHNMC), Duarte, CA 91010, USA.
Cancers (Basel). 2023 Nov 30;15(23):5674. doi: 10.3390/cancers15235674.
Mutations in the DNA polymerase delta 1 (POLD1) exonuclease domain cause DNA proofreading defects, hypermutation, hereditary colorectal and endometrial cancer, and are predictive of immunotherapy response. Exonuclease activity is carried out by two magnesium cations, bound to four highly conserved, negatively charged amino acids (AA) consisting of aspartic acid at amino acid position 316 (p.D316), glutamic acid at position 318 (p.E318), p.D402, and p.D515 (termed DEDD motif). Germline polymorphisms resulting in charge-discordant AA substitutions in the DEDD motif are classified as variants of uncertain significance (VUSs) by laboratories and thus would be considered clinically inactionable. We hypothesize this mutation class is clinically pathogenic.
A review of clinical presentation was performed in our index patient with a POLD1(p.D402N) heterozygous proband with endometrial cancer. Implications of this mutation class were evaluated by a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review, in silico analysis with orthogonal biochemical confirmation, and whole-exome and RNA sequencing analysis of the patient's tumor and engineered cell lines.
Our systematic review favored a Mendelian disease mutation class associated with endometrial and colorectal cancers. In silico analysis predicted defective protein function, confirmed by biochemical assay demonstrating loss of nuclease activity. A -specific mutational signature was found in both the patient's tumor and (p.D402N) overexpressing cell. Furthermore, paired whole-exome/transcriptome analysis of endometrial tumor demonstrated hypermutation and T cell-inflamed gene expression profile (GEP), which are joint predictive biomarkers for pembrolizumab. Our patient showed a deep, durable response to immune checkpoint inhibitor (ICI).
Charge-discordant AA substitution in the DEDD motif of is detrimental to DNA proofreading and should be reclassified as likely pathogenic and possibly predictive of ICI sensitivity.
DNA聚合酶δ1（POLD1）核酸外切酶结构域的突变会导致DNA校对缺陷、高突变、遗传性结直肠癌和子宫内膜癌，并且可预测免疫治疗反应。核酸外切酶活性由两个镁离子介导，这两个镁离子与四个高度保守的带负电荷氨基酸（AA）结合，这些氨基酸包括位于氨基酸位置316（p.D316）的天冬氨酸、位置318（p.E318）的谷氨酸、p.D402和p.D515（称为DEDD基序）。导致DEDD基序中电荷不一致的AA替换的种系多态性被实验室归类为意义未明的变异（VUS），因此在临床上被认为是不可采取行动的。我们假设这类突变具有临床致病性。
对我们索引患者（患有子宫内膜癌的POLD1（p.D402N）杂合先证者）的临床表现进行了回顾。通过系统评价和Meta分析的首选报告项目（PRISMA）指导的系统评价、计算机模拟分析及正交生化确认以及对患者肿瘤和工程细胞系的全外显子组和RNA测序分析，评估了这类突变的影响。
我们的系统评价支持与子宫内膜癌和结直肠癌相关的孟德尔疾病突变类型。计算机模拟分析预测蛋白质功能存在缺陷，生化分析证实核酸酶活性丧失，从而验证了这一预测。在患者肿瘤和（p.D402N）过表达细胞中均发现了特定的突变特征。此外，对子宫内膜肿瘤的配对全外显子组/转录组分析显示存在高突变和T细胞炎性基因表达谱（GEP），这是帕博利珠单抗的联合预测生物标志物。我们的患者对免疫检查点抑制剂（ICI）表现出深度、持久的反应。
POLD1的DEDD基序中电荷不一致的AA替换对DNA校对有害，应重新归类为可能致病，并可能预测ICI敏感性。
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