Cancer-Associated Mutations in Endometriosis without Cancer.
Cancer-Associated Mutations in Endometriosis without Cancer.
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DOI：
10.1056/nejmoa1614814
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发表时间：
2017-05-11
期刊：
影响因子：
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通讯作者：
Shih IM
中科院分区：
文献类型：
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作者：
Anglesio MS;Papadopoulos N;Ayhan A;Nazeran TM;Noë M;Horlings HM;Lum A;Jones S;Senz J;Seckin T;Ho J;Wu RC;Lac V;Ogawa H;Tessier-Cloutier B;Alhassan R;Wang A;Wang Y;Cohen JD;Wong F;Hasanovic A;Orr N;Zhang M;Popoli M;McMahon W;Wood LD;Mattox A;Allaire C;Segars J;Williams C;Tomasetti C;Boyd N;Kinzler KW;Gilks CB;Diaz L;Wang TL;Vogelstein B;Yong PJ;Huntsman DG;Shih IM
子宫内膜异位症，定义为异位子宫内膜基质和上皮的存在，影响约10%的育龄妇女，并可导致盆腔疼痛和不孕。子宫内膜异位症病变被认为是良性炎性病变，但具有癌样特征，如局部浸润和抗细胞凋亡。我们通过外显子组测序（24例患者）或癌症驱动靶向测序（3例患者）分析了27例患者的深度浸润性肿瘤病变。在显微解剖的上皮和基质中使用数字基因组方法验证突变。通过微滴数字聚合酶链反应（PCR）检测复发性激活KRAS突变，分析了另外12例患者病变的上皮和基质成分。外显子组测序显示24例患者中有19例（79%）发生体细胞突变。5名患者在ARID 1A、PIK 3CA、KRAS或PPP 2 R1 A中携带已知的癌症驱动突变，这些突变通过安全测序系统或免疫组织化学分析进行了验证。在不存在选择的情况下，驱动基因以该速率受影响的可能性估计为P = 0.001（二项式检验）。靶向测序和液滴数字PCR测定分别在3名患者中的2名和12名患者中的3名中鉴定出KRAS突变，突变在上皮中而不是基质中。一名患者携带两种不同的KRAS突变，c.35G→T和c.35G→C，另一名患者在三个不同的病变中携带相同的KRAS c.35G→A突变。我们发现，在深部浸润性子宫内膜异位症的病变，这是与几乎没有恶变的风险，港口体细胞癌驱动突变。39例深部浸润性病变中有10例（26%）携带驱动突变;所有检测的体细胞突变似乎仅限于上皮细胞病变的上皮细胞室。
Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis. We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in micro-dissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations. Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P = 0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions. We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.