CN113981080A - 晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法 - Google Patents
晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法 Download PDFInfo
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Abstract
本发明公开了晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法,本发明列出了铂类敏感性的7个预测指标,包括年龄、无疾病进展生存期、转移灶个数、是否内脏转移、既往是否使用过蒽环类化疗、既往是否使用过紫杉类化疗、BRCA1/2是否突变,根据本发明提供的预测因子,可以为该患者的治疗方案的制定提供有力的参考,方便精准制定治疗方案,同时本发明对于一个晚期三阴性乳腺癌患者,在对其进行临床决策的时候,可以先检测其BRCA1/2的体细胞突变情况,并根据提出的铂类敏感性预测指标进行评估,若评分较低,则可以使用含铂类的质粒方案,这可以使患者获得更加的临床疗效,有望延长患者的生存几率。
Description
技术领域
本发明涉及一种癌症检测技术领域,具体是晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法。
背景技术
三阴性乳腺癌是所有乳腺癌亚型里预后最差的一种亚型,且一部分三阴性乳腺癌具有BRCA1/2突变或同源重组修复障碍。因此以DNA损伤为机制的药物(如铂类)就具有较好的前景。在晚期三阴性乳腺癌的治疗中,吉西他滨联合紫杉类的治疗是常规的治疗方案,那么是否可以使用吉西他滨联合铂类作为治疗方案,铂类联合吉西他滨的疗效是否优于紫杉类联合吉西他滨,哪些患者更能从铂类联合吉西他滨中获益,这是值得我们思考的问题。
TNT临床试验、TBCR009试验、PrECOG0105试验都提示,存在BRCA1/2体细胞突变(gBRCA1/2)的患者使用铂类的敏感性较高,但是GeparSixto试验却提示野生型BRCA1/2具有较好的卡铂疗效。因此,铂类敏感性的生物标记物亟需大型的三期临床试验进行进一步的验证。
发明内容
本发明的目的在于提供晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法,以解决上述背景技术中提出的问题。
为实现上述目的,本发明提供如下技术方案:
晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法,其分析方法步骤如下:
步骤一:取一位患者的血液样本提取0.5-2ug基因组DNA,通过Covaris S1超声处理(Covaris)将其片段化至约100-300bp,并使用KAPA Hyper Prep Kit(Kapa Biosystems)构建文库中;
步骤二:S1:使用一组单独合成的5'-生物素化120bp DNA寡核苷酸,其涵盖DNA同源重组(HR)途径中的28个基因,即ATM、BARD1、BRCA1、BRCA2、BRIP1、CDH1、CHEK1、CHEK2、FANCA、FANCC、FANCD2、FANCE、FANCF、FANCG、MLH1、MRE11A、MSH2、MSH6、MUTYH、NBN、PALB2、PMS2、PTEN、RAD50、RAD51C、RAD51D、STK11和TP53;
S2:进一步将其与人类Cot-1 DNA(Invitrogen,Thermo Fisher Scientific)、接头特异性阻断剂混合;
S3:孵育后,使用Dynabeads M270链霉亲和素(Invitrogen,Thermo FisherScientific)捕获,文库中的脱靶部分用盐水-柠檬酸钠缓冲液洗掉;
S4:添加PCR预混液以直接扩增捕获的文库,然后纯化由1.8倍体积的AgencourtAmpure XP珠(Beckman Coulter)制成的扩增产物,通过Qubit 3.0(Life Technologies,Thermo Fisher Scientific);
S5:在二代测序平台illumina Nextseq 500中使用75-bp双端读数对文库进行测序;
步骤三:使用Burrows-Wheeler Aligner(BWA)v0.7.12将序列数据映射到人类基因组(hg19),Indel调用是使用Pindel进行的,保留总深度至少为30倍的indel和indel≥10%的读取比例,将变体与dbSNP、ESP6500和1000基因组数据库中存在的常见和种系多态性进行了比较,以丢弃已知的种系SNP,RefSeq基因转录本注释数据库用于转录本鉴定和确定氨基酸变化,进一步分析发生在外显子或规范剪接位点(剪接位点周围20bp)的非同义SNV和插入缺失;
步骤四:根据患者的临床预测指标(年龄、无疾病进展生存期、转移灶个数、是否内脏转移、既往是否使用过蒽环类化疗、既往是否使用过紫杉类化疗、BRCA1/2是否突变)计算患者的铂类敏感评分;评分<2.5分的患者可以推荐使用含铂类的治疗方案,如吉西他滨联合顺铂。
作为本发明进一步的方案:所述步骤二中每个样本都在>200x的深度进行测序。
作为本发明再进一步的方案:所述步骤三中为了检测SNV,实施了基于基因组分析工具包(GATK)。
作为本发明再进一步的方案:所述步骤三中GATK Mutect Module用于执行共识调用和识别SNV。如果变异等位基因频率为10%或更高且总深度至少为30倍且无链偏向,则任何SNV都将被保留。
作为本发明再进一步的方案:所述步骤三中根据最大的基因转录本注释了对应于SNV的氨基酸变化,变异的临床意义由ClinVar数据库注释,分为良性变异、可能良性变异、意义不确定变异(VOUS)、可能致病变异和致病变异,对于定义为VOUS的SNV,分析了氨基酸变化,并根据氨基酸变化的特性预测了对蛋白质功能的可能损害,这样就将VOUS分为可能致病组或可能良性组;致病性和可能致病性变异被认为是临床致病性的,而“可能良性”和“良性”被认为是临床非致病性的,并被排除在进一步分析之外。
与现有技术相比,本发明的有益效果是:
本发明对于一个晚期三阴性乳腺癌患者,在对其进行临床决策的时候,可以先检测其BRCA1/2的体细胞突变情况,并根据提出的铂类敏感性预测指标进行评估,若评分较低,则可以使用含铂类的质粒方案,这可以使患者获得更加的临床疗效,有望延长患者的生存几率。
附图说明
图1为晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法的患者的预测评分分布图。
图2为晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法铂类敏感评分与疗效的相关性图。
图3为晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法BRCA1/2突变与疗效的相关性图。
图4为晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法中临床案例中患者的腹部MRI提示肝内多发转移图。
图5为晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法中临床案例中患者的基因检测报告图。
图6为晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法中临床案例中患者的疗效评估图。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
请参阅图1~6,本发明实施例中,晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法,其分析方法步骤如下:
步骤一:取一位患者的血液样本提取0.5-2ug基因组DNA,通过Covaris S1超声处理(Covaris)将其片段化至约100-300bp,并使用KAPA Hyper Prep Kit(Kapa Biosystems)构建文库中;
步骤二:S1:使用一组单独合成的5'-生物素化120bp DNA寡核苷酸,其涵盖DNA同源重组(HR)途径中的28个基因,即ATM、BARD1、BRCA1、BRCA2、BRIP1、CDH1、CHEK1、CHEK2、FANCA、FANCC、FANCD2、FANCE、FANCF、FANCG、MLH1、MRE11A、MSH2、MSH6、MUTYH、NBN、PALB2、PMS2、PTEN、RAD50、RAD51C、RAD51D、STK11和TP53;
S2:进一步将其与人类Cot-1 DNA(Invitrogen,Thermo Fisher Scientific)、接头特异性阻断剂混合;
S3:孵育后,使用Dynabeads M270链霉亲和素(Invitrogen,Thermo FisherScientific)捕获,文库中的脱靶部分用盐水-柠檬酸钠缓冲液洗掉;
S4:添加PCR预混液以直接扩增捕获的文库,然后纯化由1.8倍体积的AgencourtAmpure XP珠(Beckman Coulter)制成的扩增产物,通过Qubit 3.0(Life Technologies,Thermo Fisher Scientific);
S5:在二代测序平台illumina Nextseq 500中使用75-bp双端读数对文库进行测序;
步骤三:使用Burrows-Wheeler Aligner(BWA)v0.7.12将序列数据映射到人类基因组(hg19),Indel调用是使用Pindel进行的,保留总深度至少为30倍的indel和indel≥10%的读取比例,将变体与dbSNP、ESP6500和1000基因组数据库中存在的常见和种系多态性进行了比较,以丢弃已知的种系SNP,RefSeq基因转录本注释数据库用于转录本鉴定和确定氨基酸变化,进一步分析发生在外显子或规范剪接位点(剪接位点周围20bp)的非同义SNV和插入缺失;
步骤四:根据患者的临床预测指标(年龄、无疾病进展生存期、转移灶个数、是否内脏转移、既往是否使用过蒽环类化疗、既往是否使用过紫杉类化疗、BRCA1/2是否突变)计算患者的铂类敏感评分;评分<2.5分的患者可以推荐使用含铂类的治疗方案,如吉西他滨联合顺铂。
所述步骤二中每个样本都在>200x的深度进行测序;
所述步骤三中PCR重复读取去除和序列度量收集使用Picard 1.130(https://github.com/broadinstitute/picard/releases/tag/1.130)和SAMtools 0.1.19完成,同时仅在目标基因组区域中进行变体调用;
所述步骤三中为了检测SNV,实施了基于基因组分析工具包(GATK);
所述步骤三中GATK Mutect Module用于执行共识调用和识别SNV。如果变异等位基因频率为10%或更高且总深度至少为30倍且无链偏向,则任何SNV都将被保留;
所述步骤三中根据最大的基因转录本注释了对应于SNV的氨基酸变化,变异的临床意义由ClinVar数据库(http://www.ncbi.nlm.nih.gov/clinvar)注释,分为良性变异、可能良性变异、意义不确定变异(VOUS)、可能致病变异和致病变异,对于定义为VOUS的SNV,分析了氨基酸变化,并根据氨基酸变化的特性预测了对蛋白质功能的可能损害,这样就将VOUS分为可能致病组或可能良性组;致病性和可能致病性变异被认为是临床致病性的,而“可能良性”和“良性”被认为是临床非致病性的,并被排除在进一步分析之外。
本发明列出了铂类敏感性的7个预测指标,包括年龄、无疾病进展生存期、转移灶个数、是否内脏转移、既往是否使用过蒽环类化疗、既往是否使用过紫杉类化疗、BRCA1/2是否突变。根据本发明提供的预测因子,可以为该患者的治疗方案的制定提供有力的参考,方便精准制定治疗方案,各预测因子的STEPP预测评分如表1所示;
表1铂类敏感性的预测因子
预测因子 | STEPP预测评分 |
年龄(年) | |
<40 | -0.148 |
≥40 | 0 |
无疾病进展生存 | |
原发IV期 | 1.049 |
<1年 | 0.403 |
≥1年 | 0 |
转移灶的个数 | |
1 | 0 |
2 | -0.033 |
≥3 | 0.432 |
是否内脏转移 | |
是 | 0.382 |
否 | 0 |
既往是否使用过蒽环化疗 | |
是 | 0.556 |
否 | 0 |
既往是否使用过紫杉类化疗 | |
是 | 0.079 |
否 | 0 |
BRCA1/2 | |
实变 | 0 |
野生型 | 0.280 |
本发明的预测指标经过了132位患者的大样本的严格验证,这132位患者是参加CBCSG006研究者的受试者,其基线临床信息如表2所示:
表2患者的基线临床病理特征
临床病理特征 | 患者数 |
年龄(年) | |
<40 | 27(20.45%) |
≥40 | 105(79.55%) |
无疾病进展生存 | |
原发IV期 | 14(10.61%) |
<1年 | 30(22.73%) |
≥1年 | 88(66.67%) |
转移灶的个数 | |
1 | 41(31.06%) |
2 | 42(31.82%) |
≥3 | 49(37.12%) |
是否内脏转移 | |
是 | 97(73.48%) |
否 | 35(26.52%) |
既往是否接受过化疗 | |
蒽环类 | 104(78.79%) |
紫衫类 | 81(61.36%) |
蒽环+紫衫 | 72(54.55%) |
绝经状态 | |
绝经前 | 66(50.0%) |
绝经后 | 66(50.0%) |
ECOG | |
0 | 40(30.3%) |
1 | 92(69.7%) |
大部分患者的铂类敏感性预测评分在2分-3分之间。对于接受含铂类药物(GP方案)的患者来说,预测评分越低铂类的治疗疗效越好:预测评分为1.84的患者6个月疾病无进展的的百分比为82%,而预测评分为3.04的患者6个月疾病无进展的的百分比仅为37%。而对于没有接受铂类药物(GT方案)的患者来说,预测评分与治疗疗效之间无明显的相关性,此外,我们还对其中的一个预测指标BRCA1/2进行了单独的验证。对于BRCA1/2体细胞突变的患者,使用含铂方案(GP方案)的客观缓解率(ORR)高达83.3%,而使用非含铂方案(GT方案)的客观缓解率仅仅只有37.5%(P=0.086),且使用含铂类方案的无疾病进展生存要显著长于非含铂类方案(8.9个月vs 3.2个月)。
患者的二代测序结果如表3所示:
表3患者的二代测序结果表
临床案例
患者是一名35岁的女性,2018年于外院行左乳癌保乳术,术后病理提示为左乳浸润性导管癌,肿块大小1.5cm,淋巴结0/9。免疫组化提示:ER(-)PR(-)HER2(-)KI67(30%)。术后外院予以TC*4程辅助化疗,并完成术后辅助放疗,但2021年1月患者复查腹部MRI时提示肝内多发转移,具体如图4所示,因此患者于我院就诊;
进一步提取患者的血液样本,并按实例1所示检测患者的BRCA1/2的胚系突变。此患者存在BRCA2的胚系突变,具体如图5所示;
进一步根据患者的临床预测指标(年龄、无疾病进展生存期、转移灶个数、是否内脏转移、既往是否使用过蒽环类化疗、既往是否使用过紫杉类化疗、BRCA1/2是否突变)及表1计算患者的铂类敏感评分,改患者的铂类敏感评分为0.313,因此推荐使用含铂的治疗方案;
综上予以该患者吉西他滨联合顺铂的一线治疗方案,最佳疗效达到部份缓解(Partial response,PR),接近完全缓解(Complete response,CR),也就是根据我们的铂类敏感评分,患者使用了含铂的治疗方案,达到了非常良好的疗效。
尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (5)
1.晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法,其特征在于:其分析方法步骤如下:
步骤一:取一位患者的血液样本提取0.5-2ug基因组DNA,通过Covaris S1超声处理(Covaris)将其片段化至约100-300bp,并使用KAPA Hyper Prep Kit(Kapa Biosystems)构建文库中;
步骤二:S1:使用一组单独合成的5'-生物素化120bp DNA寡核苷酸,其涵盖DNA同源重组(HR)途径中的28个基因,即ATM、BARD1、BRCA1、BRCA2、BRIP1、CDH1、CHEK1、CHEK2、FANCA、FANCC、FANCD2、FANCE、FANCF、FANCG、MLH1、MRE11A、MSH2、MSH6、MUTYH、NBN、PALB2、PMS2、PTEN、RAD50、RAD51C、RAD51D、STK11和TP53;
S2:进一步将其与人类Cot-1 DNA(Invitrogen,Thermo Fisher Scientific)、接头特异性阻断剂混合;
S3:孵育后,使用Dynabeads M270链霉亲和素(Invitrogen,Thermo FisherScientific)捕获,文库中的脱靶部分用盐水-柠檬酸钠缓冲液洗掉;
S4:添加PCR预混液以直接扩增捕获的文库,然后纯化由1.8倍体积的AgencourtAmpure XP珠(Beckman Coulter)制成的扩增产物,通过Qubit 3.0(Life Technologies,Thermo Fisher Scientific);
S5:在二代测序平台illumina Nextseq 500中使用75-bp双端读数对文库进行测序;
步骤三:使用Burrows-Wheeler Aligner(BWA)v0.7.12将序列数据映射到人类基因组(hg19),Indel调用是使用Pindel进行的,保留总深度至少为30倍的indel和indel≥10%的读取比例,将变体与dbSNP、ESP6500和1000基因组数据库中存在的常见和种系多态性进行了比较,以丢弃已知的种系SNP,RefSeq基因转录本注释数据库用于转录本鉴定和确定氨基酸变化,进一步分析发生在外显子或规范剪接位点(剪接位点周围20bp)的非同义SNV和插入缺失;
步骤四:根据患者的临床预测指标(年龄、无疾病进展生存期、转移灶个数、是否内脏转移、既往是否使用过蒽环类化疗、既往是否使用过紫杉类化疗、BRCA1/2是否突变)计算患者的铂类敏感评分;评分<2.5分的患者可以推荐使用含铂类的治疗方案,如吉西他滨联合顺铂。
2.根据权利要求1所述的晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法,其特征在于:所述步骤二中每个样本都在>200x的深度进行测序。
3.根据权利要求1所述的晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法,其特征在于:所述步骤三中为了检测SNV,实施了基于基因组分析工具包(GATK)。
4.根据权利要求1所述的晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法,其特征在于:所述步骤三中GATK Mutect Module用于执行共识调用和识别SNV,如果变异等位基因频率为10%或更高且总深度至少为30倍且无链偏向,则任何SNV都将被保留。
5.根据权利要求1所述的晚期三阴性乳腺癌铂类治疗敏感性的预测指标生成分析方法,其特征在于:所述步骤三中根据最大的基因转录本注释了对应于SNV的氨基酸变化,变异的临床意义由ClinVar数据库注释,分为良性变异、可能良性变异、意义不确定变异(VOUS)、可能致病变异和致病变异,对于定义为VOUS的SNV,分析了氨基酸变化,并根据氨基酸变化的特性预测了对蛋白质功能的可能损害,这样就将VOUS分为可能致病组或可能良性组;致病性和可能致病性变异被认为是临床致病性的,而“可能良性”和“良性”被认为是临床非致病性的,并被排除在进一步分析之外。
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