Ashktorab Hassan, Mokarram Pooneh, Azimi Hamed, Olumi Hasti, Varma Sudhir, Nickerson Michael L, Brim Hassan
Department of Medicine and Cancer Center, Howard University College of Medicine, Washington, DC, USA.
Current address: Department of Biochemistry, Shiraz University of Medical Sciences, Shiraz, Iran.
Oncotarget. 2017 Jan 31;8(5):7852-7866. doi: 10.18632/oncotarget.13977.
Next Generation Sequencing (NGS) is currently used to establish mutational profiles in many multigene diseases such as colorectal cancer (CRC), which is on the rise in many parts of the developing World including, Iran. Little is known about its genetic hallmarks in these populations.
To identify variants in 15 CRC-associated genes in patients of Iranian descent.
There were 51 validated variants distributed on 12 genes: 22% MSH3 (n = 11/51), 10% MSH6 (n = 5/51), 8% AMER1 (n = 4/51), 20% APC (n = 10/51), 2% BRAF (n = 1/51), 2% KRAS (n = 1/51), 12% PIK3CA (n = 6/51), 8% TGFβR2A (n = 4/51), 2% SMAD4 (n = 1/51), 4% SOX9 (n = 2/51), 6% TCF7L2 (n = 3/51), and 6% TP53 (n = 3/51). Most known and distinct variants were in mismatch repair genes (MMR, 32%) and APC (20%). Among oncogenes, PIK3CA was the top target (12%).
CRC specimens from 63 Shirazi patients were used to establish the variant' profile on an Ion Torrent platform by targeted exome sequencing. To rule-out technical artifacts, the variants were validated in 13 of these samples using an Illumina NGS platform. Validated variants were annotated and compared to variants from publically available databases. An in-silico functional analysis was performed. MSI status of the analyzed samples was established.
These results illustrate for the first time CRC mutational profile in Iranian patients. MSH3, MSH6, APC and PIK3CA genes seem to play a bigger role in the path to cancer in this population. These findings will potentially lead to informed genetic diagnosis protocol and targeted therapeutic strategies.
目前，新一代测序（NGS）技术被用于建立许多多基因疾病（如结直肠癌，在包括伊朗在内的许多发展中地区呈上升趋势）的突变图谱。对于这些人群中的遗传特征，人们了解甚少。
鉴定伊朗裔患者中15个与结直肠癌相关基因的变异。
共有51个经过验证的变异分布在12个基因上：错配修复蛋白3（MSH3，22%，n = 11/51）、错配修复蛋白6（MSH6，10%，n = 5/51）、轴蛋白1（AMER1，8%，n = 4/51）、腺瘤性息肉病蛋白（APC，20%，n = 10/51）、B-Raf原癌基因（BRAF，2%，n = 1/51）、K-Ras原癌基因（KRAS，2%，n = 1/51）、磷脂酰肌醇-3激酶催化亚基α（PIK3CA，12%，n = 6/51）、转化生长因子β受体2A（TGFβR2A，8%，n = 4/51）、Smad4蛋白（SMAD4，2%，n = 1/51）、性别决定区Y框蛋白9（SOX9，4%，n = 2/51）、转录因子7样蛋白2（TCF7L2，6%，n = 3/51）和抑癌基因p53（TP53，6%，n = 3/51）。大多数已知且独特的变异存在于错配修复基因（MMR，32%）和APC基因（20%）中。在癌基因中，PIK3CA是首要靶点（12%）。
使用来自63名设拉子患者的结直肠癌标本，通过靶向外显子组测序在Ion Torrent平台上建立变异图谱。为排除技术假象，在其中13个样本中使用Illumina NGS平台对变异进行验证。对经过验证的变异进行注释，并与公开数据库中的变异进行比较。进行了计算机功能分析。确定了所分析样本的微卫星不稳定性（MSI）状态。
这些结果首次阐明了伊朗患者的结直肠癌突变图谱。MSH3、MSH6、APC和PIK3CA基因在该人群的癌症发生过程中似乎发挥着更大作用。这些发现可能会促成明智的基因诊断方案和靶向治疗策略。
