Cancer-Associated Mutations in Endometriosis without Cancer

作者：Michael S. Anglesio, Nickolas Papadopoulos, A. Ayhan, Tayyebeh M. Nazeran, Michaël Noë, Hugo M. Horlings, Amy M. Lum, Siân Jones, Janine Senz, Tamer A. Seckin, Julie Ho, Ren‐Chin Wu, Vivian Lac, Hiroshi Ogawa, Basile Tessier‐Cloutier, Rami Alhassan, Amy Wang, Yuxuan Wang, Joshua David Cohen, Fontayne Wong, Adnan Hasanovic, Natasha L. Orr, Ming Zhang, Maria Popoli, Wyatt McMahon, Laura DeLong Wood, Austin K. Mattox, Catherine Allaire, James H. Segars, Christina M. Williams, Cristian Tomasetti, Niki Boyd, Kenneth W. Kinzler, C. Blake Gilks, Luis Alberto Diaz, Tian‐Li Wang, Bert Vogelstein, Paul J. Yong, David George Huntsman, Ie‐Ming Shih · 发表于：New England Journal of Medicine · 年份：2017 · DOI：10.1056/nejmoa1614814 · 被引用次数：640 · 研究领域：Endometriosis Research and Treatment、Endometrial and Cervical Cancer Treatments、Beetle Biology and Toxicology Studies

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 ...