Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Cancer Res Commun. 2023 Apr 24;3(4):684-696. doi: 10.1158/2767-9764.CRC-22-0364. eCollection 2023 Apr.
Gastrointestinal stromal tumors (GIST) with exon 11 deletions involving in codons 557-558 ( Δ557-558) exhibit higher proliferation rates and shorter disease-free survival times compared with GISTs with other exon 11 mutations. We analyzed 30 GIST cases and observed genomic instability and global DNA hypomethylation only in high-risk malignant GISTs with Δ557-558. Whole-genome sequencing revealed that the high-risk malignant GISTs with Δ557-558 (12 cases) had more structural variations (SV), single-nucleotide variants, and insertions and deletions compared with the low-risk, less malignant GISTs with Δ557-558 (six cases) and the high-risk (six cases) or low-risk (6 cases) GISTs with other exon 11 mutations. The malignant GISTs with Δ557-558 showed higher frequency and significance in copy number (CN) reduction on chromosome arms 9p and 22q, and 50% of them had LOH or CN-dependent expression reduction in . In addition, SVs with driver potential were detected in 75% of them, in which and were recurrently identified. Genome-wide DNA methylation and gene expression analyses showed global intergenic DNA hypomethylation, upregulation, and higher expression signatures, including p53 inactivation and chromosomal instability, as characteristics of malignant GISTs with Δ557-558 that distinguished them from other GISTs. These genomic and epigenomic profiling results revealed that Δ557-558 mutations are associated with increased genomic instability in malignant GISTs.
We present genomic and epigenomic insights into the malignant progression of GISTs with exon 11 deletions involving in 557-558, demonstrating their unique chromosomal instability and global intergenic DNA hypomethylation.
与其他外显子 11 突变的 GIST 相比，涉及密码子 557-558（Δ557-558）的外显子 11 删除的胃肠道间质瘤（GIST）具有更高的增殖率和更短的无病生存期。我们分析了 30 例 GIST 病例，仅在具有 Δ557-558 的高危恶性 GIST 中观察到基因组不稳定性和全基因组 DNA 低甲基化。全基因组测序显示，与具有 Δ557-558 的低风险、低恶性 GIST（6 例）和具有其他外显子 11 突变的高危（6 例）或低危（6 例）GIST 相比，具有 Δ557-558 的高危恶性 GIST 具有更多的结构变异（SV）、单核苷酸变异、插入和缺失。Δ557-558 的恶性 GIST 显示染色体臂 9p 和 22q 上的拷贝数（CN）减少频率和意义更高，其中 50%的 GIST 存在 LOH 或 CN 依赖性表达减少。此外，在其中 75%的恶性 GIST 中检测到具有潜在驱动能力的 SV，其中 和 被反复鉴定。全基因组 DNA 甲基化和基因表达分析显示全基因组基因间 DNA 低甲基化、上调和更高的表达特征，包括 p53 失活和染色体不稳定，这是具有 Δ557-558 的恶性 GIST 的特征，使其与其他 GIST 区分开来。这些基因组和表观基因组分析结果表明，Δ557-558 突变与恶性 GIST 的基因组不稳定性增加有关。
我们对外显子 11 缺失涉及 557-558 的 GIST 的恶性进展进行了基因组和表观基因组分析，证明了它们独特的染色体不稳定性和全基因组基因间 DNA 低甲基化。
