Genomic Alterations of NTRK, POLE, ERBB2, and Microsatellite Instability Status in Chinese Patients with Colorectal Cancer.
Genomic Alterations of NTRK, POLE, ERBB2, and Microsatellite Instability Status in Chinese Patients with Colorectal Cancer.
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DOI：
10.1634/theoncologist.2020-0356
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发表时间：
2020-11
期刊：
影响因子：
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通讯作者：
Xiao M
中科院分区：
文献类型：
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作者：
Guo Y;Guo XL;Wang S;Chen X;Shi J;Wang J;Wang K;Klempner SJ;Wang W;Xiao M
结直肠癌（CRC）分子特征的增加促使人们需要超越RAS，BRAF和微卫星不稳定性（MSI）。基因组改变，包括ERBB 2扩增和突变，POLE突变，MSI和NTRK 1 -3融合，已成为匹配治疗的目标。我们试图研究一个经过基因组分析的临床注释的中国CRC队列，以探索相对靶频率。收集了609例中国CRC患者的肿瘤和匹配的全血。分析提取的DNA中450个癌症相关基因的所有类别的基因组改变，包括单核苷酸变异（SNV）、短和长插入和缺失（indel）、拷贝数变异和基因重排。基于下一代测序的计算算法还确定了肿瘤突变负荷和MSI状态。在中国CRC患者中，TP 53（76%）、APC（72%）和KRAS（46%）的改变是常见的。首次在MSI-高CRC队列中观察到NTRK基因融合的患病率约为7%。在整个队列中，9%的患者发现MSI，3%的患者发现ERBB 2扩增，1.5%的患者发现POLE致病突变。这些结果大多与西方患者中观察到的频率平行。然而，POLE以更高的频率存在，并且与大的肿瘤T细胞浸润相关。与西方同行相比，POLE突变在我们的队列中增加。NTRK基因融合的患病率在MSI-高CRC队列中约为7%。在亚洲患者中越来越多地采用分子谱分析对于改善治疗结果至关重要。在结直肠癌（CRC）中越来越多地使用基因组分析检测，可以识别出更多受益于匹配治疗的患者子集。随着治疗数量的增加，同时评价所有候选生物标志物的测定至关重要。本研究结果为中国结直肠癌患者基因组图谱的可行性和实用性提供了早期支持。精准医学的出现已经确定了基因组变异，如NTRK基因融合，微卫星不稳定性（MSI），HER 2扩增和POLE致病性突变，作为免疫或靶向治疗的潜在激动性生物标志物。本文研究了中国结直肠癌患者队列中的NTRK、HER 2和POLE。
The increasing molecular characterization of colorectal cancers (CRCs) has spurred the need to look beyond RAS, BRAF, and microsatellite instability (MSI). Genomic alterations, including ERBB2 amplifications and mutations, POLE mutations, MSI, and NTRK1–3 fusions, have emerged as targets for matched therapies. We sought to study a clinically annotated Chinese cohort of CRC subjected to genomic profiling to explore relative target frequencies. Tumor and matched whole blood were collected from 609 Chinese patients with CRC. Extracted DNA was analyzed for all classes of genomic alterations across 450 cancer‐related genes, including single‐nucleotide variations (SNVs), short and long insertions and deletions (indels), copy number variations, and gene rearrangements. Next‐generation sequencing–based computational algorithms also determined tumor mutational burden and MSI status. Alterations in TP53 (76%), APC (72%), and KRAS (46%) were common in Chinese patients with CRC. For the first time, the prevalence of NTRK gene fusion was observed to be around 7% in the MSI‐high CRC cohort. Across the cohort, MSI was found in 9%, ERBB2 amplification in 3%, and POLE pathogenic mutation in 1.5% of patients. Such results mostly parallel frequencies observed in Western patients. However, POLE existed at a higher frequency and was associated with large tumor T‐cell infiltration. Comparing to the Western counterparts, POLE mutations were increased in our cohort. The prevalence of NTRK gene fusion was around 7% in the MSI‐high CRC cohort. Increased adoption of molecular profiling in Asian patients is essential for the improvement of therapeutic outcomes. The increasing use of genomic profiling assays in colorectal cancer (CRC) has allowed for the identification of a higher number of patient subsets benefiting from matched therapies. With an increase in the number of therapies, assays simultaneously evaluating all candidate biomarkers are critical. The results of this study provide an early support for the feasibility and utility of genomic profiling in Chinese patients with CRC. The emergence of precision medicine has identified genomic variants, such as NTRK gene fusion, microsatellite instability (MSI), HER2 amplification, and POLE pathogenic mutation, as potential agonistic biomarkers for immune or targeted therapies. This article examines NTRK, HER2, and POLE in a cohort of Chinese patients with colorectal cancer.