■体质错配修复缺陷(CMMRD)是一种癌症易感性,由于与癌症早期发作相关的错配修复(MMR)基因之一的双等位基因突变,尤其是高级别胶质瘤.我们的目的是破译这些神经胶质瘤的分子特异性。
■临床,组织病理学,分析了12例遗传证明为CMMRD和高级别神经胶质瘤的儿童的全外显子组测序数据.
■PDL1表达在50%的样品中存在于免疫组织化学中。在9名患者中,神经胶质瘤具有超超突变表型(每Mb编码104-635个编码单核苷酸变体(SNV),中位数204)。分别为8名和1名患者描述了POLE和POLD1外切核酸酶结构域中的驱动突变,并且始终存在于具有最高变异等位基因频率(VAF)的突变爆发中。突变特征由MMR相关的特征主导,并且在同一患者的不同突变爆发中相似,而随后没有POL驱动的突变特征的富集。具有高于每Mb的驱动聚合酶突变之一的VAF的编码SNV的中值数目为57(17-191)。我们的发现表明,体细胞聚合酶改变并不能完全解释超超突变表型。SETD2,TP53,NF1,EPHB2,PRKDC,与有害的体细胞聚合酶突变相比,DICER1基因经常具有更高的VAF突变。
■CMMRD相关神经胶质瘤具有特定的肿瘤发生,不涉及在散发性儿童或成人胶质母细胞瘤中常见的通路和突变。其他途径如MAPK的频繁改变可能提示使用其他靶向疗法以及PD1抑制剂。
UNASSIGNED: Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition due to biallelic mutations in one of the mismatch repair (MMR) genes associated with early onset of cancers, especially high-grade gliomas. Our aim was to decipher the molecular specificities of these gliomas.
UNASSIGNED: Clinical, histopathological, and whole exome sequencing data were analyzed in 12 children with genetically proven CMMRD and a high-grade glioma.
UNASSIGNED: PDL1 expression was present in immunohistochemistry in 50% of the samples. In 9 patients, the glioma harbored an ultra-hypermutated phenotype (104-635 coding single nucleotide variants (SNV) per Mb, median 204). Driver mutations in POLE and POLD1 exonuclease domains were described for 8 and 1 patients respectively and were always present in the mutation burst with the highest variant allele frequency (VAF). The mutational signatures were dominated by MMR-related ones and similar in the different mutation bursts of a same patient without subsequent enrichment of the mutation signatures with POL-driven ones. Median number of coding SNV with VAF above one of the driving polymerase mutation per Mb was 57 (17-191). Our findings suggest that somatic polymerase alterations does not entirely explain the ultra-hypermutant phenotype. SETD2, TP53, NF1, EPHB2, PRKDC, and DICER1 genes were frequently mutated with higher VAF than the deleterious somatic polymerase mutation.
UNASSIGNED: CMMRD-associated gliomas have a specific oncogenesis that does not involve usual pathways and mutations seen in sporadic pediatric or adult glioblastomas. Frequent alterations in other pathways such as MAPK may suggest the use of other targeted therapies along with PD1 inhibitors.