无癌症的子宫内膜异位症中的癌症相关突变
Cancer-Associated Mutations in Endometriosis without Cancer.
作者信息
Anglesio Michael S, Papadopoulos Nickolas, Ayhan Ayse, Nazeran Tayyebeh M, Noë Michaël, Horlings Hugo M, Lum Amy, Jones Siân, Senz Janine, Seckin Tamer, Ho Julie, Wu Ren-Chin, Lac Vivian, Ogawa Hiroshi, Tessier-Cloutier Basile, Alhassan Rami, Wang Amy, Wang Yuxuan, Cohen Joshua D, Wong Fontayne, Hasanovic Adnan, Orr Natasha, Zhang Ming, Popoli Maria, McMahon Wyatt, Wood Laura D, Mattox Austin, Allaire Catherine, Segars James, Williams Christina, Tomasetti Cristian, Boyd Niki, Kinzler Kenneth W, Gilks C Blake, Diaz Luis, Wang Tian-Li, Vogelstein Bert, Yong Paul J, Huntsman David G, Shih Ie-Ming
机构信息
From the Departments of Obstetrics and Gynaecology (M.S.A., C.A., C.W., P.J.Y., D.G.H.) and Pathology and Laboratory Medicine (M.S.A., T.M.N., J. Senz, B.T.-C., C.B.G., D.G.H.), University of British Columbia, the Department of Anatomical Pathology, Vancouver General Hospital (T.M.N., H.M.H., J.H., V.L., B.T.-C., A.W., C.B.G., D.G.H.), the Department of Molecular Oncology, British Columbia Cancer Agency (H.M.H., A.L., V.L., N.B., D.G.H.), and the BC Women's Centre for Pelvic Pain and Endometriosis, BC Women's Hospital and Health Centre (F.W., N.O., C.A., C.W., P.J.Y.) - all in Vancouver, BC, Canada; the Department of Oncology (N.P., C.T., K.W.K., L.D., T.-L.W., B.V., I.-M.S.) and Ludwig Center (N.P., Y.W., J.D.C., M.Z., M.P., W.M., A.M., K.W.K., L.D., B.V.), Sidney Kimmel Comprehensive Cancer Center, the Departments of Pathology (N.P., A.A., M.N., L.D.W., T.-L.W., B.V., I.-M.S.) and Gynecology and Obstetrics (J. Segars, I.-M.S.), Johns Hopkins Medical Institutions, Personal Genome Diagnostics (S.J.), and Johns Hopkins University Howard Hughes Medical Institute (B.V.) - all in Baltimore; the Department of Pathology, Seirei Mikatahara Hospital (A.A., H.O.), and the Department of Tumor Pathology, Hamamatsu University School of Medicine (A.A.), Hamamatsu, and the Department of Molecular Pathology, Hiroshima University School of Medicine, Hiroshima (A.A.) - all in Japan; the Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands (M.N.); the Departments of Obstetrics and Gynecology (T.S.) and Pathology (R.A., A.H.), Lenox Hill Hospital-Northwell Health (Hofstra University), New York; and the Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Tao-Yuan City, Taiwan (R.-C.W.).
出版信息
N Engl J Med. 2017 May 11;376(19):1835-1848. doi: 10.1056/NEJMoa1614814.
BACKGROUND
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.
METHODS
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 microdissected 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.
RESULTS
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.
CONCLUSIONS
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.
背景
子宫内膜异位症定义为异位子宫内膜间质和上皮的存在，影响约10%的育龄妇女，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症性病变，但具有类似癌症的特征，如局部侵袭和抗凋亡能力。
方法
我们通过全外显子组测序（24例患者）或癌症驱动基因靶向测序（3例患者）对27例患者的深度浸润性子宫内膜异位症病变进行了分析。使用数字基因组方法在显微切割的上皮和间质中验证突变。另外12例患者病变的上皮和间质成分通过液滴数字聚合酶链反应（PCR）检测复发性激活型KRAS突变进行分析。
结果
全外显子组测序显示24例患者中有19例（79%）存在体细胞突变。5例患者在ARID1A、PIK3CA、KRAS或PPP2R1A中携带已知的癌症驱动基因突变，这些突变通过安全测序系统或免疫组织化学分析得到验证。在无选择情况下，驱动基因以这种频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检测分别在3例患者中的2例和12例患者中的3例中鉴定出KRAS突变，突变存在于上皮而非间质中。1例患者携带两种不同的KRAS突变，即c.35G→T和c.35G→C，另1例在三个不同病变中携带相同的KRAS c.35G→A突变。
结论
我们发现，与几乎没有恶性转化风险相关的深度浸润性子宫内膜异位症病变存在体细胞癌症驱动基因突变。39个深度浸润性病变中有10个（26%）携带驱动基因突变；所有检测到的体细胞突变似乎都局限于子宫内膜异位症病变的上皮部分。
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