1170例女性乳腺癌HER2基因状态的荧光原位杂交结果分析

HER2 status in breast cancer of Chinese women： a study of 1170 cases using fluorescence in-situ hybridization

目的以大样本量准确地检测乳腺浸润性导管癌的HER2基因各种异常类型及其频率。方法采用PathVysion^TM探针试剂盒，以荧光原位杂交（FISH）方法，分析1170例拟采用曲妥珠单抗治疗或相关化疗的女性乳腺癌患者石蜡切片标本的HER2基因拷贝状态。结果直接用FISH分析的1170例标本中，408例（34．87％）阴性，762例（65．13％）阳性，其中信号成簇扩增者87例，占全部阳性病例的11．42％；其余675例中，低度扩增159例（23．56％），中度扩增422例（62．52％），高度扩增94例（13．93％）。1170例中，FISH结果为临界值（结果不确定）的14例（1．20％），其中比值为1．8～2．0的HER2阴性临界者1．23％（5／408），比值为2．0～2．2的HER2阳性临界者1．18％（9／762）；17号染色体非整体性发生率为73．00％（854／1170），其中亚二体性为22．65％（265／1170），低多体性为38．38％（449／1170），高多体性为11．97％（140／1170）；17号染色体多体性50．34％。阳性762例中，二体性182例（23．88％），亚二体性184例（24．15％），低多体性300例（39．37％），高多体性96例（12．60％）；17号染色体多体性51．97％。阴性408例中，二体性134例（32．84％），亚二体性81例（19．85％），低多体性149例（36．52％），高多体性44例（10．78％）。17号染色体多体性47．30％。HER2基因单等位基因缺失者占1170例之2．39％，17号染色体单体性在FISH阳性病例中占5．00％（38／762），在FISH阴性病例中占4．41％（18／408）；HER2比值〈1．5者占1170例之32．30％，占FISH阴性408例之92．65％；比值介于1．5～2．2之间的占9．23％（108／1170）。结论经临床筛选出拟进行生物靶向及相关治疗的中国内地女性乳腺癌患者FISH检测HER2扩增率高，其中以HER2基因中度扩增为常见类型；17号染色体非整体性，尤其是17号染色体多体性十分常见，其意义值得关注。

Objective To assess the prevalence of HER2 amplification according to HER2 and chromosome 17 copy numbers and HER2 FISH （fluorescence in-situ hybridization） ratio in breast cancer occurring in Chinese women. Methods Eleven hundreds and seventy cases of breast cancer occurring in Chinese women, who would be treated by trastuzumab and/or relevant chemotherapy based on HER2 status, were enrolled into the study. The formalin-fixed and paraffin-embedded tumor tissues were tested by FISH （PathVysion, Vysis）. Results Among the 1170 cases of breast cancer studied, 408 cases （34. 87% ） were FISH-negative, whereas 762 cases （65. 13% ） were FISH-positive, including 87 cases （87/762, 11.42% ） with highly amplified HER2 gene （ signals arranged in aggregates）. As for the remaining 675 FISH-positive cases, 159 cases （23. 56% ） showed low amplification （HER2/CEP17 ratio = 2 to 4）, 422 cases （62. 52% ） showed moderate amplification （ratio = 4 to 10） and 94 cases （ 13.93% ） showed high amplification （ratio 〉 10） for HER2 gene. Only 14 of the 1170 cases （1.20%） had indeterminate results （ratio between 1.8 and 2. 2） , including 1.23% （5/408） borderline FISH-negative （ratio between 1.8 and 2. 0） and 1.18% （9/762） berderline FISH-positive （ratio between 2. 0 and 2. 2）. Our data showed that 73.00% （854/1170） of cases were chromosome 17 aneusomy, including 22. 65% （265/1170） hypodisomy （chromosome 17 copy number per cell 〈 or = 1.75） , 38.38% （449/1170） low polysomy （chromosome 17 copy number per cell 2. 26 to 3.75 ） and 11.97% （140/1170） high polysomy （ chromosome 17 copy number per cell 〉 or = 3.76）. The frequency of chromosome 17 polysomy was 50. 34%. In the FISH- positive subgroup, 23.88% （182/762） was disomy （chromosome 17 copy number per cell between 1.76 and 2. 25）, 24.15% （184/762） hypodisomy, 39.37% （300/762） low polysomy and 12. 60% （96/762） high polysomy. The frequency of chromosome 17 polysomy in the FISH-positive subgroup was 51.97%. In the FISH-negative subgroup, 32. 84% （134/408） were disomy, 19. 85% （81/408） hypodisomy, 36. 52% （149/408） low polysomy and 10. 78% （44/408） high polysomy. The frequency of chromosome 17 polysomy in the FISH-negative subgroup was 47.30%. On the other hand, HER2 monoallelie deletion （HER2/CEP17 〈or = 0. 7） was observed in 2. 39% of eases. Chromosome 17 monosomy was detected in 5.00% （38/762） and 4. 41% （18/408） of HER2-positive and HER2-negative groups, respectively. A HER2 ratio of 〈 1.5 was noted in 32. 30% of all eases （ including 92.65% of HER2-negative eases） , compared with 9. 23% （108/1170） with ratio between 1.5 and 2. 2. Conclusions The results show that a high amplification of HER2 gene is detected by FISH. Moderate amplification of HER2 gene and chromosome 17 polysomy are commonly seen in breast cancer patients in China Mainland. These findings may carry significant clinical and pathogenetie implication.