染色体不稳定性是广泛存在于癌细胞的特征之一，当癌细胞分裂时，染色体被错误复制，导致非整倍染色体。对全套染色体的基因DNA进行基因组分析有助于为乳腺癌患者提供新的诊疗策略，不过既往基因组研究主要关注早期乳腺癌的原发灶，较少关注晚期乳腺癌的转移灶，肿瘤内异质性以及难以重复进行组织活检可能是主要原因，尤其对于晚期乳腺癌的转移灶。对血液循环中游离于肿瘤细胞外的DNA进行大规模并行测序是解决上述问题的办法之一，受肿瘤内异质性的影响最小，与组织活检相比，优势在于微创、基因组分析更全面。既往基因组分析主要针对体细胞特定基因特定突变或特定基因拷贝数量变化，可能无法提供基因组的全貌，通过细胞游离DNA全基因组测序进行染色体不稳定性分析可能提供一种新的诊疗策略。
2020年7月29日，欧洲乳腺癌专科医师学会《乳腺》在线发表中国医学科学院肿瘤医院莫红楠、马飞、易宗毕、管秀雯、刘斌亮、徐兵河等学者的研究报告，利用细胞游离DNA全基因组测序，展现了晚期乳腺癌患者染色体不稳定性的全貌，并分析了对患者生存结局的预测价值。
该单中心回顾研究对2015年3月～2015年10月中国医学科学院肿瘤医院65例晚期乳腺癌患者的冷冻血浆和临床资料进行回顾分析，对血浆中的细胞游离DNA进行低覆盖全基因组测序，通过染色体非整倍超敏检测法，对染色体不稳定性进行评分。
结果，对于激素受体和HER2处于不同状态的肿瘤，全基因组测序发现其染色体不稳定性不同。
根据受试者操作特征曲线和统计学分布，将染色体不稳定性评分高与低的临界值定为3881分。
32例患者（53.3%）染色体不稳定性评分高，与染色体不稳定性评分低的患者相比：
临床病理特征相似
总生存时间较短：中位21.2个月（95%置信区间：14.1～28.3）比未达中位（P=0.006）
无进展生存时间较短：中位7.3个月比11.0个月（P=0.034）
多因素比例风险回归模型分析表明，染色体不稳定性评分为独立预后因素，评分高与低相比，总死亡风险高3.563倍（95%置信区间：1.481～8.572，P=0.005）。
此外，该研究还成功地通过该方法从细胞游离DNA测出HER2基因拷贝数量变化，与通过免疫组织化学法和荧光原位杂交法从肿瘤组织测出的HER2状态高度一致，可用于预测曲妥珠单抗的疗效。
因此，该研究首次通过细胞游离DNA全基因组测序阐明了染色体不稳定性对晚期乳腺癌的独立预后价值，故有必要进一步开展多中心大样本前瞻研究对该结果进行验证。
Breast. 2020 Jul 29;53:111-118. Online ahead of print.
Genome-wide chromosomal instability by cell-free DNA sequencing predicts survival in patients with metastatic breast cancer.
Mo H, Wang X, Ma F, Qian Z, Sun X, Yi Z, Guan X, Li L, Liu B, Xu B.
National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Prophet Genomics Inc, San Jose, USA; Suzhou Hongyuan Biotech Inc, Biobay, Suzhou, China; Cancer Hospital of Huanxing, Beijing, China.
HIGHLIGHTS
Novel UCAD pipeline to profile genome-wide chromosomal instability in cfDNA.
Genome-wide chromosomal instability is a robust independent prognostic biomarker.
HER2 amplification was successfully identified from cfDNA in our cohort.
BACKGROUND: Genome-wide chromosomal instability, instead of specific somatic mutations or copy-number alterations in selected genes, is a significant property of cancer and may suggest a new strategy for treatment. Here we utilized cell-free DNA (cfDNA) sequencing to display the whole picture of chromosomal instability in patients with metastatic breast cancer (MBC), and evaluate its predictive value for patient survival.
METHODS: The clinical data of 65 patients who had frozen plasma and planned to change the therapeutic regimen were retrospectively enrolled. Low-coverage whole-genome sequencing of cfDNA was performed to generate the chromosomal instability represented by chromosomal instability (CIN) score.
RESULTS: Tumors with diverse status of hormone receptor and HER2 represented diverse chromosomal instability across the whole genome. According to the receiver operating characteristic curve and the statistical distribution, CIN score exceed 3881 was defined as "High". 32 (53.3%) patients with high CIN score had similar clinicopathologic characteristics compared with low CIN score patients. The median overall survival of patients with high CIN score was 21.2 months (95% CI 14.1-28.3), which was significantly inferior to those with low CIN score (not reached, P = 0.006). Regardless of various treatment regimens, the median progression free survival in patients with high CIN score was 7.3 months, which was significantly worse than those in the low CIN score population (11.0 months, P = 0.034). Multivariate analysis revealed that CIN score was an independent prognostic factor, with hazard ratio of 3.563 (P = 0.005).
CONCLUSIONS: To our knowledge, this is the first study illustrating the prognostic value of chromosomal instability derived from cfDNA in MBC.
KEYWORDS: Cell-free nucleic acids, Chromosomal instability, DNA Copy number alteration, Breast neoplasms, Prognosis
PMID: 32738630
DOI: 10.1016/j.breast.2020.07.004
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