Clustered 8-Oxo-Guanine Mutations and Oncogenic Gene Fusions in Microsatellite-Unstable Colorectal Cancer.
Clustered 8-Oxo-Guanine Mutations and Oncogenic Gene Fusions in Microsatellite-Unstable Colorectal Cancer.
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DOI：
10.1200/po.21.00477
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发表时间：
2022-05
影响因子：
4.6
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中科院分区：
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具有微卫星不稳定性（MSI）的结直肠癌（CRC）富含致癌激酶融合（KFs），包括NTRK 1，RET和BRAF，但这一发现的机制尚不清楚。分析了32，218例晚期CRC肿瘤标本的基因组图谱，以评估微卫星稳定和微卫星不稳定CRC中致癌改变（包括KF）的融合断点。分析这种改变的基因组背景以获得机制见解。基因组分析表明，在MSI肿瘤致癌融合断点不优先涉及重复或低复杂性序列。相反，它们的连接区域显示出明显的鸟嘌呤和胞嘧啶偏置，并且在G：C背景下突变频率升高。相关内含子中G：C碱基突变频率升高可预测MSI CRC中相关致癌融合的患病率。具有错配修复特征的CRC富集了产丁酸盐的微生物物种，据报道与肠道中8-氧代鸟嘌呤病变的诱导相关。MSI相关KFs中断点的详细分析支持一种模型，其中MSI CRC中微生物组诱导的簇状8-氧代鸟嘌呤损伤的修复和/或处理效率低下导致特定致癌融合的发生率增加。
Colorectal carcinomas (CRCs) with microsatellite-instability (MSI) are enriched for oncogenic kinase fusions (KFs), including NTRK1, RET, and BRAF, but the mechanism underlying this finding is unclear. The genomic profiles of 32,218 advanced CRC tumor specimens were analyzed to assess the fusion breakpoints of oncogenic alterations including KFs in microsatellite-stable and microsatellite-unstable CRC. Genomic contexts of such alterations were analyzed to obtain mechanistic insights. Genomic analysis demonstrated that oncogenic fusion breakpoints in MSI tumors do not preferentially involve repetitive or low-complexity sequences. Instead, their junction regions showed pronounced guanine and cytosine bias and elevated mutation frequency at G:C contexts. Elevated mutation frequency at G:C bases in relevant introns predicted prevalence of associated oncogenic fusions in MSI CRCs. CRCs harboring mismatch repair signatures had enrichment of butyrate-producing microbial species, reported to be associated with induction of 8-oxoguanine lesions in the intestine. Detailed analysis of breakpoints in MSI-associated KFs support a model in which inefficient repair and/or processing of microbiome-induced clustered 8-oxoguanine damage in MSI CRC contributes to the increased incidence of specific oncogenic fusions.