Abdul Shafina-Nadiawati, Ab Mutalib Nurul-Syakima, Sean Khor S, Syafruddin Saiful E, Ishak Muhiddin, Sagap Ismail, Mazlan Luqman, Rose Isa M, Abu Nadiah, Mokhtar Norfilza M, Jamal Rahman
UKM Medical Molecular Biology InstituteUniversiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
Thermo Fisher ScientificShah Alam, Malaysia.
Front Pharmacol. 2017 Jul 18;8:465. doi: 10.3389/fphar.2017.00465. eCollection 2017.
Despite global progress in research, improved screening and refined treatment strategies, colorectal cancer (CRC) remains as the third most common malignancy. As each type of cancer is different and exhibits unique alteration patterns, identifying and characterizing gene alterations in CRC that may serve as biomarkers might help to improve diagnosis, prognosis and predict potential response to therapy. With the emergence of next generation sequencing technologies (NGS), it is now possible to extensively and rapidly identify the gene profile of individual tumors. In this study, we aimed to identify actionable somatic alterations in Dukes' B and C in CRC via NGS. Targeted sequencing of 409 cancer-related genes using the Ion Ampliseq Comprehensive Cancer Panel was performed on genomic DNA obtained from paired fresh frozen tissues, cancer and normal, of Dukes' B ( = 10) and Dukes' C ( = 9) CRC. The sequencing results were analyzed using Torrent Suite, annotated using ANNOVAR and validated using Sanger sequencing. A total of 141 somatic non-synonymous sequence variations were identified in 86 genes. Among these, 64 variants (45%) were predicted to be deleterious, 38 variants (27%) possibly deleterious while the other 39 variants (28%) have low or neutral protein impact. Seventeen genes have alterations with frequencies of ≥10% in the patient cohort and with 14 overlapped genes in both Dukes' B and C. The adenomatous polyposis coli gene (APC) was the most frequently altered gene in both groups ( = 6 in Dukes' B and C). In addition, was more frequently altered in Dukes' C ( = 7) compared to Dukes' B ( = 4). Ten variants in , namely p.R283, p.N778fs, p.R805, p.Y935fs, p.E941fs, p.E1057, p.I1401fs, p.Q1378, p.E1379, and p.A1485fs were predicted to be driver variants. APC remains as the most frequently altered gene in the intermediate stages of CRC. Wnt signaling pathway is the major affected pathway followed by P53, RAS, TGF-β, and PI3K signaling. We reported the alteration profiles in each of the patient which has the potential to affect the clinical decision. We believe that this study will add further to the understanding of CRC molecular landscape.
尽管在研究、改进筛查和优化治疗策略方面取得了全球进展，但结直肠癌（CRC）仍然是第三大常见恶性肿瘤。由于每种癌症都不同且表现出独特的改变模式，识别和表征CRC中可能作为生物标志物的基因改变可能有助于改善诊断、预后并预测对治疗的潜在反应。随着下一代测序技术（NGS）的出现，现在有可能广泛且快速地识别个体肿瘤的基因图谱。在本研究中，我们旨在通过NGS识别CRC中Dukes' B和C期的可操作体细胞改变。使用Ion Ampliseq Comprehensive Cancer Panel对409个癌症相关基因进行靶向测序，该测序是在从Dukes' B期（n = 10）和Dukes' C期（n = 9）CRC的配对新鲜冷冻组织（癌组织和正常组织）中获得的基因组DNA上进行的。测序结果使用Torrent Suite进行分析，使用ANNOVAR进行注释，并使用Sanger测序进行验证。在86个基因中总共鉴定出141个体细胞非同义序列变异。其中，64个变异（45%）被预测为有害，38个变异（27%）可能有害，而其他39个变异（28%）对蛋白质的影响较低或为中性。17个基因在患者队列中的改变频率≥10%，且在Dukes' B和C期有14个重叠基因。腺瘤性息肉病大肠杆菌基因（APC）是两组中改变最频繁的基因（Dukes' B和C期均为6例）。此外，与Dukes' B期（4例）相比，Dukes' C期（7例）中[此处原文缺失基因名称]的改变更频繁。[此处原文缺失基因名称]中的10个变异，即p.R283、p.N778fs、p.R805、p.Y935fs、p.E941fs、p.E1057、p.I1401fs、p.Q1378、p.E1379和p.A1485fs被预测为驱动变异。APC仍然是CRC中间阶段改变最频繁的基因。Wnt信号通路是主要受影响的通路，其次是P53、RAS、TGF-β和PI3K信号通路。我们报告了每个患者的改变图谱，这些图谱有可能影响临床决策。我们相信这项研究将进一步加深对CRC分子格局的理解。
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