Abstract P3-05-01: Molecular effects of surgical resection on primary breast tumor

Sudeep Gupta, R. Chaubal, N. Gardi, Sunil Pachakar, Dimple R. Bhatia, P. Gera, N. Nair, S. Joshi, V. Parmar, P. Thakkar, G. Chitkara, Rasika Kadam, S. Gujarathi, H. Oza, R. Hawaldar, V. Vanmali, K. Buetow, A. Dutt, R. Badwe
{"title":"Abstract P3-05-01: Molecular effects of surgical resection on primary breast tumor","authors":"Sudeep Gupta, R. Chaubal, N. Gardi, Sunil Pachakar, Dimple R. Bhatia, P. Gera, N. Nair, S. Joshi, V. Parmar, P. Thakkar, G. Chitkara, Rasika Kadam, S. Gujarathi, H. Oza, R. Hawaldar, V. Vanmali, K. Buetow, A. Dutt, R. Badwe","doi":"10.1158/1538-7445.SABCS19-P3-05-01","DOIUrl":null,"url":null,"abstract":"Rationale: Surgery results in rapid and progressively severe exposure of tumor tissue to hypoxia, up to the point of complete removal, but its effect on tumor gene expression is not well characterized. We document the molecular effects of surgery on primary breast cancer tumor with a serial tissue sampling strategy, including an intra-operative sample. Methods: We included treatment naive, non-metastatic breast cancer patients and sampled tumor and tumour adjacent normal tissue during surgery at three time points: beginning of surgery (Sample A), after half the tumor circumference had been devascularized (Sample B) and from completely resected tumor (Sample C). Patients were divided into two groups: discovery and validation. Tumor or adjacent normal samples from the discovery group underwent whole transcriptome paired-end sequencing (RNA-Seq) generating at least 50 million reads using next generation sequencing. Findings from discovery group were evaluated in a validation group using qRT-PCR and Nanostring nCounter gene expression profiling. Results: 81 breast cancer patients were eligible for this study of whom 46 with at least 1 quality passed sample at time-point A, B or C comprised the discovery group whose samples underwent RNA-seq. Validation group comprised two subsets: 35 independent patients (8 patients’ samples qRT-PCR, data included here; 27 patients’ samples nCounter gene expression, data will be presented) and 17 patients from discovery group whose samples also underwent nCounter gene expression profiling (data will be presented). Individual patient based analyses for A vs B vs C in discovery group revealed 249 significantly de-regulated genes in at least 20% of patients, in at least one comparison (AvB or BvC or AvC). Genes involved in stress response (FOSB, FOS, JUN, JUNB, DUSP1, CYR61, EGR1-3, ATF3, RGS1, RGS2), inflammation (IL20, IL8, SOCS3, GABRP, PIGR, NR4A1-2, CCL2- 3, CCL21, CCL14, CCL18-19, CXCL2, CXCL9-10, CXCL14), invasion & migration (PTGS2, MMP9-13), lipid metabolism (CD36, LIPE, TAT, FABP4, PLIN1, PLIN4, LPL, LEP), epithelial markers (KRT5, KRT7, KRT14-17, KRT23, KRT6A-6B) and cellular differentiation(SOX10, LRP2, S100A2, S100A7-A9, S100B, S100P) were significantly deregulated at time-point B versus A and many of these genes were also significantly deregulated in C versus A comparison, suggesting sustained deregulation through surgical resection. Replicative analysis involving comparison of tumors grouped by time points (A vs B vs C) identified 192 genes uniquely de-regulated in any one of the 3 comparisons, of which 42 overlapped with patient-wise analysis. These 42 genes included all the AP-1 transcription factor network signaling genes, epithelial markers (KRT14, KRT6A), inflammation related genes (SOCS3, PIGR, GABRP, NR4A1, NR4A2), lipid metabolism related genes (PLIN1) and cellular differentiation & cell fate related genes (SOX10, LRP2). Pathway analyses will be presented. qRT-PCR on paired samples in 8 independent patients validated the differential expression of eight genes in either AvB or AvC or both comparisons: FOS, FOSB, JUNB, DUSP1, RGS1, NR4A2, ZFP36, andMMP13. Comparison of biopsy (corresponding to A) with surgical samples (corresponding to C) in 6 cancer types (breast, cervical, lymphoma, mesothelioma, esophageal and sarcoma) in TCGA studies showed statistically significant de-regulation of 11 AP-1 transcription factor network signaling related genes in at least 4 cancers, further validating our experimental results. Conclusions: Our experiment, uniquely including an intra-operative tumor sample, shows that surgical removal induces a conserved stress response in the primary tumor that is potentially capable of bestowing metastatic capability on the tumor cells. Citation Format: Sudeep Gupta, Rohan Chaubal, Nilesh Gardi, Sunil Pachakar, Dimple Bhatia, Poonam Gera, Nita Nair, Shalaka Joshi, Vani Parmar, Purvi Thakkar, Garvit Chitkara, Rasika Kadam, Sejal Gujarathi, Harsh Oza, Rohini Hawaldar, Vaibhav Vanmali, Kenneth Buetow, Amit Dutt, Rajendra Badwe. Molecular effects of surgical resection on primary breast tumor [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. 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引用次数: 1

Abstract

Rationale: Surgery results in rapid and progressively severe exposure of tumor tissue to hypoxia, up to the point of complete removal, but its effect on tumor gene expression is not well characterized. We document the molecular effects of surgery on primary breast cancer tumor with a serial tissue sampling strategy, including an intra-operative sample. Methods: We included treatment naive, non-metastatic breast cancer patients and sampled tumor and tumour adjacent normal tissue during surgery at three time points: beginning of surgery (Sample A), after half the tumor circumference had been devascularized (Sample B) and from completely resected tumor (Sample C). Patients were divided into two groups: discovery and validation. Tumor or adjacent normal samples from the discovery group underwent whole transcriptome paired-end sequencing (RNA-Seq) generating at least 50 million reads using next generation sequencing. Findings from discovery group were evaluated in a validation group using qRT-PCR and Nanostring nCounter gene expression profiling. Results: 81 breast cancer patients were eligible for this study of whom 46 with at least 1 quality passed sample at time-point A, B or C comprised the discovery group whose samples underwent RNA-seq. Validation group comprised two subsets: 35 independent patients (8 patients’ samples qRT-PCR, data included here; 27 patients’ samples nCounter gene expression, data will be presented) and 17 patients from discovery group whose samples also underwent nCounter gene expression profiling (data will be presented). Individual patient based analyses for A vs B vs C in discovery group revealed 249 significantly de-regulated genes in at least 20% of patients, in at least one comparison (AvB or BvC or AvC). Genes involved in stress response (FOSB, FOS, JUN, JUNB, DUSP1, CYR61, EGR1-3, ATF3, RGS1, RGS2), inflammation (IL20, IL8, SOCS3, GABRP, PIGR, NR4A1-2, CCL2- 3, CCL21, CCL14, CCL18-19, CXCL2, CXCL9-10, CXCL14), invasion & migration (PTGS2, MMP9-13), lipid metabolism (CD36, LIPE, TAT, FABP4, PLIN1, PLIN4, LPL, LEP), epithelial markers (KRT5, KRT7, KRT14-17, KRT23, KRT6A-6B) and cellular differentiation(SOX10, LRP2, S100A2, S100A7-A9, S100B, S100P) were significantly deregulated at time-point B versus A and many of these genes were also significantly deregulated in C versus A comparison, suggesting sustained deregulation through surgical resection. Replicative analysis involving comparison of tumors grouped by time points (A vs B vs C) identified 192 genes uniquely de-regulated in any one of the 3 comparisons, of which 42 overlapped with patient-wise analysis. These 42 genes included all the AP-1 transcription factor network signaling genes, epithelial markers (KRT14, KRT6A), inflammation related genes (SOCS3, PIGR, GABRP, NR4A1, NR4A2), lipid metabolism related genes (PLIN1) and cellular differentiation & cell fate related genes (SOX10, LRP2). Pathway analyses will be presented. qRT-PCR on paired samples in 8 independent patients validated the differential expression of eight genes in either AvB or AvC or both comparisons: FOS, FOSB, JUNB, DUSP1, RGS1, NR4A2, ZFP36, andMMP13. Comparison of biopsy (corresponding to A) with surgical samples (corresponding to C) in 6 cancer types (breast, cervical, lymphoma, mesothelioma, esophageal and sarcoma) in TCGA studies showed statistically significant de-regulation of 11 AP-1 transcription factor network signaling related genes in at least 4 cancers, further validating our experimental results. Conclusions: Our experiment, uniquely including an intra-operative tumor sample, shows that surgical removal induces a conserved stress response in the primary tumor that is potentially capable of bestowing metastatic capability on the tumor cells. Citation Format: Sudeep Gupta, Rohan Chaubal, Nilesh Gardi, Sunil Pachakar, Dimple Bhatia, Poonam Gera, Nita Nair, Shalaka Joshi, Vani Parmar, Purvi Thakkar, Garvit Chitkara, Rasika Kadam, Sejal Gujarathi, Harsh Oza, Rohini Hawaldar, Vaibhav Vanmali, Kenneth Buetow, Amit Dutt, Rajendra Badwe. Molecular effects of surgical resection on primary breast tumor [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-05-01.
摘要P3-05-01:手术切除对乳腺原发肿瘤的分子效应
理由:手术导致肿瘤组织迅速且逐渐严重地暴露于缺氧中,直至完全切除,但其对肿瘤基因表达的影响尚不清楚。我们通过一系列组织采样策略,包括术中样本,记录了手术对原发性乳腺癌肿瘤的分子效应。方法:我们纳入了未接受治疗的非转移性乳腺癌患者,并在手术期间在三个时间点取样肿瘤和肿瘤邻近组织:手术开始(样本A),肿瘤周长一半断流后(样本B)和完全切除肿瘤(样本C)。患者分为两组:发现组和验证组。来自发现组的肿瘤或邻近正常样本进行了全转录组配对端测序(RNA-Seq),使用下一代测序产生至少5000万reads。在验证组中使用qRT-PCR和Nanostring nCounter基因表达谱对发现组的发现进行评估。结果:81例乳腺癌患者符合本研究条件,其中46例在时间点A、B或C至少有1个质量合格的样本构成发现组,其样本进行了RNA-seq。验证组包括两个亚组:35例独立患者(8例患者样本qRT-PCR,数据包括在这里;27例患者样本的nCounter基因表达(数据将提交)和发现组17例患者的样本也进行了nCounter基因表达谱分析(数据将提交)。在发现组对A、B、C的个体患者分析显示,在至少一个比较(AvB、BvC或AvC)中,至少20%的患者中有249个显着去调控基因。参与应激反应(FOSB、FOS、JUN、JUNB、DUSP1、CYR61、EGR1-3、ATF3、RGS1、RGS2)、炎症(IL20、IL8、SOCS3、GABRP、PIGR、NR4A1-2、CCL2- 3、CCL21、CCL14、CCL18-19、CXCL2、CXCL9-10、CXCL14)、侵袭与迁移(PTGS2、MMP9-13)、脂质代谢(CD36、LIPE、TAT、FABP4、PLIN1、PLIN4、LPL、LEP)、上皮标志物(KRT5、KRT7、KRT14-17、KRT23、KRT6A-6B)和细胞分化(SOX10、LRP2、S100A2、S100A7-A9、S100B、S100P)在时间点B与A相比,这些基因中的许多在时间点C与A相比也显着去调控,这表明通过手术切除持续去调控。复制分析包括肿瘤按时间点分组(A、B、C)的比较,发现192个基因在3个比较中的任何一个都有独特的去调控,其中42个与患者分析重叠。这42个基因包括所有AP-1转录因子网络信号基因、上皮标志物(KRT14、KRT6A)、炎症相关基因(SOCS3、PIGR、GABRP、NR4A1、NR4A2)、脂质代谢相关基因(PLIN1)和细胞分化与细胞命运相关基因(SOX10、LRP2)。将介绍通路分析。8例独立患者配对样本的qRT-PCR验证了8个基因在AvB或AvC或两者的差异表达:FOS、FOSB、JUNB、DUSP1、RGS1、NR4A2、ZFP36和mmp13。TCGA研究中6种癌症类型(乳腺癌、宫颈癌、淋巴瘤、间皮瘤、食管癌和肉瘤)的活检(对应A)与手术样本(对应C)的比较显示,至少4种癌症中11个AP-1转录因子网络信号相关基因的去调控具有统计学意义,进一步验证了我们的实验结果。结论:我们的实验,独特地包括术中肿瘤样本,表明手术切除在原发肿瘤中诱导保守的应激反应,这可能使肿瘤细胞具有转移能力。引文格式:Sudeep Gupta, Rohan Chaubal, Nilesh Gardi, Sunil Pachakar, Dimple Bhatia, Poonam Gera, Nita Nair, Shalaka Joshi, Vani Parmar, Purvi Thakkar, Garvit Chitkara, Rasika Kadam, Sejal Gujarathi, Harsh Oza, Rohini Hawaldar, Vaibhav Vanmali, Kenneth Buetow, Amit Dutt, Rajendra Badwe。乳腺原发肿瘤手术切除的分子效应[摘要]。摘自:2019年圣安东尼奥乳腺癌研讨会论文集;2019年12月10日至14日;费城(PA): AACR;中国癌症杂志,2020;21(增刊):P3-05-01。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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