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中华乳腺病杂志(电子版)

中华乳腺病杂志(电子版) ›› 2022, Vol. 16 ›› Issue (05) : 276 -283. doi: 10.3877/cma.j.issn.1674-0807.2022.05.003

论著

139例不同分子分型乳腺癌患者的基因突变特征分析
周璐1, 张姝1, 张刚1, 姜燕1, 徐静1, 徐琰1,†()   
  1. 1. 400042　重庆，陆军军医大学大坪医院乳腺甲状腺外科
  • 收稿日期:2022-03-03 出版日期:2022-10-01
  • 通信作者: 徐琰
  • 基金资助:
    陆军军医大学临床重大领域技术创新项目(CX2019LC120)

Landscape of gene mutations in different molecular subtypes of 139 breast cancer patients

Lu Zhou1, Shu Zhang1, Gang Zhang1, Yan Jiang1, Jing Xu1, Yan Xu1,†()   

  1. 1. Department of Breast and Thyroid Surgery, Daping Hospital of Army Medical University, Chongqinq 400042, China
  • Received:2022-03-03 Published:2022-10-01
  • Corresponding author: Yan Xu
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引用本文：

周璐, 张姝, 张刚, 姜燕, 徐静, 徐琰. 139例不同分子分型乳腺癌患者的基因突变特征分析[J/OL]. 中华乳腺病杂志(电子版), 2022, 16(05): 276-283.

Lu Zhou, Shu Zhang, Gang Zhang, Yan Jiang, Jing Xu, Yan Xu. Landscape of gene mutations in different molecular subtypes of 139 breast cancer patients[J/OL]. Chinese Journal of Breast Disease(Electronic Edition), 2022, 16(05): 276-283.

目的

探讨不同分子分型乳腺癌的基因突变特征以及同源重组修复(HRR)相关基因的突变特征。

方法

根据纳入及排除标准，纳入2017年3月至2021年3月陆军军医大学大坪医院经病理确诊和接受1 021个肿瘤相关基因体细胞或/和胚系突变检测的139例乳腺癌患者进行回顾性研究。根据基因检测结果，对5种分子分型乳腺癌患者的体细胞单核苷酸位点变异(SNV)、拷贝数变异(CNV)和胚系SNV进行分析，并单独调查HRR相关基因的突变特征。多组比较使用χ2检验，使用Fisher确切概率法进行两两比较，并使用Bonferroni法校正。

结果

139例患者中，108例进行了体细胞突变检测，139例进行了胚系突变检测；luminal A型42例，luminal B型(HER-2阴性)25例，luminal B型(HER-2阳性)11例，HER-2过表达型26例，三阴型30例，其余5例分子分型不详。在检测了体细胞突变且分子分型明确的103例患者中，SNV突变频率排名前5的基因分别为：TP53(57.3%，59/103)、PIK3CA(43.7%，45/103)、MLL3(12.6%，13/103)、GATA3(9.7%，10/103)、MAP3K1(8.7%，9/103)。TP53与PIK3CA在5种分子分型乳腺癌患者中的SNV突变频率比较，差异有统计学意义(χ2＝16.617、16.434，P均＝0.002)。相较于luminal A型患者，TP53突变频率在HER-2过表达型患者中更高(P＝0.004)。相较于luminal A型和luminal B型(HER-2阳性)患者，PIK3CA突变频率在三阴型患者中更低(P＝0.006, 0.005)。CNV扩增频率最高的10个基因分别是：ERBB2(27.2%，28/103)、CDK12(16.5%，17/103)、MYC(14.6%，15/103)、CCND1(11.6%，12/103)、FGF19(8.7%，9/103)、FGF3(8.7%，9/103)、FGF4(8.7%，9/103)、SPOP(5.8%，6/103)、FGFR1(5.8%，6/103)、MCL1(5.8%，6/103)。ERBB2、CDK12、SPOP在5种分子分型乳腺癌患者中的扩增频率比较，差异有统计学意义(χ2＝69.996、38.192、14.859，P均<0.050)。两两比较结果显示：ERBB2扩增显著富集在luminal B型(HER-2阳性)和HER-2过表达型患者中[与luminal A型比较，P＝0.001、<0.001；与luminal B型(HER-2阴性)比较，P＝0.007、<0.001；与三阴型比较，P＝0.005、<0.001]；相对于luminal A、luminal B型(HER-2阴性)和三阴型，CDK12扩增频率在HER-2过表达型患者中更高(P<0.001、<0.001、P＝0.004)；相对于luminal B型(HER-2阴性)患者，CDK12扩增频率在luminal B型(HER-2阳性)患者中更高(P＝0.040)。胚系基因突变分析发现，胚系突变频率最高的2个基因是BRCA2和BRCA1,分别为10.4%(14/134)及6.0%(8/134)。在36个HRR相关基因中，CDK12基因扩增频率在不同分子分型中比较，差异有统计学意义(χ2＝38.192，P＝0.001)。

结论

不同分子分型的乳腺癌患者具有不同的基因突变特征，其中TP53、PIK3CA的SNV突变频率和ERBB2、CDK12、SPOP扩增频率有明显差异。

关键词: 乳腺肿瘤, 分子分型, 突变, 同源重组修复
Objective

To investigate the characteristics of gene mutations and homologous recombination repair (HRR)-related gene mutations in different molecular subtypes of breast cancer.

Methods

According to the inclusion and exclusion criteria, 139 patients who were pathologically diagnosed with breast cancer and tested for somatic or/and germline mutations of 1021 tumor-related genes in the Daping Hospital of Army Medical University from March 2017 to March 2021 was included for a retrospective study. Based on the results of genetic testing, the somatic single nucleotide variants (SNV), copy number variants (CNV) and germline SNV in patients with five molecular subtypes were compared, and the mutation characteristics of HRR-related genes were also analyzed. Comparison among multiple groups was performed using χ2 test, and Fisher's exact test and Bonferroni correction were used for pairwise comparison.

Results

Among 139 patients, 108 patients were tested for somatic mutations and 139 patients were tested for germline mutations; there were 42 patients with luminal A subtype, 25 luminal B subtype (HER-2 negative), 11 luminal B subtype (HER-2 positive), 26 HER-2 overexpression subtype, 30 triple negative subtype and 5 unknown subtype. Among the 103 patients with clear molecular subtype and gene mutation detection, the five genes with the highest SNV mutation frequency were as follow: TP53 (57.3%, 59/103), PIK3CA (43.7%, 45/103), MLL3 (12.6%, 13/103), GATA3 (9.7%, 10/103) and MAP3K1 (8.7%, 9/103). The SNV mutation frequencies of TP53 and PIK3CA showed a significant difference among breast cancer patients with different molecular subtypes (χ2=16.617, 16.434, both P=0.002). Compared with luminal A subtype, TP53 mutation frequency was significantly higher in HER-2 overexpression subtype (P=0.004). Compared with luminal A and luminal B (HER-2 positive) subtypes, PIK3CA mutation frequency was significantly lower in triple negative subtype (P=0.006, 0.005). The ten genes with the highest CNV amplification frequency were as follow: ERBB2 (27.2%, 28/103), CDK12 (16.5%, 17/103), MYC (14.6%, 15/103), CCND1 (11.6%, 12/103)), FGF19 (8.7%, 9/103), FGF3 (8.7%, 9/103), FGF4 (8.7%, 9/103), SPOP (5.8%, 6/103), FGFR1 (5.8%, 6/103) and MCL1 (5.8%, 6/103). The amplification frequencies of ERBB2, CDK12 and SPOP showed a significant difference among breast cancer patients with different molecular subtypes (χ2=69.996, 38.192, 14.859, all P<0.050). Pairwise comparison results showed that ERBB2 amplification was significantly enriched in luminal B subtype (HER-2 positive) and HER-2 overexpression subtype [compared with luminal A subtype, P=0.001, <0.001; compared with luminal B subtype (HER-2 negative), P=0.007, <0.001; compared with triple negative subtype, P=0.005, <0.001]; compared with luminal A, luminal B (HER-2 negative) and TNBC subtypes, CDK12 amplification frequency was significantly higher in HER-2 overexpression subtype (P<0.001, <0.001, P=0.004); CDK12 amplification frequency in luminal B (HER-2 positive) subtype was significantly higher than that in luminal B (HER-2 negative) subtype (P=0.040). The germline gene mutation analysis showed that the top two genes with the highest germline mutation frequency were BRCA2 and BRCA1 [10.4% (14/134), 6.0% (8/134)]. Among the 36 HRR-related genes, the amplification frequency of CDK12 showed a significant difference among different molecular subtypes (χ2=38.192, P=0.001).

Conclusions

Breast cancer patients with different molecular subtypes have different gene mutation characteristics. Among them, the mutation frequency of TP53, PIK3CA, SNV and the amplification frequency of ERBB2, CDK12 and SPOP are significantly different among five molecular subtypes.

Key words: Breast neoplasms, Molecular typing, Mutation, Homologous recombinational repair
表1 139例乳腺癌患者的临床病理特征
临床病理特征 例(%)
肿瘤大小  
  Tis 3(2.2)
  T1 33(23.7)
  T2 76(54.7)
  T3 11(7.9)
  T4 7(5.0)
  未知 9(6.5)
淋巴结状态  
  阴性 65(46.8)
  阳性 63(45.3)
  不详 11(7.9)
TNM分期  
  0期 3(2.2)
  Ⅰ期 20(14.4)
  Ⅱ期 71(51.1)
  Ⅲ期 27(19.4)
  Ⅳ期 4(2.9)
  不详 14(10.1)
家族史  
  是 32(23.0)
  否 105(75.5)
  不详 2(1.4)
手术史  
  是 135(97.1)
  否 4(2.9)
辅助化疗  
  新辅助 80(57.6)
  辅助 46(33.1)
  无 5(3.6)
  不详 8(5.8)
分子分型  
  luminal A型 42(30.2)
  luminal B型(HER-2阴性) 25(18.0)
  luminal B型(HER-2阳性) 11(7.9)
  HER-2过表达型 26(18.7)
  三阴型 30(21.6)
  不详 5(3.6)
表2 103例乳腺癌患者中体细胞单核苷酸位点变异频率前5位基因的分布[例(%)]
分子分型 例数 TP53 PIK3CA MLL3 GATA3 MAP3K1
luminal A型 33 11(33.3) 19(57.6)b 6(18.2) 7(21.1) 4(12.1)
luminal B型(HER-2阴性) 22 11(50.0) 8(36.4) 2(9.1) 0 1(4.5)
luminal B型(HER-2阳性) 9 6(6/9) 7(7/9)b 3(3/9) 1(1/9) 2(2/9)
HER-2过表达型 23 19(82.6)a 10(43.5) 1(4.3) 1(4.3) 0
三阴型 16 12(12/16) 1(1/16) 1(1/16) 1(1/16) 2(2/16)
χ2值   16.617 16.434 6.691 8.340 5.497
P值   0.002 0.002 0.153 0.080 0.240
表3 103例乳腺癌患者中体细胞拷贝数变异扩增频率前10位基因的分布[例(%)]
分子分型 例数 ERBB2 CDK12 MYC CCND1 FGF19 FGF3 FGF4 SPOP FGFR1 MCL1
luminal A型 33 1(3.0) 1(3.0) 2(6.1) 7(21.2) 4(12.1) 4(12.1) 4(12.1) 2(6.1) 2(6.1) 2(6.1)
luminal B型(HER-2阴性) 22 1(4.5) 0 7(31.8) 2(9.1) 2(9.1) 2(9.1) 2(9.1) 0 3(13.6) 3(13.6)
luminal B型(HER-2阳性) 9 6(6/9)abc 4(4/9)b 1(1/9) 1(1/9) 1(1/9) 1(1/9) 1(1/9) 3(3/9) 1(1/9) 0
HER-2过表达型 23 20(87.0)abc 12(52.2)abc 3(13.0) 2(8.7) 2(8.7) 2(8.7) 2(8.7) 1(4.3) 0 1(4.3)
三阴型 16 0 0 2(2/16) 0 0 0 0 0 0 0
χ2值   69.996 38.192 7.365 5.379 2.073 2.073 2.073 14.859 5.321 4.088
P值   <0.001 0.001 0.118 0.251 0.722 0.722 0.722 0.005 0.256 0.394
表4 134例乳腺癌患者中胚系单核苷酸位点变异频率前5位基因的分布[例(%)]
分子分型 例数 BRCA2 BRCA1 ATM MUTYH PALB2
luminal A型 42 5(11.9) 0 1(2.4) 0 1(2.4)
luminal B型(HER-2阴性) 25 4(16.0) 2(8.0) 2(8.0) 2(8.0) 0
luminal B型(HER-2阳性) 11 0 1(1/11) 0 0 0
HER-2过表达型 26 4(15.4) 1(3.8) 0 0 1(3.8)
三阴型 30 1(3.3) 4(13.3) 0 1(3.3) 1(3.3)
χ2值   4.503 6.147 5.329 5.765 1.299
P值   0.342 0.188 0.255 0.217 0.861
表5 103例乳腺癌患者中HRR相关基因的体细胞SNV和CNV特征分布[例(%)]
突变类型 luminal A型(n＝33) luminal B型(HER-2阴性)(n＝22) luminal B型(HER-2阳性)(n＝9) HER-2过表达型(n＝23) 三阴型(n＝16) χ2值 P值
体细胞SNV              
  BRIP1 2(6.1) 0 0 2(8.7) 0 3.745 0.442
  ATRX 1(3.0) 0 0 1(4.3) 1(1/16) 1.729 0.785
  BRAC1 1(3.0) 1(4.5) 0 1(4.3) 0 1.127 0.890
  FANCG 2(6.1) 0 1(1/9) 0 0 5.126 0.275
  ATM 1(3.0) 0 0 0 1(1/16) 2.834 0.586
  BARD1 0 1(4.5) 0 0 0 3.718 0.445
  BRCA2 1(3.0) 0 0 1(4.3) 0 1.835 0.766
  FANCD2 0 1(4.5) 0 1(4.3) 0 2.631 0.621
  NBN 0 1(4.5) 1(1/9) 0 0 6.183 0.186
  ATR 0 0 0 0 1(1/16) 5.491 0.240
  CHEK1 0 0 0 1(4.3) 0 3.512 0.476
  CHEK2 0 0 0 1(4.3) 0 3.512 0.476
  FANCA 0 1(4.5) 0 0 0 3.718 0.445
  FANCC 0 1(4.5) 0 0 0 3.718 0.445
  MRE11A 1(3.0) 0 0 0 0 2.142 0.710
  PALB2 0 1(4.5) 0 0 0 3.718 0.445
  RAD51B 0 0 0 1(4.3) 0 3.512 0.476
  RECQL 1(3.0) 0 0 0 0 2.142 0.710
  RECQL4 0 0 0 0 1(1/16) 5.491 0.240
体细胞CNV              
  CDK12 1(3.0) 0 4(4/9) 12(52.2) 0 38.192 0.001
  BRIP1 3(9.1) 0 0 1(4.3) 1(1/16) 2.944 0.567
  NBN 0 1(4.5) 0 1(4.3) 1(1/16) 2.265 0.687
  RAD51C 1(3.0) 0 0 1(4.3) 0 1.835 0.766
  RAD52 1(3.0) 0 0 1(4.3) 0 1.835 0.766
  BRCA1 0 0 0 1(4.3) 0 3.512 0.476
  RECQL 0 1(4.5) 0 0 0 3.718 0.445
  RECQL4 0 1(4.5) 0 0 0 3.718 0.445
表6 134例乳腺癌患者中HRR相关基因胚系SNV特征分布[例(%)]
突变类型 luminal A型(n＝42) luminal B型(HER-2阴性)(n＝25) luminal B型(HER-2阳性)(n＝11) HER-2过表达型(n＝26) 三阴型(n＝30) χ2值 P值
BRCA2 5(11.9) 4(16.0) 0 4(15.4) 1(3.3) 4.503 0.342
BRCA1 0 2(8.0) 1(1/11) 1(3.8) 4(13.3) 6.147 0.188
ATM 1(2.4) 2(8.0) 0 0 0 5.329 0.255
PALB2 1(2.4) 0 0 1(3.8) 1(3.3) 1.299 0.861
BRIP1 1(2.4) 0 0 0 1(3.3) 1.856 0.762
CHEK2 0 1(4.0) 1(1/11) 0 0 6.873 0.143
MRE11A 1(2.4) 1(4.0) 0 0 0 2.310 0.679
NBN 0 0 1(1/11) 0 1(3.3) 6.420 0.170
RAD50 0 0 0 2(7.7) 0 8.434 0.077
BAP1 0 0 0 0 1(3.3) 3.493 0.479
BLM 0 0 0 0 1(3.3) 3.493 0.479
BARD1 0 0 0 1(3.8) 0 4.185 0.381
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