津白2小鼠自發(fā)性乳腺癌的克隆演化研究
發(fā)布時(shí)間：2018-08-25 19:19
【摘要】：目的:津白2小鼠(Tientsin Albino II,TA2)是天津醫(yī)科大學(xué)培育成功的高發(fā)乳腺癌純系小鼠,是被國(guó)際小鼠遺傳標(biāo)準(zhǔn)命名委員會(huì)(International Committee on Standardized Genetic Nomenclature for Mice,ICLAS)和我國(guó)衛(wèi)生部承認(rèn)的近交系小鼠。自發(fā)性乳腺癌是TA2小鼠的主要特征,不經(jīng)過(guò)任何人工處理,經(jīng)產(chǎn)TA2母鼠的乳腺癌發(fā)生率為81%。與其他類型的小鼠模型相比,TA2自發(fā)性乳腺癌最突出的優(yōu)點(diǎn)是能夠反映乳腺癌的自然進(jìn)程。腫瘤的克隆演化(clonal evolution)是指在自然選擇作用下,具有不同基因突變的腫瘤細(xì)胞相互競(jìng)爭(zhēng),腫瘤由起始的單一克隆,演變?yōu)槎鄠�(gè)亞克隆,這類似于物種的達(dá)爾文進(jìn)化過(guò)程。既往研究顯示不同類型乳腺癌的基因組的克隆演化具有各自的特征,TA2小鼠的遺傳背景相同,其自發(fā)性乳腺癌的克隆演化具有什么特點(diǎn)尚不清楚。為了揭示TA2自發(fā)性乳腺癌的克隆演化特征,本研究首先明確了TA2自發(fā)性乳腺癌的病理學(xué)特征和分子分型;對(duì)4個(gè)TA2自發(fā)性乳腺癌標(biāo)本進(jìn)行了全基因組重測(cè)序,分析比較樣本之間的克隆結(jié)構(gòu)和克隆演化特點(diǎn);另外,在本研究中初步驗(yàn)證了TA2小鼠DNA雙鏈斷裂(DNA double-strand breaks,DSBs)修復(fù)機(jī)制的缺陷。方法:1.收集17例TA2自發(fā)性乳腺癌樣本,觀察小鼠的見(jiàn)瘤時(shí)間、產(chǎn)次和腫瘤發(fā)生部位;HE染色觀察TA2自發(fā)性乳腺癌的病理學(xué)特點(diǎn);應(yīng)用免疫組織化學(xué)染色檢測(cè)ER、PR、HER2、EGFR,確定TA2自發(fā)性乳腺癌的分子分型;應(yīng)用免疫組織化學(xué)染色檢測(cè)Ki67的表達(dá)情況,評(píng)估TA2自發(fā)性乳腺癌的增殖活性。2.選取4例TA2自發(fā)性乳腺癌(R01、R02、R03、R04)樣本,其中R01和R02來(lái)源于同一只TA2小鼠,R01是原發(fā)性乳腺癌,R02是頸背部轉(zhuǎn)移性乳腺癌,R03和R04分別來(lái)自另外2只TA2,均為原發(fā)性乳腺癌;4個(gè)樣本的病理學(xué)類型均為浸潤(rùn)性導(dǎo)管癌,其中R03的組織學(xué)分級(jí)為3級(jí),其余3個(gè)樣本均為2級(jí);4個(gè)樣本的分子分型均為基底細(xì)胞樣乳腺癌。對(duì)TA2自發(fā)性乳腺癌和鼠尾DNA進(jìn)行全基因組重測(cè)序,參考基因組為Mouse.C57BL/6J,進(jìn)行以下生物信息學(xué)分析:(1)檢測(cè)和注釋單核苷酸變異(Single Nucleotide Variation,SNV)、小片段插入/缺失(small In Del)、結(jié)構(gòu)變異(Structure Variation,SV)和拷貝數(shù)變異(copy number variation,CNV)等遺傳學(xué)變異;并對(duì)變異的基因進(jìn)行功能注釋,篩選出TA2自發(fā)性乳腺癌相關(guān)的遺傳學(xué)變化。(2)根據(jù)SNV、CNV和LOH等遺傳變異,應(yīng)用Sci Clone方法和EXPANDS方法進(jìn)行TA2自發(fā)性乳腺癌的克隆演化研究。3.原代培養(yǎng)TA2小鼠、TA1低瘤鼠和C57BL/6小鼠胚胎成纖維細(xì)胞(Mouse embryonic fibroblasts,MEFs),應(yīng)用博來(lái)霉素處理各MEFs,造成人為的DSBs,應(yīng)用免疫熒光檢測(cè)γ-H2AX,比較TA2與其他種系小鼠的DSB修復(fù)能力的不同;應(yīng)用雙抗體夾心ELISA法檢測(cè)TA2、TA1和C57BL/6小鼠的血清Ig A水平,比較TA2與其他種系小鼠的非同源末端連接(non-homologous end joining,NHEJ)能力的不同。結(jié)果:1.17例TA2自發(fā)性乳腺癌小鼠的平均見(jiàn)瘤鼠齡為315±71天;荷瘤鼠均為經(jīng)產(chǎn)母鼠,平均分娩次數(shù)為3.06±1.12次;腫瘤好發(fā)部位依次為右前胸(8例)、右下腹(4例)、左下腹(4例)和左前胸(1例),另有2例合并頸背部腫瘤,其他部位未見(jiàn)腫瘤。17例TA2自發(fā)性乳腺癌在組織病理學(xué)上均與人乳腺浸潤(rùn)性導(dǎo)管癌類似;大多數(shù)樣本的組織學(xué)分級(jí)為2級(jí),除了1例的組織學(xué)分級(jí)為3級(jí);分子分型均類似于人基底細(xì)胞樣乳腺癌的表型:ER、PR和HER2均為陰性,EGFR陽(yáng)性表達(dá);TA2自發(fā)性乳腺癌Ki67高表達(dá),細(xì)胞增殖活性高。2.對(duì)全基因組測(cè)序數(shù)據(jù)進(jìn)行分析,包括遺傳變異分析和克隆演化分析兩部分。(1)遺傳變異分析:與參考基因組相比,TA2自發(fā)性乳腺癌存在一系列的SNVs、In Dels、CNVs和SVs等遺傳學(xué)變異。全基因組范圍內(nèi),4個(gè)樣本的SNVs均以CT或TC為主;韋恩(Venn)分析顯示,全基因組范圍內(nèi),4個(gè)樣本之間99.02%SNVs是相同的,95.45%In Dels是相同的。對(duì)蛋白編碼區(qū)(coding sequence,CDS)區(qū)域發(fā)生變異的基因進(jìn)行功能注釋,共分為25類不同功能的基因,4個(gè)樣本之間每類基因的變異基因數(shù)目基本一致。結(jié)合基因功能注釋,我們對(duì)參與DSBs修復(fù)的兩個(gè)經(jīng)典通路——同源重組(homologous recombination,HR)和NHEJ的基因進(jìn)行分析,發(fā)現(xiàn)4個(gè)樣本中均發(fā)生相同的DSB修復(fù)相關(guān)基因Brca2、Rad52、Rif1和Trp53bp1的基因突變;結(jié)合文獻(xiàn),對(duì)16個(gè)乳腺癌相關(guān)的DNA修復(fù)相關(guān)基因進(jìn)行分析,發(fā)現(xiàn)4個(gè)樣本中均發(fā)生相同的Trp53、Kmt2c基因突變。(2)克隆演化分析:應(yīng)用Sci Clone方法分析發(fā)現(xiàn),4個(gè)樣本均含有6個(gè)亞克隆,對(duì)4個(gè)樣本兩兩比較發(fā)現(xiàn),各個(gè)亞克隆的等位基因頻率(variant allele frequency,VAF)差別不大,提示4個(gè)樣本的亞克隆結(jié)構(gòu)類似;應(yīng)用EXPANDS方法分析發(fā)現(xiàn),4個(gè)樣本均有11個(gè)亞克隆,4個(gè)樣本各亞克隆的系統(tǒng)發(fā)生樹(shù)均呈“樹(shù)狀”結(jié)構(gòu),提示4個(gè)樣本的克隆演化模式相類似。3.(1)博來(lái)霉素處理MEFs后,γ-H2AX在細(xì)胞核內(nèi)呈點(diǎn)狀聚集(foci)。去除博來(lái)霉素4h后,TA2、TA1和C57BL/6 MEFs的γ-H2AX聚集點(diǎn)的平均數(shù)目分別為23.96±7.19、21.52±6.80和21.30±6.47,兩兩比較3種MEFs的γ-H2AX聚集點(diǎn)數(shù)目,組間差異沒(méi)有統(tǒng)計(jì)學(xué)意義(P0.05)。去除博來(lái)霉素24h后,TA2、TA1和C57BL/6 MEFs的γ-H2AX聚集點(diǎn)的平均數(shù)目分別為5.98±2.27、1.22±0.98和1.32±0.79,TA1和C57BL/6 MEFs的γ-H2AX聚集點(diǎn)數(shù)目的差異沒(méi)有統(tǒng)計(jì)學(xué)意義(P0.05);分別與TA1和C57BL/6 MEFs相比,TA2 MEFs的γ-H2AX聚集點(diǎn)數(shù)目更多(P0.05),顯示TA2 MEFs產(chǎn)生的γ-H2AX聚集點(diǎn)消失的更慢,提示TA2小鼠存在DSB修復(fù)缺陷。(2)TA2、TA1和C57BL/6小鼠血清的Ig A濃度分別為418.60±47.18μg/m L、472.69±36.46μg/m L、470.34±37.49μg/m L。TA1和C57BL/6小鼠血清中Ig A水平的差異沒(méi)有統(tǒng)計(jì)學(xué)意義(P0.05);分別與TA1和C57BL/6相比,TA2小鼠血清中Ig A水平下降(P0.05),提示TA2小鼠可能存在NHEJ缺陷。結(jié)論:本研究初步證實(shí)TA2自發(fā)性乳腺癌不同個(gè)體之間在組織病理學(xué)類型、分子分型、遺傳變異和克隆演化等方面類似,具體表現(xiàn)在:(1)病理學(xué)類型類似于人乳腺浸潤(rùn)性導(dǎo)管癌,大部分的組織學(xué)分級(jí)為2級(jí);(2)分子分型均為基底細(xì)胞樣乳腺癌;(3)全基因組的遺傳變異類似,具有相同的DSB修復(fù)基因突變。(4)克隆演化分析顯示TA2自發(fā)性乳腺癌的克隆結(jié)構(gòu)和克隆演化類似�；谝陨献C據(jù),我們推測(cè)TA2自發(fā)性乳腺癌基因組的克隆演化存在某種相對(duì)固定的模式。本研究還初步證實(shí)了TA2可能存在DSB修復(fù)缺陷,這可能是TA2自發(fā)性乳腺癌形成的一個(gè)重要原因。
[Abstract]:OBJECTIVE: Tientsin Albino II (TA2) is a high-risk pure-line breast cancer mouse bred by Tianjin Medical University. It is an inbred mouse recognized by the International Committee on Standardized Genetic Nomenclature for Mice (ICLAS) and the Ministry of Health of China. The main feature of the mice, without any artificial treatment, was that the incidence of breast cancer in TA2-bearing mothers was 81%. Mutant tumor cells compete with each other, and the tumor evolves from a single clone to multiple subclones, which is similar to the Darwinian evolution of species. In order to reveal the clonal evolution of TA2 spontaneous breast cancer, we first clarified the pathological features and molecular typing of TA2 spontaneous breast cancer, sequenced the whole genome of four TA2 spontaneous breast cancer specimens, analyzed and compared the clonal structure and clonal evolution characteristics between the samples; and, in addition, in this study, we studied the clonal evolution of TA2 spontaneous breast cancer. Methods: 1. Seventeen cases of TA2 spontaneous breast cancer were collected to observe the time of tumor occurrence, parity and location of tumor occurrence; HE staining was used to observe the pathological characteristics of TA2 spontaneous breast cancer; immunohistochemical staining was used to detect ER, PR, H. ER2 and EGFR were used to determine the molecular typing of TA2 spontaneous breast cancer; immunohistochemical staining was used to detect the expression of Ki67 and evaluate the proliferative activity of TA2 spontaneous breast cancer. Sexual breast cancer, R03 and R04 were derived from two other TA2 breast cancers, all of them were primary breast cancer; the pathological types of the four samples were invasive ductal carcinoma, of which the histological grade of R03 was grade 3 and the other three samples were grade 2; the molecular typing of the four samples were basal cell-like breast cancer. The following bioinformatics analyses were performed: (1) Detection and annotation of single nucleotide variations (SNV), small in Del, structural variations (SV) and copy number variations (CNV) and other genetic variations. (2) According to the genetic variation of SNV, CNV and LOH, the clonal evolution of TA2 spontaneous breast cancer was studied by Sci Clone method and EXPANDS method. 3. Primary culture of TA2 mice, TA1 hypotumor mice and C57BL/6 mouse embryonic fibroblasts (Mouse embryonic fibroblasts) Blasts, MEFs) were treated with bleomycin to induce artificial DSBs. Immunofluorescence was used to detect gamma-H2AX and compare the repair ability of DSB between TA2 and other strains of mice. The serum Ig A levels of TA2, TA1 and C57BL/6 mice were detected by sandwich ELISA, and the non-homologous End-Joints (non-homolog) between TA2 and other strains of mice were compared. Results: The average age of tumor mice in 17 TA2 spontaneous breast cancer mice was 315 65 17 cases of TA2 spontaneous breast cancer were similar to invasive ductal carcinoma of human breast in histopathology; most of the samples were histologically graded 2, except 1 case was histologically graded 3; the molecular typing was similar to the phenotype of human basal cell-like breast cancer: ER, PR and HER2 were negative, and EGFR was positive; Genetic variation analysis: Compared with reference genome, TA2 spontaneous breast cancer has a series of genetic variations such as SNVs, In Dels, CNVs and SVs. All the SNVs in the four samples were mainly CT or TC. Venn analysis showed that 99.02% of the SNVs were the same in the whole genome and 95.45% of the in Dels were the same in the four samples. According to the functional annotation, we analyzed the two classical pathways involved in DSBs repair, homologous recombination (HR) and NHEJ, and found that the same DSB repair related genes Brca2, Rad52, Rif1 and Trp53bp1 were mutated in all four samples. Sixteen breast cancer-related DNA repair-related genes were analyzed, and the same Trp53 and Kmt2c gene mutations were found in all four samples. (2) Clonal evolution analysis: Sci Clone analysis showed that all the four samples contained six subclones, and the allele frequ frequencies of each subclone were found by comparing two of the four samples. The results of EXPANDS analysis showed that there were 11 subclones in all four samples, and the phylogenetic trees of each subclone in all four samples showed a "tree" structure, suggesting that the clonal evolution patterns of the four samples were similar. After removing bleomycin for 4 hours, the average number of gamma-H2AX aggregation points of TA2, TA 1 and C57BL/6 MEFs were 23.96 (+ 7.19), 21.52 (+ 6.80) and 21.30 (+ 6.47), respectively. There was no significant difference in the number of gamma-H2AX aggregation points of three MEFs between groups (P 0.05). After removing bleomycin for 24 hours, the aggregation points of TA2, TA 1 and C57BL/6 MEFs were 23.96 (+ 7.19), 21.52 (+ 6.80) and 21.30 (+ 6.47). There was no significant difference in the number of gamma-H2AX aggregation points between TA 1 and C57BL/6 MEFs (P 0.05). Compared with TA 1 and C57BL/6 MEFs, the number of gamma-H2AX aggregation points of TA2 MEFs was more (P 0.05), indicating that the disappearance of gamma-H2AX aggregation points produced by TA2 MEFs was slower, suggesting the presence of DSB in TA2 mice. (2) The serum Ig A levels of TA2, TA1 and C57BL/6 mice were 418.60 (+47.18) ug/m L, 472.69 (+36.46) ug/m L, 470.34 (+37.49) ug/m L.TA1 and C57BL/6 mice, respectively. There was no significant difference in serum Ig A levels between TA2, TA1 and C57BL/6 mice (P 0.05), suggesting that TA2 mice might have lower serum Ig A levels than TA1 and C57BL/6 mice (P 0.05). Conclusion: This study preliminarily confirmed that the histopathological types, molecular typing, genetic variation and clonal evolution of TA2 spontaneous breast cancer were similar among different individuals. The specific manifestations were as follows: (1) Pathological types were similar to human breast invasive ductal carcinoma, most of which were histologically graded to grade 2; (2) Molecular typing was basal. (4) Clonal evolution analysis showed that the clonal structure and clonal evolution of TA2 spontaneous breast cancer were similar. Based on the above evidence, we speculated that there was a relatively fixed pattern in the clonal evolution of TA2 spontaneous breast cancer genome. It is preliminarily confirmed that TA2 may have defective DSB repair, which may be an important cause of spontaneous breast cancer.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R737.9
[Abstract]:OBJECTIVE: Tientsin Albino II (TA2) is a high-risk pure-line breast cancer mouse bred by Tianjin Medical University. It is an inbred mouse recognized by the International Committee on Standardized Genetic Nomenclature for Mice (ICLAS) and the Ministry of Health of China. The main feature of the mice, without any artificial treatment, was that the incidence of breast cancer in TA2-bearing mothers was 81%. Mutant tumor cells compete with each other, and the tumor evolves from a single clone to multiple subclones, which is similar to the Darwinian evolution of species. In order to reveal the clonal evolution of TA2 spontaneous breast cancer, we first clarified the pathological features and molecular typing of TA2 spontaneous breast cancer, sequenced the whole genome of four TA2 spontaneous breast cancer specimens, analyzed and compared the clonal structure and clonal evolution characteristics between the samples; and, in addition, in this study, we studied the clonal evolution of TA2 spontaneous breast cancer. Methods: 1. Seventeen cases of TA2 spontaneous breast cancer were collected to observe the time of tumor occurrence, parity and location of tumor occurrence; HE staining was used to observe the pathological characteristics of TA2 spontaneous breast cancer; immunohistochemical staining was used to detect ER, PR, H. ER2 and EGFR were used to determine the molecular typing of TA2 spontaneous breast cancer; immunohistochemical staining was used to detect the expression of Ki67 and evaluate the proliferative activity of TA2 spontaneous breast cancer. Sexual breast cancer, R03 and R04 were derived from two other TA2 breast cancers, all of them were primary breast cancer; the pathological types of the four samples were invasive ductal carcinoma, of which the histological grade of R03 was grade 3 and the other three samples were grade 2; the molecular typing of the four samples were basal cell-like breast cancer. The following bioinformatics analyses were performed: (1) Detection and annotation of single nucleotide variations (SNV), small in Del, structural variations (SV) and copy number variations (CNV) and other genetic variations. (2) According to the genetic variation of SNV, CNV and LOH, the clonal evolution of TA2 spontaneous breast cancer was studied by Sci Clone method and EXPANDS method. 3. Primary culture of TA2 mice, TA1 hypotumor mice and C57BL/6 mouse embryonic fibroblasts (Mouse embryonic fibroblasts) Blasts, MEFs) were treated with bleomycin to induce artificial DSBs. Immunofluorescence was used to detect gamma-H2AX and compare the repair ability of DSB between TA2 and other strains of mice. The serum Ig A levels of TA2, TA1 and C57BL/6 mice were detected by sandwich ELISA, and the non-homologous End-Joints (non-homolog) between TA2 and other strains of mice were compared. Results: The average age of tumor mice in 17 TA2 spontaneous breast cancer mice was 315 65 17 cases of TA2 spontaneous breast cancer were similar to invasive ductal carcinoma of human breast in histopathology; most of the samples were histologically graded 2, except 1 case was histologically graded 3; the molecular typing was similar to the phenotype of human basal cell-like breast cancer: ER, PR and HER2 were negative, and EGFR was positive; Genetic variation analysis: Compared with reference genome, TA2 spontaneous breast cancer has a series of genetic variations such as SNVs, In Dels, CNVs and SVs. All the SNVs in the four samples were mainly CT or TC. Venn analysis showed that 99.02% of the SNVs were the same in the whole genome and 95.45% of the in Dels were the same in the four samples. According to the functional annotation, we analyzed the two classical pathways involved in DSBs repair, homologous recombination (HR) and NHEJ, and found that the same DSB repair related genes Brca2, Rad52, Rif1 and Trp53bp1 were mutated in all four samples. Sixteen breast cancer-related DNA repair-related genes were analyzed, and the same Trp53 and Kmt2c gene mutations were found in all four samples. (2) Clonal evolution analysis: Sci Clone analysis showed that all the four samples contained six subclones, and the allele frequ frequencies of each subclone were found by comparing two of the four samples. The results of EXPANDS analysis showed that there were 11 subclones in all four samples, and the phylogenetic trees of each subclone in all four samples showed a "tree" structure, suggesting that the clonal evolution patterns of the four samples were similar. After removing bleomycin for 4 hours, the average number of gamma-H2AX aggregation points of TA2, TA 1 and C57BL/6 MEFs were 23.96 (+ 7.19), 21.52 (+ 6.80) and 21.30 (+ 6.47), respectively. There was no significant difference in the number of gamma-H2AX aggregation points of three MEFs between groups (P 0.05). After removing bleomycin for 24 hours, the aggregation points of TA2, TA 1 and C57BL/6 MEFs were 23.96 (+ 7.19), 21.52 (+ 6.80) and 21.30 (+ 6.47). There was no significant difference in the number of gamma-H2AX aggregation points between TA 1 and C57BL/6 MEFs (P 0.05). Compared with TA 1 and C57BL/6 MEFs, the number of gamma-H2AX aggregation points of TA2 MEFs was more (P 0.05), indicating that the disappearance of gamma-H2AX aggregation points produced by TA2 MEFs was slower, suggesting the presence of DSB in TA2 mice. (2) The serum Ig A levels of TA2, TA1 and C57BL/6 mice were 418.60 (+47.18) ug/m L, 472.69 (+36.46) ug/m L, 470.34 (+37.49) ug/m L.TA1 and C57BL/6 mice, respectively. There was no significant difference in serum Ig A levels between TA2, TA1 and C57BL/6 mice (P 0.05), suggesting that TA2 mice might have lower serum Ig A levels than TA1 and C57BL/6 mice (P 0.05). Conclusion: This study preliminarily confirmed that the histopathological types, molecular typing, genetic variation and clonal evolution of TA2 spontaneous breast cancer were similar among different individuals. The specific manifestations were as follows: (1) Pathological types were similar to human breast invasive ductal carcinoma, most of which were histologically graded to grade 2; (2) Molecular typing was basal. (4) Clonal evolution analysis showed that the clonal structure and clonal evolution of TA2 spontaneous breast cancer were similar. Based on the above evidence, we speculated that there was a relatively fixed pattern in the clonal evolution of TA2 spontaneous breast cancer genome. It is preliminarily confirmed that TA2 may have defective DSB repair, which may be an important cause of spontaneous breast cancer.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R737.9
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