全基因组二代测序及甲基化芯片法在探明肠癌患者个体化分子标记物中的应用
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摘要
大肠癌是全世界范围内主要致死性疾病之一,转移性结直肠癌的高发病率和较差预后使寻求与疗效、预后密切相关的分子标记物的需求变得非常紧迫。全基因组分析可测定与疾病发生、严重性密切相关,并可导致基因功能丧失的序列改变。同时,表观遗传学修饰,如DNA甲基化,被认为在许多种恶性肿瘤中广泛存在。而亚洲大肠癌患者的甲基化状态仍有待进一步研究。在此,我们报道应用全基因组外显子区域二代测序的方法来测定关键基因的重要突变状态,以及采用全基因组甲基化芯片的方法来测定肠癌特征性的甲基化谱改变。
第一部分：Ion Torrent二代测序平台对肠癌外显子区域体细胞突变的测定以及关键性药物靶向基因的筛选
方法：
收集福尔马林固定石蜡包埋的转移性结直肠癌患者活检标本,应用Ion AmpliSeqTM肿瘤基因列表进行检测。该列表被设计用来检测46个癌基因和抑癌基因中604个位点的739种突变。我们应用Ion的个体化基因组仪@(PGMTM)系统来运行整个反应,并且仅用到低至10纳克的DNA.之后样本经过含有最新版Ampliseq变异识别插件的Ion Torrent软件包分析。Ingenuity软件被用于信号通路分析。Cox回归被用来分析有效率,无病生存时间,总生存时间等临床因素和突变数量的潜在关系。
结果：
(1)在10例标本中,我们在根据dbSNP数据库剔除了正常突变后,共在24个基因中发现了65个异常突变。其中35%的突变基因可以在COSMIC数据库(癌症体细胞突变目录)中找到。经过单因素回归分析,并未发现任何临床因素和患者的突变数量有关。
(2)值得注意的是,有包括意料之中的APC, BRAF, KRAS, PK3CA和TP53等基因在内的11个基因,每个基因至少在2个样本中有表达。Ingenuity信号通路分析证明了“结直肠癌转移信号通路“是主要的固有突变途径。分析更进一步揭示了显著活跃的包括Wnt, PI3K/AKT和TGF-beta/SMAD等在内的经典信号通路及其突变的基因。
(3)有趣的是,90%的样本含有至少一个可以被作为药靶的基因突变(1到6个不等),而所有该类型突变均有相应的靶向药物或正在进行临床试验的新型靶向治疗的选择。这些药物和靶向基因的组合包括：vemurafenib和BRAF;西妥昔单抗和表皮生长因子受体；palifermin和FGFR2; pazopanib和FGFR3;AEE788和KDR以及BEZ235和PIK3CA..
第二部分：Illumina的HumanMethylation27芯片平台对肠癌DNA甲基化谱的测定以及显著异常甲基化基因的筛选
方法：
肿瘤以及相对应的正常癌旁组织由大肠癌患者手术标本获取。基因组DNA被分离并进行亚硫酸氢盐转化。此后即以Illumina公司的Infinium HumanMethylation27BeadChip平台进行DNA甲基化谱的比较分析。
结果：
(1)两个肠癌标本中分别发现了258个和74个,与相应的正常癌旁组织相比,异常甲基化的基因。CMTM2, ECRG4和SH3GL3等三个基因被发现其高甲基化位点在启动子区域,而该三个基因已被前期研究证明与大肠癌生物学行为密切相关。
(2)在应用热图聚类分析后,发现有8个高甲基化和10个低甲基化基因在肿瘤组织中达到了显著不同于正常癌旁组织的表观遗传学状态改变。
结论：
(1)对于癌基因和抑癌基因的二代测序,可在单个结直肠癌患者中探明宜作为药物作用靶点的一个或多个关键突变,凸显了该技术在肿瘤个体化治疗时代的巨大优势和广阔前景。
(2)对肿瘤细胞的快速和同时性全基因组甲基化谱分析可以灵敏的发现甲基化生物标记,为特异性诊断和预后判断服务。我们的研究显示了现代甲基化高通量芯片技术在探明肠癌潜在甲基化生物标记方面可能发挥的重要作用。
Colorectal cancer is one of the leading causes of mortality worldwide. The frequency and poor prognosis in patients with metastasis colorectal cancer (mCRC) emphasizes the need for better markers usable for both treatment and prognosis. Genome wide analysis studies have identified sequence mutations causing loss-of-function that are associated with disease occurrence and severity. Epigenetic modifications, such DNA methylation, have also been implicated in many cancers but have yet to be examined in the East Asian population of colorectal cancer patients. Here we described an approach of identifying whole genomic variants in exon regions of key genes. Meanwhile, we used genome-wide methylation chip to analysis the characteristic methylation profiles of colorectal cancer patients.
Part one:"Druggable" alterations of somatic mutation in exon region detected by Ion Torrent in metastasis colorectal cancer patients
Methods:
Formalin-fixed paraffin embedded (FFPE) metastasis colorectal cancer patients biopsy tissue were collected. Ion AmpliSeqTM Cancer Panel was designed to detect739COSMIC mutations in604loci from46oncogenes and tumor suppressor genes. We applied the Ion Personal Genome Machine(?)(PGMTM) System to run the whole reaction by using only as little as lOng of input DNA. Samples were then analyzed by the Ampliseq Variant Caller plug-in within the newest version of the Ion Torrent Suite Software. Ingenuity Pathway Software was used to do pathway analysis. Cox regression analysis was tested regarding the potential relationship between the alteration numbers and the clinical factors including response rate, disease free survival and overall survival, etc.
Results:
(1) Among10specimens, we identified65genetic alterations in24genes after excluding the germline mutations according the dbSNP database.35%of those alterations were also present in the COSMIC database (Catalogue of Somatic Mutations in Cancer). No clinical factor was found to be significantly associated with the alteration numbers in patients by univariate analysis.
(2) Notably, there are11genes including the expected APC, BRAF, KRAS, PIK3CA and TP53that were mutated in at least2samples. Pathway analysis identified "Colorectal Cancer Metastasis Signaling" as the top mutated canonical pathway. This analysis further revealed mutated genes in the classic signal pathways of Wnt, PI3K/AKT, and TGF-beta/SMAD as significantly present.
(3) Interestingly,90%of CRCs (9out of10) harbored at least one "druggable" alteration (range from1-6)that has been linked to a clinical treatment option or is currently being investigated in clinical trials of new targeted therapies. Those pairs of drug and targeted genes are vemurafenib to BRAF; cetuximab to EGFR; palifermin to FGFR2; pazopanib to FGFR3; AEE788to KDR and BEZ235to PIK3CA.
Part two:Using Illumina HumanMethylation27Chip based platform to detect the methylation profiles and the significant abrant methylated genes of colorectal cancer patients
Methods:
Biopsies of tumors and matched non-cancerous tissue types were obtained from colorectal cancer patients. Genomic DNA was isolated and subjected to the bisulphite conversion method for comparative DNA methylation analysis on the Illumina Infinium HumanMethylation27BeadChip.
Results:
(1) A total of258and74genes were found to be differentially methylated in the two tumor tissues, respectively, as compared to the individual's matched control tissue. Interestingly, the three genes that exhibited hypermethylation in their promoter regions, CMTM2, ECRG4, and SH3GL3, are known to be significantly associated with colorectal cancer in previous studies.
(2) Using heatmap cluster analysis, eight hypermethylated and10hypomethylated genes were identified as significantly differentially methylated genes in the tumour tissues.
Conclusions:
(1) DNA deep sequencing of key oncogenes and tumor suppressors enables identification of "druggable" mutations for individual colorectal cancer patients. Our study reveals the Next Generation Sequencing' great advantage and hopeful perspective in the era of individualized medicine.
(2) Genome-wide methylation profiling facilitates the rapid and simultaneous analysis of cancerous cells which may help to identify methylation markers with high sensitivity and specificity for diagnosis and prognosis. Our results show the promise of the microarray technology in identification of potential methylation biomarkers for colorectal cancers.
第一部分：Ion Torrent二代测序平台对肠癌外显子区域体细胞突变的测定以及关键性药物靶向基因的筛选
方法：
收集福尔马林固定石蜡包埋的转移性结直肠癌患者活检标本,应用Ion AmpliSeqTM肿瘤基因列表进行检测。该列表被设计用来检测46个癌基因和抑癌基因中604个位点的739种突变。我们应用Ion的个体化基因组仪@(PGMTM)系统来运行整个反应,并且仅用到低至10纳克的DNA.之后样本经过含有最新版Ampliseq变异识别插件的Ion Torrent软件包分析。Ingenuity软件被用于信号通路分析。Cox回归被用来分析有效率,无病生存时间,总生存时间等临床因素和突变数量的潜在关系。
结果：
(1)在10例标本中,我们在根据dbSNP数据库剔除了正常突变后,共在24个基因中发现了65个异常突变。其中35%的突变基因可以在COSMIC数据库(癌症体细胞突变目录)中找到。经过单因素回归分析,并未发现任何临床因素和患者的突变数量有关。
(2)值得注意的是,有包括意料之中的APC, BRAF, KRAS, PK3CA和TP53等基因在内的11个基因,每个基因至少在2个样本中有表达。Ingenuity信号通路分析证明了“结直肠癌转移信号通路“是主要的固有突变途径。分析更进一步揭示了显著活跃的包括Wnt, PI3K/AKT和TGF-beta/SMAD等在内的经典信号通路及其突变的基因。
(3)有趣的是,90%的样本含有至少一个可以被作为药靶的基因突变(1到6个不等),而所有该类型突变均有相应的靶向药物或正在进行临床试验的新型靶向治疗的选择。这些药物和靶向基因的组合包括：vemurafenib和BRAF;西妥昔单抗和表皮生长因子受体；palifermin和FGFR2; pazopanib和FGFR3;AEE788和KDR以及BEZ235和PIK3CA..
第二部分：Illumina的HumanMethylation27芯片平台对肠癌DNA甲基化谱的测定以及显著异常甲基化基因的筛选
方法：
肿瘤以及相对应的正常癌旁组织由大肠癌患者手术标本获取。基因组DNA被分离并进行亚硫酸氢盐转化。此后即以Illumina公司的Infinium HumanMethylation27BeadChip平台进行DNA甲基化谱的比较分析。
结果：
(1)两个肠癌标本中分别发现了258个和74个,与相应的正常癌旁组织相比,异常甲基化的基因。CMTM2, ECRG4和SH3GL3等三个基因被发现其高甲基化位点在启动子区域,而该三个基因已被前期研究证明与大肠癌生物学行为密切相关。
(2)在应用热图聚类分析后,发现有8个高甲基化和10个低甲基化基因在肿瘤组织中达到了显著不同于正常癌旁组织的表观遗传学状态改变。
结论：
(1)对于癌基因和抑癌基因的二代测序,可在单个结直肠癌患者中探明宜作为药物作用靶点的一个或多个关键突变,凸显了该技术在肿瘤个体化治疗时代的巨大优势和广阔前景。
(2)对肿瘤细胞的快速和同时性全基因组甲基化谱分析可以灵敏的发现甲基化生物标记,为特异性诊断和预后判断服务。我们的研究显示了现代甲基化高通量芯片技术在探明肠癌潜在甲基化生物标记方面可能发挥的重要作用。
Colorectal cancer is one of the leading causes of mortality worldwide. The frequency and poor prognosis in patients with metastasis colorectal cancer (mCRC) emphasizes the need for better markers usable for both treatment and prognosis. Genome wide analysis studies have identified sequence mutations causing loss-of-function that are associated with disease occurrence and severity. Epigenetic modifications, such DNA methylation, have also been implicated in many cancers but have yet to be examined in the East Asian population of colorectal cancer patients. Here we described an approach of identifying whole genomic variants in exon regions of key genes. Meanwhile, we used genome-wide methylation chip to analysis the characteristic methylation profiles of colorectal cancer patients.
Part one:"Druggable" alterations of somatic mutation in exon region detected by Ion Torrent in metastasis colorectal cancer patients
Methods:
Formalin-fixed paraffin embedded (FFPE) metastasis colorectal cancer patients biopsy tissue were collected. Ion AmpliSeqTM Cancer Panel was designed to detect739COSMIC mutations in604loci from46oncogenes and tumor suppressor genes. We applied the Ion Personal Genome Machine(?)(PGMTM) System to run the whole reaction by using only as little as lOng of input DNA. Samples were then analyzed by the Ampliseq Variant Caller plug-in within the newest version of the Ion Torrent Suite Software. Ingenuity Pathway Software was used to do pathway analysis. Cox regression analysis was tested regarding the potential relationship between the alteration numbers and the clinical factors including response rate, disease free survival and overall survival, etc.
Results:
(1) Among10specimens, we identified65genetic alterations in24genes after excluding the germline mutations according the dbSNP database.35%of those alterations were also present in the COSMIC database (Catalogue of Somatic Mutations in Cancer). No clinical factor was found to be significantly associated with the alteration numbers in patients by univariate analysis.
(2) Notably, there are11genes including the expected APC, BRAF, KRAS, PIK3CA and TP53that were mutated in at least2samples. Pathway analysis identified "Colorectal Cancer Metastasis Signaling" as the top mutated canonical pathway. This analysis further revealed mutated genes in the classic signal pathways of Wnt, PI3K/AKT, and TGF-beta/SMAD as significantly present.
(3) Interestingly,90%of CRCs (9out of10) harbored at least one "druggable" alteration (range from1-6)that has been linked to a clinical treatment option or is currently being investigated in clinical trials of new targeted therapies. Those pairs of drug and targeted genes are vemurafenib to BRAF; cetuximab to EGFR; palifermin to FGFR2; pazopanib to FGFR3; AEE788to KDR and BEZ235to PIK3CA.
Part two:Using Illumina HumanMethylation27Chip based platform to detect the methylation profiles and the significant abrant methylated genes of colorectal cancer patients
Methods:
Biopsies of tumors and matched non-cancerous tissue types were obtained from colorectal cancer patients. Genomic DNA was isolated and subjected to the bisulphite conversion method for comparative DNA methylation analysis on the Illumina Infinium HumanMethylation27BeadChip.
Results:
(1) A total of258and74genes were found to be differentially methylated in the two tumor tissues, respectively, as compared to the individual's matched control tissue. Interestingly, the three genes that exhibited hypermethylation in their promoter regions, CMTM2, ECRG4, and SH3GL3, are known to be significantly associated with colorectal cancer in previous studies.
(2) Using heatmap cluster analysis, eight hypermethylated and10hypomethylated genes were identified as significantly differentially methylated genes in the tumour tissues.
Conclusions:
(1) DNA deep sequencing of key oncogenes and tumor suppressors enables identification of "druggable" mutations for individual colorectal cancer patients. Our study reveals the Next Generation Sequencing' great advantage and hopeful perspective in the era of individualized medicine.
(2) Genome-wide methylation profiling facilitates the rapid and simultaneous analysis of cancerous cells which may help to identify methylation markers with high sensitivity and specificity for diagnosis and prognosis. Our results show the promise of the microarray technology in identification of potential methylation biomarkers for colorectal cancers.
引文
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