由于癌症的早期诊断对于治疗非常重要，故乳腺癌的早期发现和治疗监测，仍然是亟待解决的重大问题。
2017年12月22日，英国生物医学中心旗下《基因组医学》在线发表英国伦敦大学学院、捷克布拉格大学、瑞士巴塞尔基因数据、德国慕尼黑大学、乌尔姆大学、GATC生物技术、勃林格殷格翰的研究报告，发现新的乳腺癌标志能够比现有方法提前一年发现乳腺癌。
乳腺癌DNA甲基化过程有一些微小的碳氢分子黏附于EFC#93片段，该变化发生于乳腺癌非常早期，可以通过分析该DNA片段判断乳腺癌早期迹象。该方法的优点为仅需血清样本即可进行诊断，时间远早于影像学或组织学检出乳腺肿瘤之前。由于异常的循环游离DNA甲基化模式可能提供高度特异性癌症信号，故作者假设细胞游离DNA甲基化提示可以指示转移性乳腺癌，即使存在大量背景DNA。作者首先对两组独立前瞻血清（110例）使用31种组织简化甲基化亚硫酸氢盐测序（RRBS）并根据超高覆盖亚硫酸氢盐测序建立血清检测法。随后，对吉西他滨＋多西他赛＋双膦酸盐辅助治疗研究（SUCCESS）419例乳腺癌患者（辅助化疗前后标本）和英国卵巢癌筛查协作研究（UKCTOCS）人群队列925例健康女性（诊断前标本）验证特定片段EFC#93的临床意义，将总生存和乳腺癌（致命或非致命）发生率分别作为主要终点。
结果在组织中，共发现18种乳腺癌相关DNA甲基化模式，其中前6种在血清中进一步检测，并对相关性最高的EFC#93进行临床验证。对于化疗前标本，EFC#93血清DNA甲基化阳性与阴性相比，死亡风险显著较高（死亡风险比：7.689），对于死亡风险的预测效果优于循环肿瘤细胞（死亡风险比：5.681）。如果化疗前标本的EFC#93血清DNA甲基化和循环肿瘤细胞同时为阳性，超过70%的患者在5年内复发。化疗后标本的EFC#93阳性转移性病变似乎对抗激素治疗有效。对于3～6和6～12个月内被诊断为致命乳腺癌女性的标本，EFC#93血清DNA甲基化阳性的敏感性分别为42.9%和25%，特异性为88%。检测致命乳腺癌与非致命乳腺癌相比，灵敏性高约4倍。
因此，EFC#93血清DNA甲基化模式检测为转移性乳腺癌早期诊断和治疗提供了新的工具，可使乳腺癌诊断更高效，与现有方法相比，最早可提前12个月检出。有必要开展临床研究以评估在尚无影像学可检出乳腺癌的情况下，EFC#93阳性女性在乳腺病变出现临床表现之前接受抗激素治疗能否获益。未来或许可以在尚未出现乳腺影像学检测证据的情况下，及早对患者开始治疗。
Methylation patterns in serum DNA for early identification of disseminated breast cancer.
Widschwendter M, Evans I, Jones A, Ghazali S, Reisel D, Ryan A, Gentry-Maharaj A, Zikan M, Cibula D, Eichner J, Alunni-Fabbroni M, Koch J, Janni WJ, Paprotka T, Wittenberger T, Menon U, Wahl B, Rack B, Lempiainen H.
University College London, London, UK; Charles University Prague, Prague, Czech Republic; Genedata AG, Basel, Switzerland; Klinikum Innenstadt, Ludwig-Maximilians Universitaet Muenchen, Munich, Germany; University Hospital Ulm, Ulm, Germany; GATC Biotech AG, Konstanz, Germany; Boehringer Ingelheim Pharma, GmbH & Co. KG, Target Discovery Research, Biberach, Germany.
BACKGROUND: Monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant circulating DNA methylation (DNAme) patterns are likely to provide a highly specific cancer signal. We hypothesized that cell-free DNAme markers could indicate disseminated breast cancer, even in the presence of substantial quantities of background DNA.
METHODS: We used reduced representation bisulfite sequencing (RRBS) of 31 tissues and established serum assays based on ultra-high coverage bisulfite sequencing in two independent prospective serum sets (n=110). The clinical use of one specific region, EFC#93, was validated in 419 patients (in both pre- and post-adjuvant chemotherapy samples) from SUCCESS (Simultaneous Study of Gemcitabine-Docetaxel Combination adjuvant treatment, as well as Extended Bisphosphonate and Surveillance-Trial) and 925 women (pre-diagnosis) from the UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening) population cohort, with overall survival and occurrence of incident breast cancer (which will or will not lead to death), respectively, as primary endpoints.
RESULTS: A total of 18 BC specific DNAme patterns were discovered in tissue, of which the top six were further tested in serum. The best candidate, EFC#93, was validated for clinical use. EFC#93 was an independent poor prognostic marker in pre-chemotherapy samples (hazard ratio [HR] for death=7.689) and superior to circulating tumor cells (CTCs) (HR for death=5.681). More than 70% of patients with both CTCs and EFC#93 serum DNAme positivity in their pre-chemotherapy samples relapsed within five years. EFC#93-positive disseminated disease in post-chemotherapy samples seems to respond to anti-hormonal treatment. The presence of EFC#93 serum DNAme identified 42.9% and 25% of women who were diagnosed with a fatal BC within 3-6 and 6-12 months of sample donation, respectively, with a specificity of 88%. The sensitivity with respect to detecting fatal BC was~4-fold higher compared to non-fatal BC.
CONCLUSIONS: Detection of EFC#93 serum DNAme patterns offers a new tool for early diagnosis and management of disseminated breast cancers. Clinical trials are required to assess whether EFC#93-positive women in the absence of radiological detectable breast cancers will benefit from anti-hormonal treatment before the breast lesions become clinically apparent.
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