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无癌子宫内膜异位症携带癌症相关基因突变的研究
Cancer-Associated Mutations in Endometriosis without Cancer


Michael S. Anglesio ... 肿瘤 • 2017.05.11
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摘要


背景

子宫内膜异位症系指子宫间质和上皮在异位出现;它可累及大约10%的育龄妇女,可引起盆腔疼痛和不育。子宫内膜异位症的病灶被认为属于良性的炎症性病变,但具有癌症样的特征,例如局部浸润和抗凋亡等。

 

方法

我们对27例患者的深部浸润型子宫内膜异位症病灶进行了分析,采用的方法为全外显子组测序(exomewide sequencing)(24例患者)或癌症驱动基因靶向测序(3例患者)。我们采用数字基因组法(digital genomic method)对显微切割的上皮与间质中的基因突变进行验证。我们对另外12例患者病灶的上皮和间质进行了微滴数字聚合酶链反应(PCR)检测,以分析这些标本中重复出现的KRAS激活突变(recurrent activating KRAS mutations)。

 

结果

外显子组测序结果显示,24例患者中有19例(79%)携带体细胞突变。5例患者携带已知的下列癌症驱动基因突变:ARID1A、PIK3CA、KRASPPP2R1A;我们通过安全测序系统(safe-sequencing system)或免疫组织化学检测法对其进行了验证。我们估计,在不加选择的情况下,驱动基因突变达到这一比例可能性的P值为0.001(二项式检验)。靶向测序法在3例患者中检出2例携带KRAS突变,而微滴数字PCR法则在12例患者中检出3例携带KRAS突变;KRAS突变仅存在于上皮细胞中,间质中不存在该基因突变。1例患者携带两种不同的KRAS突变,分别是c.35G→T突变和c.35G→C突变;另一例患者的三处不同病灶存在相同的KRAS突变,c.35G→A突变。

 

结论

我们发现,对于基本没有恶变风险的深部浸润型子宫内膜异位症,其病灶存在体细胞癌症驱动基因突变。在39处深部浸润型病灶中,10处(26%)携带癌症驱动基因突变;所有检测到的体细胞基因突变似乎均只限于子宫内膜异位症病灶的上皮细胞内。





作者信息

Michael S. Anglesio, Ph.D., Nickolas Papadopoulos, Ph.D., Ayse Ayhan, M.D., Ph.D., Tayyebeh M. Nazeran, M.D., Michaël Noë, M.D., Hugo M. Horlings, M.D., Ph.D., Amy Lum, B.Sc., Siân Jones, Ph.D., Janine Senz, B.Sc., Tamer Seckin, M.D., Julie Ho, M.H.A., Ren-Chin Wu, M.D., Ph.D., Vivian Lac, B.Sc., Hiroshi Ogawa, M.D., Basile Tessier-Cloutier, M.D., Rami Alhassan, M.D., Amy Wang, Yuxuan Wang, B.Sc., Joshua D. Cohen, B.Sc., Fontayne Wong, B.Sc., Adnan Hasanovic, M.D., Natasha Orr, B.Sc., Ming Zhang, Ph.D., Maria Popoli, B.Sc., Wyatt McMahon, Ph.D., Laura D. Wood, M.D., Ph.D., Austin Mattox, B.Sc., Catherine Allaire, M.D., James Segars, M.D., Christina Williams, M.D., Cristian Tomasetti, Ph.D., Niki Boyd, Ph.D., Kenneth W. Kinzler, Ph.D., C. Blake Gilks, M.D., Luis Diaz, M.D., Tian-Li Wang, Ph.D., Bert Vogelstein, M.D., Paul J. Yong, M.D., Ph.D., David G. Huntsman, M.D., and Ie-Ming Shih, M.D., Ph.D.
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.). Address reprint requests to Dr. Shih at the Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans St., Baltimore, MD 21231, or at ishih@jhmi.edu; to Dr. Huntsman at the Department of Molecular Oncology, British Columbia Cancer Agency, 675 W. 10th Ave., Vancouver, BC V5Z 1L3, Canada, or at dhuntsma@bccancer.bc.ca; to Dr. Yong at the BC Women’s Centre for Pelvic Pain and Endometriosis, BC Women’s Hospital and Health Centre, 4500 Oak St., Vancouver, BC V6H 3N1, Canada, or at pyong@cw.bc.ca; or to Dr. Papadopoulos at the Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, 1650 Orleans St., Baltimore, MD 21287, or at npapado1@jhmi.edu.

 

参考文献

1. Giudice LC. Endometriosis. N Engl J Med 2010;362:2389-2398

2. Reese KA, Reddy S, Rock JA. Endometriosis in an adolescent population: the Emory experience. J Pediatr Adolesc Gynecol 1996;9:125-128

3. Bulun SE. Endometriosis. N Engl J Med 2009;360:268-279

4. Leyland N, Casper R, Laberge P, Singh SS. Endometriosis: diagnosis and management. J Obstet Gynaecol Can 2010;32:Suppl 2:S1-S32

5. Tosti C, Pinzauti S, Santulli P, Chapron C, Petraglia F. Pathogenetic mechanisms of deep infiltrating endometriosis. Reprod Sci 2015;22:1053-1059

6. Ferrero S, Alessandri F, Racca A, Leone Roberti Maggiore U. Treatment of pain associated with deep endometriosis: alternatives and evidence. Fertil Steril 2015;104:771-792

7. Donnez J, Squifflet J, Pirard C, Jadoul P, Wyns C, Smets M. The efficacy of medical and surgical treatment of endometriosis-associated infertility and pelvic pain. Gynecol Obstet Invest 2002;54:Suppl 1:2-7

8. Ferguson BR, Bennington JL, Haber SL. Histochemistry of mucosubstances and histology of mixed Müllerian pelvic lymph node glandular inclusions: evidence for histogenesis by Müllerian metaplasia of coelomic epithelium. Obstet Gynecol 1969;33:617-625

9. Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol 1927;3:93-110.43

10. Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927;14:422-469

11. Sasson IE, Taylor HS. Stem cells and the pathogenesis of endometriosis. Ann N Y Acad Sci 2008;1127:106-115

12. Figueira PG, Abrão MS, Krikun G, Taylor HS. Stem cells in endometrium and their role in the pathogenesis of endometriosis. Ann N Y Acad Sci 2011;1221:10-17

13. Fung JN, Rogers PA, Montgomery GW. Identifying the biological basis of GWAS hits for endometriosis. Biol Reprod 2015;92:87-87

14. Anglesio MS, Bashashati A, Wang YK, et al. Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden. J Pathol 2015;236:201-209

15. Kurman RJ, Shih IM. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am J Pathol 2016;186:733-747

16. Vestergaard AL, Thorup K, Knudsen UB, et al. Oncogenic events associated with endometrial and ovarian cancers are rare in endometriosis. Mol Hum Reprod 2011;17:758-761

17. Sato N, Tsunoda H, Nishida M, et al. Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res 2000;60:7052-7056

18. Samartzis EP, Samartzis N, Noske A, et al. Loss of ARID1A/BAF250a-expression in endometriosis: a biomarker for risk of carcinogenic transformation? Mod Pathol 2012;25:885-892

19. Borrelli GM, Abrão MS, Taube ET, et al. (Partial) loss of BAF250a (ARID1A) in rectovaginal deep-infiltrating endometriosis, endometriomas and involved pelvic sentinel lymph nodes. Mol Hum Reprod 2016;22:329-337

20. Chene G, Ouellet V, Rahimi K, Barres V, Provencher D, Mes-Masson AM. The ARID1A pathway in ovarian clear cell and endometrioid carcinoma, contiguous endometriosis, and benign endometriosis. Int J Gynaecol Obstet 2015;130:27-30

21. Fassbender A, Rahmioglu N, Vitonis AF, et al. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: IV. Tissue collection, processing, and storage in endometriosis research. Fertil Steril 2014;102:1244-1253

22. Robles AI, Traverso G, Zhang M, et al. Whole-exome sequencing analyses of inflammatory bowel disease-associated colorectal cancers. Gastroenterology 2016;150:931-943

23. Anglesio MS, Wang YK, Maassen M, et al. Synchronous endometrial and ovarian carcinomas: evidence of clonality. J Natl Cancer Inst 2016;108:djv428-djv428

24. Kinde I, Wu J, Papadopoulos N, Kinzler KW, Vogelstein B. Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci U S A 2011;108:9530-9535

25. Ayhan A, Mao TL, Seckin T, et al. Loss of ARID1A expression is an early molecular event in tumor progression from ovarian endometriotic cyst to clear cell and endometrioid carcinoma. Int J Gynecol Cancer 2012;22:1310-1315

26. Guan B, Mao TL, Panuganti PK, et al. Mutation and loss of expression of ARID1A in uterine low-grade endometrioid carcinoma. Am J Surg Pathol 2011;35:625-632

27. Wu RC, Ayhan A, Maeda D, et al. Frequent somatic mutations of the telomerase reverse transcriptase promoter in ovarian clear cell carcinoma but not in other major types of gynaecological malignancy. J Pathol 2014;232:473-481

28. Mao TL, Ardighieri L, Ayhan A, et al. Loss of ARID1A expression correlates with stages of tumor progression in uterine endometrioid carcinoma. Am J Surg Pathol 2013;37:1342-1348

29. De Graaff AA, D’Hooghe TM, Dunselman GA, Dirksen CD, Hummelshoj L, Simoens S. The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey. Hum Reprod 2013;28:2677-2685

30. Cullen TS. Adenoma-myoma uteri diffusum benignum. Johns Hopkins Hosp Bull 1896;6:133-7.

31. Russell WW. Aberrant portions of the Mullerian duct found in an ovary. Johns Hopkins Hosp Bull 1899;10:8-9.

32. Gao X, Outley J, Botteman M, Spalding J, Simon JA, Pashos CL. Economic burden of endometriosis. Fertil Steril 2006;86:1561-1572

33. Klein S, D’Hooghe T, Meuleman C, Dirksen C, Dunselman G, Simoens S. What is the societal burden of endometriosis-associated symptoms? A prospective Belgian study. Reprod Biomed Online 2014;28:116-124

34. Simoens S, Dunselman G, Dirksen C, et al. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod 2012;27:1292-1299

35. McConechy MK, Anglesio MS, Kalloger SE, et al. Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas. J Pathol 2011;223:567-573

36. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature 2009;458:719-724

37. Forbes SA, Bindal N, Bamford S, et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 2011;39:D945-D950

38. Wiegand KC, Shah SP, Al-Agha OM, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 2010;363:1532-1543

39. Thomas EJ, Campbell IG. Molecular genetic defects in endometriosis. Gynecol Obstet Invest 2000;50:Suppl 1:44-50

40. Yamamoto S, Tsuda H, Takano M, Tamai S, Matsubara O. Loss of ARID1A protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with PIK3CA mutations. Mod Pathol 2012;25:615-624

41. Wei JJ, William J, Bulun S. Endometriosis and ovarian cancer: a review of clinical, pathologic, and molecular aspects. Int J Gynecol Pathol 2011;30:553-568

42. Cheng CW, Licence D, Cook E, et al. Activation of mutated K-ras in donor endometrial epithelium and stroma promotes lesion growth in an intact immunocompetent murine model of endometriosis. J Pathol 2011;224:261-269

43. Martincorena I, Roshan A, Gerstung M, et al. Tumor evolution: high burden and pervasive positive selection of somatic mutations in normal human skin. Science 2015;348:880-886

44. McConnell MJ, Lindberg MR, Brennand KJ, et al. Mosaic copy number variation in human neurons. Science 2013;342:632-637

45. Krimmel JD, Schmitt MW, Harrell MI, et al. Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues. Proc Natl Acad Sci U S A 2016;113:6005-6010

46. Kato S, Lippman SM, Flaherty KT, Kurzrock R. The conundrum of genetic “drivers” in benign conditions. J Natl Cancer Inst 2016;108:108-108

47. Masuda H, Matsuzaki Y, Hiratsu E, et al. Stem cell-like properties of the endometrial side population: implication in endometrial regeneration. PLoS One 2010;5:e10387-e10387

48. Cervelló I, Mas A, Gil-Sanchis C, et al. Reconstruction of endometrium from human endometrial side population cell lines. PLoS One 2011;6:e21221-e21221

49. Jubanyik KJ, Comite F. Extrapelvic endometriosis. Obstet Gynecol Clin North Am 1997;24:411-440

50. Vercellini P, Fedele L, Aimi G, Pietropaolo G, Consonni D, Crosignani PG. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod 2007;22:266-271

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