肺腺癌预后相关的临床病理因素分析及分子病理研究
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摘要
为满足临床预后评估和个体化治疗的需求,以TNM分期和形态学为基础寻找可以预警预后的病理特征和分子标记是肺腺癌研究亟待解决的问题。本研究入组263例手术切除且有完整随访记录的肺腺癌病例,按UICC/AJCC第7版TNM分期标准和肺腺癌IASLC/ATS/ERS新分类标准对肿瘤分期和组织学分类再评估；构建组织芯片,在组织芯片平台上利用免疫组织化学方法检测Napsin A、 TTF-1、ERCC1、RRM1、EGFR野生型、EGFR exon21和exon19突变型、ERa、ERβ、PR、HER2和Bcl-2蛋白在肺腺癌中的表达；利用微阵列比较基因组杂交(array CGH)技术分析32例Ⅰ期肺腺癌福尔马林固定石蜡包埋(FFPE)组织基因组DNA改变。旨在获得与肺腺癌预后相关的形态学特征、免疫标记物表达特点,并试图从肺腺癌组织“DNA片段拷贝数变化谱型”中筛选出一组有鉴别意义的扩增或缺失基因/染色体区段作为肺腺癌预后相关的分子标志。
第一部分分析肺腺癌临床病理特征与预后关系。结果显示,263例肺腺癌5年总生存率为73.2%,按第7版TNM分期标准Ⅰ-Ⅳ期5年总生存率分别为89.2%、63.4%、37.0%和0,按第6版分期标准Ⅰ-Ⅳ期5年总生存率分别为86.9%、47.4%、40.5%和9.1%,差异均有统计学意义,P<0.001,分期间生存率差异在第7版更显著。单因素生存分析显示,总生存与肿瘤大小(2cm为截点)、分化程度、2011组织学新分类、核分裂数、坏死、胸膜侵犯和脉管瘤栓相关,无病生存与肿瘤大小、分化程度、核分裂数和脉管瘤栓相关,均P<0.05；以5%和30%为截点的附壁样(lepidic)生长方式含量可划分3个临床结局显著不同的预后组,P<0.05。多因素生存分析显示,第6及第7版TNM分期、核分裂数、脉管瘤栓和附壁样(lepidic)生长方式含量是总生存相关的独立预后因素,第6及第7版TNM分期、核分裂数、脉管瘤栓和术后辅助治疗是无病生存相关的独立预后因素。
第二部分探讨12项免疫标记物在肺腺癌中的表达及与预后的关系。结果显示,基于组织芯片平台的12项标记物免疫组化检测有效率为91.2%～95.6%;单因素生存分析：Napsin A、TTF-1和ERCC1表达与总生存有关,均为阳性组预后好,P<0.05；TTF-1表达还与无病生存有关,P<0.05。但多因素生存分析结果显示,12种标记物均非肺腺癌的独立预后因素。
第三部分利用array CGH技术分析32例Ⅰ期肺腺癌基因组DNA拷贝数改变。结果显示,5q22.3-q23.1、9p24.1、15ql4-ql5.1缺失和6p21.22-p21.32、7p14.1-p13、7q21.3-q22.1、8p11.21、8q22.2.11q22.1-q22.3、11q13、11q13.1-q13.2、17q12、17ql2-q21.2以及17q21.2-q21.31扩增是与I期肺腺癌肿瘤进展相关,P<0.001。上述染色体片段包含244个已知的基因,基因功能集中在NFκB结合、金属肽酶活性等22种生物学功能。后续基因挑选及验证工作正在进行。
本研究结论：与第6版TNM分期标准相比,第7版分期标准能为患者提供更准确的预后信息；2011肺腺癌IASLC/ATS/ERS多学科新分类标准显示了预后分组优势,但非独立预后因素；以5%和30%为截点的附壁样(lepidic)生长方式含量是本组病例的独立预后因素；Napsin A、TTF-1和ERCC1表达均提示患者预后好,但均非独立预后因素,可作为相同分期患者预后评价的辅助分层指标。5q22.3-q23.1、9p24.1、15ql4-q15.1缺失和6p21.22-p21.32、7p14.1-p137q21.3-q22.1、8p11.21、8q22.2、11q22.1-q22.3、11q13.1、11ql3.1-q13.2、17q12、17q12-q21.2以及17q21.2-q21.31扩增可能与I期肺腺癌预后有关,染色体11q22.1-q22.3扩增及位于该区段的MMPs、BIRC家族及YAP1基因更值得关注,有必要进一步验证及深入研究。
To meet the needs of assessment for clinical outcomes and individualized treatment, looking for pathological and molecular prognostic factors of lung adenocarcinoma based on TNM staging and morphology is a critical problem to be solved. In this study, a total of263cases who were underwent surgical resection and followed-up at least5years were re-classified according to UICC/AJCC7th edition of TNM staging system and2011IASLC/ATS/ERS international multidisciplinary classification; Immunohistochemistry were performed on tissue microarray platform to detect expression of Napsin A, TTF-1, ERCC1, RRM1, total EGFR, EGFR special for exon21and exonl9mutant, ERα, ERβ1,PR, HER2, Bcl-2protein in lung adenocarcinoma;31cases of stage I were analyzed by array comparative genomic hybridization (array CGH). In the current study, morphological characteristics and expression of immune markers were analyzed to evaluate the relationship with prognosis in lung adenocarcinoma. We also attempt to pick up a cluster of gene/chromosome fragment with amplification or deletion from the "DNA copy number variation (CNV) profiles" as molecular markers specialized in predicting.
The first part was analysis of the clinicopathology features related to prognosis. The results showed that5-year overall survival (OS) rate of263cases was73.2%, according to the7th edition TNM classification,5-year OS rates for Ⅰ-Ⅳ stages were89.2%,63.4%,37.0%and0respectively, as to the6th edition, they were86.9%,47.4%,40.5%and9.1%respectively. Difference between the two editions was statistically significant, P<0.001; According to univariate survival analysis, tumor size, degree of differentiation, the new IASLC/ATS/ERS classification, mitotic count, necrosis, pleural invasion, and vascular invasion were associated with overall survival. Tumor size, degree of differentiation, mitotic count and tumor embolus also related to disease-free survival, P<0.05; Cutoffs of5%and30%for lepidic growth pattern component can stratify patients into three groups with significantly different clinical outcom, P<0.05. Multivariate survival analysis showed that,6th and7th edition TNM staging, mitotic count, tumor embolus and lepidic growth pattern were independent prognostic factors for overall survival; The two editions TNM staging, mitotic count, vascular invasion and postoperative adjuvant therapy were independent prognostic factors related to disease-free survival.
In the second part, we analysed expression of12immune markers in lung adenocarcinoma. The results showed that, efficiency of immunohistochemistry test on tissue microarray platform were91.2%-95.6%; By univariate survival analysis: Napsin A, TTF-1and ERCC1expression associated with longer overall survival (P<0.05), TTF-1expression related to longer disease-free survival, P<0.05. By multivariate survival analysis, all12markers were not independent prognostic factors for lung adenocarcinoma.
Genomic DNA copy number variations were analysed on FFPE tissue of31stage Ⅰ cases using array CGH technology in the third part. The results showed that,5q22.3-q23.1,9p24.1,15q14-q15.1deletion and6p21.22-p21.32,7p14.1-p13,7q21.3-q22.1,8p11.21,8q22.2,11q22.1-q22.3,11q13.1,11q13.1-q13.2,17q12,17q12-q21.2and17q21.2-q21.31amplification were chromosome fragments associated with prognosis of stage Ⅰ lung adenocarcinoma. There were244known genes existed in the above fragments, gene functions concentrated in biological functions such as NFkB binding and metalloendopeptidase activity et al. Selection of genes of interest and validation work are in progress.
In conclusion, compared with the6th edition, the7th TNM staging system was better in reflecting the different prognosis of patients with the same stage and could provide more accurate prognostic information;2011IASLC/ATS/ERS international multidisciplinary classification for lung adenocarcinoma showed an advantage in prognostic grouping, but not an independent prognostic factor; Cutoff of5%and30%for lepidic growth pattern was independent prognostic factor in the current patients; Napsin A, TTF-1and ERCC1expression prompted better prognosis, but none of them was not an independent prognostic factor, they could be viewed as assistant index to stratify patients of the same stage into different prognostic group. Chromosome fragments5q22.3-q23.1,9p24.1,15q14-q15.1deletion and6p21.22-p21.32,7p14.1-p13,7q21.3-q22.1,8p11.21,8q22.2,11q22.1-q22.3,11q13.1,11q13.1-q13.2,17q12,17q12-q21.2and17q21.2-q21.31amplification were associated with the poor prognosis of stage Ⅰ lung adenocarcinoma, chromosome fragment11q22.1-q22.3amplification and genes located in the section such as MMPs, BIRC family and YAP1were worth for more attention and further validation and study are needed.
第一部分分析肺腺癌临床病理特征与预后关系。结果显示,263例肺腺癌5年总生存率为73.2%,按第7版TNM分期标准Ⅰ-Ⅳ期5年总生存率分别为89.2%、63.4%、37.0%和0,按第6版分期标准Ⅰ-Ⅳ期5年总生存率分别为86.9%、47.4%、40.5%和9.1%,差异均有统计学意义,P<0.001,分期间生存率差异在第7版更显著。单因素生存分析显示,总生存与肿瘤大小(2cm为截点)、分化程度、2011组织学新分类、核分裂数、坏死、胸膜侵犯和脉管瘤栓相关,无病生存与肿瘤大小、分化程度、核分裂数和脉管瘤栓相关,均P<0.05；以5%和30%为截点的附壁样(lepidic)生长方式含量可划分3个临床结局显著不同的预后组,P<0.05。多因素生存分析显示,第6及第7版TNM分期、核分裂数、脉管瘤栓和附壁样(lepidic)生长方式含量是总生存相关的独立预后因素,第6及第7版TNM分期、核分裂数、脉管瘤栓和术后辅助治疗是无病生存相关的独立预后因素。
第二部分探讨12项免疫标记物在肺腺癌中的表达及与预后的关系。结果显示,基于组织芯片平台的12项标记物免疫组化检测有效率为91.2%～95.6%;单因素生存分析：Napsin A、TTF-1和ERCC1表达与总生存有关,均为阳性组预后好,P<0.05；TTF-1表达还与无病生存有关,P<0.05。但多因素生存分析结果显示,12种标记物均非肺腺癌的独立预后因素。
第三部分利用array CGH技术分析32例Ⅰ期肺腺癌基因组DNA拷贝数改变。结果显示,5q22.3-q23.1、9p24.1、15ql4-ql5.1缺失和6p21.22-p21.32、7p14.1-p13、7q21.3-q22.1、8p11.21、8q22.2.11q22.1-q22.3、11q13、11q13.1-q13.2、17q12、17ql2-q21.2以及17q21.2-q21.31扩增是与I期肺腺癌肿瘤进展相关,P<0.001。上述染色体片段包含244个已知的基因,基因功能集中在NFκB结合、金属肽酶活性等22种生物学功能。后续基因挑选及验证工作正在进行。
本研究结论：与第6版TNM分期标准相比,第7版分期标准能为患者提供更准确的预后信息；2011肺腺癌IASLC/ATS/ERS多学科新分类标准显示了预后分组优势,但非独立预后因素；以5%和30%为截点的附壁样(lepidic)生长方式含量是本组病例的独立预后因素；Napsin A、TTF-1和ERCC1表达均提示患者预后好,但均非独立预后因素,可作为相同分期患者预后评价的辅助分层指标。5q22.3-q23.1、9p24.1、15ql4-q15.1缺失和6p21.22-p21.32、7p14.1-p137q21.3-q22.1、8p11.21、8q22.2、11q22.1-q22.3、11q13.1、11ql3.1-q13.2、17q12、17q12-q21.2以及17q21.2-q21.31扩增可能与I期肺腺癌预后有关,染色体11q22.1-q22.3扩增及位于该区段的MMPs、BIRC家族及YAP1基因更值得关注,有必要进一步验证及深入研究。
To meet the needs of assessment for clinical outcomes and individualized treatment, looking for pathological and molecular prognostic factors of lung adenocarcinoma based on TNM staging and morphology is a critical problem to be solved. In this study, a total of263cases who were underwent surgical resection and followed-up at least5years were re-classified according to UICC/AJCC7th edition of TNM staging system and2011IASLC/ATS/ERS international multidisciplinary classification; Immunohistochemistry were performed on tissue microarray platform to detect expression of Napsin A, TTF-1, ERCC1, RRM1, total EGFR, EGFR special for exon21and exonl9mutant, ERα, ERβ1,PR, HER2, Bcl-2protein in lung adenocarcinoma;31cases of stage I were analyzed by array comparative genomic hybridization (array CGH). In the current study, morphological characteristics and expression of immune markers were analyzed to evaluate the relationship with prognosis in lung adenocarcinoma. We also attempt to pick up a cluster of gene/chromosome fragment with amplification or deletion from the "DNA copy number variation (CNV) profiles" as molecular markers specialized in predicting.
The first part was analysis of the clinicopathology features related to prognosis. The results showed that5-year overall survival (OS) rate of263cases was73.2%, according to the7th edition TNM classification,5-year OS rates for Ⅰ-Ⅳ stages were89.2%,63.4%,37.0%and0respectively, as to the6th edition, they were86.9%,47.4%,40.5%and9.1%respectively. Difference between the two editions was statistically significant, P<0.001; According to univariate survival analysis, tumor size, degree of differentiation, the new IASLC/ATS/ERS classification, mitotic count, necrosis, pleural invasion, and vascular invasion were associated with overall survival. Tumor size, degree of differentiation, mitotic count and tumor embolus also related to disease-free survival, P<0.05; Cutoffs of5%and30%for lepidic growth pattern component can stratify patients into three groups with significantly different clinical outcom, P<0.05. Multivariate survival analysis showed that,6th and7th edition TNM staging, mitotic count, tumor embolus and lepidic growth pattern were independent prognostic factors for overall survival; The two editions TNM staging, mitotic count, vascular invasion and postoperative adjuvant therapy were independent prognostic factors related to disease-free survival.
In the second part, we analysed expression of12immune markers in lung adenocarcinoma. The results showed that, efficiency of immunohistochemistry test on tissue microarray platform were91.2%-95.6%; By univariate survival analysis: Napsin A, TTF-1and ERCC1expression associated with longer overall survival (P<0.05), TTF-1expression related to longer disease-free survival, P<0.05. By multivariate survival analysis, all12markers were not independent prognostic factors for lung adenocarcinoma.
Genomic DNA copy number variations were analysed on FFPE tissue of31stage Ⅰ cases using array CGH technology in the third part. The results showed that,5q22.3-q23.1,9p24.1,15q14-q15.1deletion and6p21.22-p21.32,7p14.1-p13,7q21.3-q22.1,8p11.21,8q22.2,11q22.1-q22.3,11q13.1,11q13.1-q13.2,17q12,17q12-q21.2and17q21.2-q21.31amplification were chromosome fragments associated with prognosis of stage Ⅰ lung adenocarcinoma. There were244known genes existed in the above fragments, gene functions concentrated in biological functions such as NFkB binding and metalloendopeptidase activity et al. Selection of genes of interest and validation work are in progress.
In conclusion, compared with the6th edition, the7th TNM staging system was better in reflecting the different prognosis of patients with the same stage and could provide more accurate prognostic information;2011IASLC/ATS/ERS international multidisciplinary classification for lung adenocarcinoma showed an advantage in prognostic grouping, but not an independent prognostic factor; Cutoff of5%and30%for lepidic growth pattern was independent prognostic factor in the current patients; Napsin A, TTF-1and ERCC1expression prompted better prognosis, but none of them was not an independent prognostic factor, they could be viewed as assistant index to stratify patients of the same stage into different prognostic group. Chromosome fragments5q22.3-q23.1,9p24.1,15q14-q15.1deletion and6p21.22-p21.32,7p14.1-p13,7q21.3-q22.1,8p11.21,8q22.2,11q22.1-q22.3,11q13.1,11q13.1-q13.2,17q12,17q12-q21.2and17q21.2-q21.31amplification were associated with the poor prognosis of stage Ⅰ lung adenocarcinoma, chromosome fragment11q22.1-q22.3amplification and genes located in the section such as MMPs, BIRC family and YAP1were worth for more attention and further validation and study are needed.
引文
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