血清DNA甲基化模式用於早期識別彌散性乳腺癌
論文標題:Methylation patterns in serum DNA for early identification of disseminated breast cancer
作者:Martin Widschwendter, Iona Evans, Allison Jones, Shohreh Ghazali, Daniel Reisel, Andy Ryan, Aleksandra Gentry-Maharaj, Michal Zikan, David Cibula, Johannes Eichner, Marianna Alunni-Fabbroni, Julian Koch, Wolfgang J. Janni, Tobias Paprotka, Timo Wittenberger, Usha Menon, Benjamin Wahl?, Brigitte Rack? and Harri Lempi?inen?
數字識別碼: 10.1186/s13073-017-0499-9
目前,致死性乳腺癌(BC)的治療監測和早期檢測仍然是一項迫切需求。異常循環DNA甲基化(DNAme)模式或提供了一種高度特異性的癌症信號。在一篇發表於Genome Medicine的文章中,來自英國倫敦大學學院的Martin Widschwendter及其團隊做了一個假設,即無細胞DNAme標記可預示彌散性乳腺癌的存在,即使在存在大量背景DNA的情況下,依然如此。
打開今日頭條,查看更多圖片研究者們對31個組織採用了簡化甲基化亞硫酸氫鹽測序(RRBS),基於超高覆蓋率的甲基化測序結果,對兩個獨立的前瞻性血清組進行血清分析(n=110)。他們將總生存和乳腺癌(致死性或非致死性)發生率作為主要終點,通過吉西他濱+多西他賽聯合輔助治療,+擴展的雙膦酸鹽輔助治療與監測研究(SUCCESS),在419例乳腺癌患者(輔助化療前後的標本)和英國卵巢癌篩選協同試驗(UKCTOCS)人群隊列中的925例健康女性(診斷前標本)中驗證了特定片段EFC#93的臨床應用。
圖:實驗設計
研究發現,在組織中共發現18種乳腺癌特異性DNA甲基化模式,研究者們對其中的前6種在血清中進行了進一步檢測,並對特異性最高的EFC#93進行了臨床驗證。對於化療前的標本,EFC#93是一個獨立不良預後指標(死亡風險比為7.689),對死亡風險的預測效果優於循環腫瘤細胞(死亡風險比為5.681)。化療前標本的EFC#93與循環腫瘤細胞均呈陽性的患者中,超過70%的患者會在5年內複發。化療後的標本中,EFC#93陽性播散性病變似乎對抗激素治療有反應。對於在標本捐贈後3~6和6~12個月內被診斷為致死乳腺癌的女性,標本中EFC#93血清DNA甲基化陽性的診斷敏感性分別為42.9%和25%,特異性為88%。相比非致死性乳腺癌,其檢測致死性乳腺癌的敏感性高出約4倍。
本研究認為,EFC#93血清DNA甲基化模式檢測為轉移性乳腺癌早期診斷和治療提供了一種新工具。尚需要開展相關臨床研究來評估在影像學無法檢出乳腺癌的情況下,EFC#93陽性女性在乳腺病變出現臨床表現之前接受抗激素治療能否獲益。
摘要:
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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期刊介紹:
Genome Medicine(https://genomemedicine.biomedcentral.com/,8.898 -2-year Impact Factor, 8.265 -5-year Impact Factor) is an open access journal publishing outstanding research in the application of genetics, genomics and multi-omics to understand, diagnose and treat disease. Our publication policy combines selection for broad interest and importance with a commitment to serving authors well.
(來源:Genome Medicine)
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