Spans Lien, Van den Broeck Thomas, Smeets Elien, Prekovic Stefan, Thienpont Bernard, Lambrechts Diether, Karnes R Jeffrey, Erho Nicholas, Alshalalfa Mohammed, Davicioni Elai, Helsen Christine, Gevaert Thomas, Tosco Lorenzo, Haustermans Karin, Lerut Evelyne, Joniau Steven, Claessens Frank
Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
Current address: Laboratory for Genetics of Malignant Disorders, Department of Human Genetics, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
Oncotarget. 2016 Apr 26;7(17):24326-38. doi: 10.18632/oncotarget.8220.
The clinical heterogeneity of prostate cancer (PCa) makes it difficult to identify those patients that could benefit from more aggressive treatments. As a contribution to a better understanding of the genomic changes in the primary tumor that are associated with the development of high-risk disease, we performed exome sequencing and copy number determination of a clinically homogeneous cohort of 47 high-risk PCas. We confirmed recurrent mutations in SPOP, PTEN and TP53 among the 850 point mutations we detected. In seven cases, we discovered genomic aberrations in the TET1 (Ten-Eleven Translocation 1) gene which encodes a DNA hydroxymethylase than can modify methylated cytosines in genomic DNA and thus is linked with gene expression changes. TET1 protein levels were reduced in tumor versus non-tumor prostate tissue in 39 of 40 cases. The clinical relevance of changes in TET1 levels was demonstrated in an independent PCa cohort, in which low TET1 mRNA levels were significantly associated with worse metastases-free survival. We also demonstrate a strong reduction in hydroxymethylated DNA in tumor tissue in 27 of 41 cases. Furthermore, we report the first exploratory (h)MeDIP-Seq analyses of eight high-risk PCa samples. This reveals a large heterogeneity in hydroxymethylation changes in tumor versus non-tumor genomes which can be linked with cell polarity.
前列腺癌（PCa）的临床异质性使得难以识别那些可能从更积极治疗中获益的患者。为了更好地理解与高危疾病发展相关的原发性肿瘤中的基因组变化，我们对47例高危PCa的临床同质队列进行了外显子组测序和拷贝数测定。在我们检测到的850个点突变中，我们证实了SPOP、PTEN和TP53中的复发性突变。在7例病例中，我们在TET1（十一-易位蛋白1）基因中发现了基因组畸变，该基因编码一种DNA羟甲基化酶，可修饰基因组DNA中的甲基化胞嘧啶，因此与基因表达变化有关。在40例病例中的39例中，肿瘤组织与非肿瘤前列腺组织相比，TET1蛋白水平降低。TET1水平变化的临床相关性在一个独立的PCa队列中得到证实，其中低TET1 mRNA水平与无转移生存期较差显著相关。我们还在41例病例中的27例中证明了肿瘤组织中羟甲基化DNA的显著减少。此外，我们报告了对8个高危PCa样本的首次探索性（h）MeDIP-Seq分析。这揭示了肿瘤基因组与非肿瘤基因组中羟甲基化变化的巨大异质性，这可能与细胞极性有关。
