CD24 polymorphisms in breast cancer: Impact on prognosis and risk

Breast Cancer Research and Treatment

Volumn 137, Issue 3, 2013, Pages 927-937

  Buck, Katharina ^a   Hug, Sarah ^c   Seibold, Petra ^a   Ferschke, Irmgard ^c   Altevogt, Peter ^a   Sohn, Christof ^c   Schneeweiss, Andreas ^c,d   Burwinkel, Barbara ^a,c   Jäger, Dirk ^d   Flesch Janys, Dieter ^b   Chang Claude, Jenny ^a   Marmé, Frederik ^c,d  

^a GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^b UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

^c UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

^d UNIVERSITY OF HEIDELBERG   (Germany)

Author keywords

Breast cancer; CD24; Polymorphism; Prognosis; Risk; Susceptibility

Indexed keywords

CD24 ANTIGEN; TUMOR MARKER; VALINE;

3' UNTRANSLATED REGION; ADULT; AGED; ARTICLE; BREAST CANCER; CANCER MORTALITY; CANCER PROGNOSIS; CANCER RISK; CANCER SURVIVAL; CD24 GENE; CONTROLLED STUDY; FEMALE; GENE FREQUENCY; GENE OVEREXPRESSION; GENETIC ASSOCIATION; GENETIC RISK; GENETIC VARIABILITY; HUMAN; LYMPHOCYTIC INFILTRATION; MAJOR CLINICAL STUDY; OUTCOME ASSESSMENT; OVERALL SURVIVAL; POPULATION BASED CASE CONTROL STUDY; PRIMARY TUMOR; PRIORITY JOURNAL; RISK ASSESSMENT; RISK FACTOR; SINGLE NUCLEOTIDE POLYMORPHISM; BREAST TUMOR; CANCER STAGING; CASE CONTROL STUDY; GENETIC POLYMORPHISM; GENETICS; GENOTYPE; MIDDLE AGED; PATHOLOGY; PROGNOSIS; RISK;

3' UNTRANSLATED REGIONS; AGED; ANTIGENS, CD24; BREAST NEOPLASMS; CASE-CONTROL STUDIES; FEMALE; GENOTYPE; HUMANS; MIDDLE AGED; NEOPLASM STAGING; POLYMORPHISM, GENETIC; PROGNOSIS; RISK;

MLCS; MLOWN;

EID: 84879375968     PISSN: 01676806     EISSN: 15737217     Source Type: Journal    
DOI: 10.1007/s10549-012-2325-9     Document Type: Article

References (53)

1. Aigner S, Ramos CL, Hafezi-moghadam A, Lawrence MB, Friederichs J, Altevogt P, Ley K (1998) CD24 mediates rolling of breast carcinoma cells on P-selectin. FASEB J 12:1241-1251
2. Aigner S, Sthoeger ZM, Fogel M, Weber E, Zarn J, Ruppert M, Zeller Y, Vestweber D, Stahel R, Sammar M, Altevogt P (1997) CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells. Blood 89:3385-3395
3. Apetoh L, Ghiringhelli F, Tesniere A, Criollo A, Ortiz C, Lidereau R, Mariette C, Chaput N, Mira JP, Delaloge S, Andre F, Tursz T, Kroemer G, Zitvogel L (2007) The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev 220:47-59. doi: 10.1111/j.1600-065X.2007.00573.x
4. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira JP, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, Andre F, Delaloge S, Tursz T, Kroemer G, Zitvogel L (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050-1059. doi: 10.1038/nm1622
5. Askew D, Harding CV (2008) Antigen processing and CD24 expression determine antigen presentation by splenic CD4+ and CD8+ dendritic cells. Immunology 123:447-455. doi: 10.1111/j.1365-2567.2007.02711.x
6. Bai XF, Li O, Zhou Q, Zhang H, Joshi PS, Zheng X, Liu Y, Wang Y, Zheng P (2004) CD24 controls expansion and persistence of autoreactive T cells in the central nervous system during experimental autoimmune encephalomyelitis. J Exp Med 200:447-458. doi: 10.1084/jem.20040131
7. Baumann P, Cremers N, Kroese F, Orend G, Chiquet-Ehrismann R, Uede T, Yagita H, Sleeman JP (2005) CD24 expression causes the acquisition of multiple cellular properties associated with tumor growth and metastasis. Cancer Res 65:10783-10793
8. Bretz N, Noske A, Keller S, Erbe-Hofmann N, Schlange T, Salnikov AV, Moldenhauer G, Kristiansen G, Altevogt P (2012) CD24 promotes tumor cell invasion by suppressing tissue factor pathway inhibitor-2 (TFPI-2) in a c-Src-dependent fashion. Clin Exp Metastasis 29:27-38. doi: 10.1007/s10585-011- 9426-4
9. Bretz NP, Salnikov AV, Perne C, Keller S, Wang X, Mierke CT, Fogel M, Erbe-Hofmann N, Schlange T, Moldenhauer G, Altevogt P (2012) CD24 controls Src/STAT3 activity in human tumors. Cell Mol Life Sci. doi: 10.1007/s00018-012- 1055-9
10. Broeks A, Schmidt MK, Sherman ME, Couch FJ, Hopper JL, Dite GS, Apicella C, Smith LD, Hammet F, Southey MC, Van 't Veer LJ, de Groot R, Smit VTHBM, Fasching PA, Beckmann MW, Jud S, Ekici AB, Hartmann A, Hein A, Schulz-Wendtland R, Burwinkel B, Marme F, Schneeweiss A, Sinn HP, Sohn C, Tchatchou S, Bojesen SE, Nordestgaard BG, Flyger H, Orsted DD, Kaur-Knudsen D, Milne RL, Perez JIA, Zamora P, Rodriguez PM, Benitez J, Brauch H, Justenhoven C, Ko YD, Hamann U, Fischer HP, Bruning T, Pesch B, Chang-Claude J, Wang-Gohrke S, Bremer M, Karstens JH, Hillemanns P, Dork T, Nevanlinna HA, Heikkinen T, Heikkila P, Blomqvist C, Aittomaki K, Aaltonen K, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Kauppinen JM, Kataja V, Auvinen P, Eskelinen M, Soini Y, Chenevix-Trench G, Spurdle AB, Beesley J, Chen X, Holland H, Lambrechts D, Claes B, Vandorpe T, Neven P, Wildiers H, Flesch-Janys D, Hein R, Loning T, Kosel M, Fredericksen ZS, Wang X, Giles GG, Baglietto L, Severi G, McLean C, Haiman CA, Henderson BE, Le Marchand L, Kolonel LN, Grenaker Alnaes G, Kristensen V, Borresen-Dale AL, Hunter DJ, Hankinson SE, Andrulis IL, Marie Mulligan A, O'Malley FP, Devilee P, Huijts PEA, Tollenaar RAEM, Van Asperen CJ, et al (2011) Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium. Hum Mol Genet 20:3289-3303. doi: 10.1093/hmg/ddr228
11. Buck K, Zaineddin AK, Vrieling A, Heinz J, Linseisen J, Flesch-Janys D, Chang-Claude J (2011) Estimated enterolignans, lignan-rich foods, and fibre in relation to survival after postmenopausal breast cancer. Br J Cancer 105:1151-1157. doi: 10.1038/bjc.2011.374
12. Carl JW Jr, Liu JQ, Joshi PS, El-Omrani HY, Yin L, Zheng X, Whitacre CC, Liu Y, Bai XF (2008) Autoreactive T cells escape clonal deletion in the thymus by a CD24-dependent pathway. J Immunol 181:320-328
13. Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Torne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G (2009) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. doi: 10.1200/JCO.2009.23.7370
14. Fasching PA, Ekici AB, Adamietz B (2011) Breast cancer risk - genes, environment, and clinical practice. Geburtsh Frauenheilk 71:1056-1066. doi: 10.1055/s-0031-1280437
15. Fasching PA, Pharoah PD, Cox A, Nevanlinna H, Bojesen SE, Karn T, Broeks A, van Leeuwen FE, van 't Veer LJ, Udo R, Dunning AM, Greco D, Aittomaki K, Blomqvist C, Shah M, Nordestgaard BG, Flyger H, Hopper JL, Southey MC, Apicella C, Garcia-Closas M, Sherman M, Lissowska J, Seynaeve C, Huijts PE, Tollenaar RA, Ziogas A, Ekici AB, Rauh C, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Andrulis I, Ozcelik H, Mulligan AM, Glendon G, Hall P, Czene K, Liu J, Chang-Claude J, Wang-Gohrke S, Eilber U, Nickels S, Dork T, Schiekel M, Bremer M, Park-Simon TW, Giles GG, Severi G, Baglietto L, Hooning MJ, Martens JW, Jager A, Kriege M, Lindblom A, Margolin S, Couch FJ, Stevens KN, Olsen JE, Kosel M, Cross SS, Balasubramanian SP, Reed MW, Miron A, John E, Winqvist R, Pylkas K, Jukkola-Vuorinen A, Kauppila S, Burwinkel B, Marme F, Schneeweiss A, Sohn C, Chenevix-Trench G, Lambrechts D, Dieudonne AS, Hatse S, van Limbergen E, Benitez J, Milne RL, Zamora MP, Arias Perez JI, Bonanni B, Peissel B, Loris B, Peterlongo P, Rajaraman P, Schonfeld SJ, Anton-Culver H, Devilee P, Beckmann MW, Slamon DJ, Phillips KA, Figueroa JD, Humphreys MK, Easton DF, Schmidt MK (2012) The role of genetic breast cancer susceptibility variants as prognostic factors. Hum Mol Genet. doi: 10.1093/hmg/dds159
16. Flesch-Janys D, Slanger T, Mutschelknauss E, Kropp S, Obi N, Vettorazzi E, Braendle W, Bastert G, Hentschel S, Berger J, Chang-Claude J (2008) Risk of different histological types of postmenopausal breast cancer by type and regimen of menopausal hormone therapy. Int J Cancer 123:933-941. doi: 10.1002/ijc.23655
17. Fogel M, Friederichs J, Zeller Y, Husar M, Smirnov A, Roitman L, Altevogt P, Sthoeger ZM (1999) CD24 is a marker for human breast carcinoma. Cancer Lett 143:87-94
18. Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415-445. doi: 10.1146/annurev-immunol-031210-101322
19. Hemminki K, Liu X, Ji J, Forsti A, Sundquist J, Sundquist K (2012) Effect of autoimmune diseases on risk and survival in female cancers. Gynecol Oncol 127:180-185. doi: 10.1016/j.ygyno.2012.07.100
20. Hornychova H, Melichar B, Tomsova M, Mergancova J, Urminska H, Ryska A (2008) Tumor-infiltrating lymphocytes predict response to neoadjuvant chemotherapy in patients with breast carcinoma. Cancer Invest 26:1024-1031. doi: 10.1080/07357900802098165
21. Hudis CA, Barlow WE, Costantino JP, Gray RJ, Pritchard KI, Chapman JA, Sparano JA, Hunsberger S, Enos RA, Gelber RD, Zujewski JA (2007) Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol 25:2127-2132. doi: 10.1200/JCO.2006.10. 3523
22. Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, Wacholder S, Wang Z, Welch R, Hutchinson A, Wang J, Yu K, Chatterjee N, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Hayes RB, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover RN, Thomas G, Chanock SJ (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39:870-874. doi: 10.1038/ng2075
23. Jacob J, Bellach J, Grutzmann R, Alldinger I, Pilarsky C, Dietel M, Kristiansen G (2004) Expression of CD24 in adenocarcinomas of the pancreas correlates with higher tumor grades. Pancreatology 4:454-460
24. Kristiansen G, Denkert C, Schluns K, Dahl E, Pilarsky C, Hauptmann S (2002) CD24 is expressed in ovarian cancer and is a new independent prognostic marker of patient survival. Am J Pathol 161:1215-1221
25. Kristiansen G, Pilarsky C, Pervan J, Sturzebecher B, Stephan C, Jung K, Loening S, Rosenthal A, Dietel M (2004) CD24 expression is a significant predictor of PSA relapse and poor prognosis in low grade or organ confined prostate cancer. Prostate 58:183-192
26. Kristiansen G, Schluns K, Yongwei Y, Denkert C, Dietel M, Petersen I (2003) CD24 is an independent prognostic marker of survival in nonsmall cell lung cancer patients. Br J Cancer 88:231-236
27. Kristiansen G, Winzer KJ, Mayordomo E, Bellach J, Schluns K, Denkert C, Dahl E, Pilarsky C, Altevogt P, Guski H, Dietel M (2003) CD24 expression is a new prognostic marker in breast cancer. Clin Cancer Res 9:4906-4913
28. Li D, Zheng L, Jin L, Zhou Y, Li H, Fu J, Shi M, Du P, Wang L, Wu H, Chen GY, Zheng P, Liu Y, Wang FS, Wang S (2009) CD24 polymorphisms affect risk and progression of chronic hepatitis B virus infection. Hepatology. doi: 10.1002/hep.23047
29. Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, Pusztai L (2008) Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26:1275-1281. doi: 10.1200/JCO.2007.14.4147
30. Liu F, Lang R, Zhao J, Zhang X, Pringle GA, Fan Y, Yin D, Gu F, Yao Z, Fu L (2011) CD8(+) cytotoxic T cell and FOXP3(+) regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat. doi: 10.1007/s10549-011-1647-3
31. Liu F, Li Y, Ren M, Zhang X, Guo X, Lang R, Gu F, Fu L (2012) Peritumoral FOXP3(+) regulatory T cell is sensitive to chemotherapy while intratumoral FOXP3(+) regulatory T cell is prognostic predictor of breast cancer patients. Breast Cancer Res Treat. doi: 10.1007/s10549-012-2132-3
32. Liu Y, Zheng P (2007) CD24: a genetic checkpoint in T cell homeostasis and autoimmune diseases. Trends Immunol 28:315-320. doi: 10.1016/j.it.2007.05. 001
33. Mahmoud SM, Lee AH, Paish EC, Macmillan RD, Ellis IO, Green AR (2012) The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat 132:545-553. doi: 10.1007/s10549-011-1620-1
34. Mahmoud SMA, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AHS, Ellis IO, Green AR (2011) Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol 29:1949-1955. doi: 10.1200/jco.2010.30.5037
35. Marme F, Werft W, Walter A, Keller S, Wang X, Benner A, Burwinkel B, Sinn P, Hug S, Sohn C, Bretz N, Moldenhauer G, Rupp C, Rupp AK, Biakhov MY, Bottini A, Friedrichs K, Khailenko VA, Manikhas GM, Ruiz A, Sanchez-Rovira P, Santoro A, Segui MA, Villena C, Lichter P, Kristiansen G, Altevogt P, Schneeweiss A (2012) CD24 Ala57Val polymorphism predicts pathologic complete response to sequential anthracycline- and taxane-based neoadjuvant chemotherapy for primary breast cancer. Breast Cancer Res Treat 132:819-831. doi: 10.1007/s10549-011-1759-9
36. Otaegui D, Saenz A, Camano P, Blazquez L, Goicoechea M, Ruiz-Martinez J, Olaskoaga J, Emparanza JA, Lopez de Munain A (2006) CD24V/V is an allele associated with the risk of developing multiple sclerosis in the Spanish population. Mult Scler 12:511-514
37. Ronaghi M, Vallian S, Etemadifar M (2009) CD24 gene polymorphism is associated with the disease progression and susceptibility to multiple sclerosis in the Iranian population. Psychiatry Res. doi: 10.1016/j.psychres.2009.01.002
38. Rueda B, Miranda-Filloy JA, Martin J, Gonzalez-Gay MA (2008) Association of CD24 gene polymorphisms with susceptibility to biopsy-proven giant cell arteritis. J Rheumatol 35:850-854
39. Sagiv E, Starr A, Rozovski U, Khosravi R, Altevogt P, Wang T, Arber N (2008) Targeting CD24 for treatment of colorectal and pancreatic cancer by monoclonal antibodies or small interfering RNA. Cancer Res 68:2803-2812. doi: 10.1158/0008-5472.CAN-07-6463
40. Sanchez E, Abelson AK, Sabio JM, Gonzalez-Gay MA, Ortego-Centeno N, Jimenez-Alonso J, de Ramon E, Sanchez-Roman J, Lopez-Nevot MA, Gunnarsson I, Svenungsson E, Sturfelt G, Truedsson L, Jonsen A, Gonzalez-Escribano MF, Witte T, Alarcon-Riquelme ME, Martin J (2007) Association of a CD24 gene polymorphism with susceptibility to systemic lupus erythematosus. Arthritis Rheum 56:3080-3086. doi: 10.1002/art.22871
41. Schabath H, Runz S, Joumaa S, Altevogt P (2006) CD24 affects CXCR4 function in pre-B lymphocytes and breast carcinoma cells. J Cell Sci 119:314-325
42. Sell H, Habich C, Eckel J (2012) Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol. doi: 10.1038/nrendo.2012.114
43. Stevens KN, Fredericksen Z, Vachon CM, Wang X, Margolin S, Lindblom A, Nevanlinna H, Greco D, Aittomaki K, Blomqvist C, Chang-Claude J, Vrieling A, Flesch-Janys D, Sinn HP, Wang-Gohrke S, Nickels S, Brauch H, Ko YD, Fischer HP, Schmutzler RK, Meindl A, Bartram CR, Schott S, Engel C, Godwin AK, Weaver J, Pathak HB, Sharma P, Brenner H, Muller H, Arndt V, Stegmaier C, Miron P, Yannoukakos D, Stavropoulou A, Fountzilas G, Gogas HJ, Swann R, Dwek M, Perkins A, Milne RL, Benitez J, Zamora MP, Perez JI, Bojesen SE, Nielsen SF, Nordestgaard BG, Flyger H, Guenel P, Truong T, Menegaux F, Cordina-Duverger E, Burwinkel B, Marme F, Schneeweiss A, Sohn C, Sawyer E, Tomlinson I, Kerin MJ, Peto J, Johnson N, Fletcher O, Dos Santos Silva I, Fasching PA, Beckmann MW, Hartmann A, Ekici AB, Lophatananon A, Muir K, Puttawibul P, Wiangnon S, Schmidt MK, Broeks A, Braaf LM, Rosenberg EH, Hopper JL, Apicella C, Park DJ, Southey MC, Swerdlow AJ, Ashworth A, Orr N, Schoemaker MJ, Anton-Culver H, Ziogas A, Bernstein L, Dur CC, Shen CY, Yu JC, Hsu HM, Hsiung CN, Hamann U, Dunnebier T, Rudiger T, Ulmer HU, Pharoah PP, Dunning AM, Humphreys MK, Wang Q, Cox A, et al (2012) 19p13.1 is a triple-negative-specific breast cancer susceptibility locus. Cancer Res 72:1795-1803. doi: 10.1158/0008-5472.CAN-11-3364
44. Surowiak P, Materna V, Klak K, Spaczynski M, Dietel M, Kristiansen G, Lage H, Zabel M (2005) Prognostic value of immunohistochemical estimation of CD24 and Ki67 expression in cisplatin and paclitaxel treated ovarian carcinoma patients. Pol J Pathol 56:69-74
45. Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F, Aymeric L, Michaud M, Apetoh L, Barault L, Mendiboure J, Pignon JP, Jooste V, van Endert P, Ducreux M, Zitvogel L, Piard F, Kroemer G (2009) Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene. doi: 10.1038/onc.2009.356
46. Wang L, Lin S, Rammohan KW, Liu Z, Liu JQ, Liu RH, Guinther N, Lima J, Zhou Q, Wang T, Zheng X, Birmingham DJ, Rovin BH, Hebert LA, Wu Y, Lynn DJ, Cooke G, Yu CY, Zheng P, Liu Y (2007) A dinucleotide deletion in CD24 confers protection against autoimmune diseases. PLoS Genet 3:e49
47. Weichert W, Denkert C, Burkhardt M, Gansukh T, Bellach J, Altevogt P, Dietel M, Kristiansen G (2005) Cytoplasmic CD24 expression in colorectal cancer independently correlates with shortened patient survival. Clin Cancer Res 11:6574-6581
48. West NR, Milne K, Truong PT, Macpherson N, Nelson BH, Watson PH (2011) Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res 13:R126. doi: 10.1186/bcr3072
49. Winkler A, Zigeuner R, Rehak P, Hutterer G, Chromecki T, Langner C (2007) CD24 expression in urothelial carcinoma of the upper urinary tract correlates with tumour progression. Virchows Arch 450:59-64
50. Yamaguchi R, Tanaka M, Yano A, Tse GM, Yamaguchi M, Koura K, Kanomata N, Kawaguchi A, Akiba J, Naito Y, Ohshima K, Yano H (2012) Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer. Hum Pathol. doi: 10.1016/j.humpath.2011.12.013
51. Yang XR, Xu Y, Yu B, Zhou J, Li JC, Qiu SJ, Shi YH, Wang XY, Dai Z, Shi GM, Wu B, Wu LM, Yang GH, Zhang BH, Qin WX, Fan J (2009) CD24 is a novel predictor for poor prognosis of hepatocellular carcinoma after surgery. Clin Cancer Res 15:5518-5527. doi: 10.1158/1078-0432.CCR-09-0151
52. Zhou Q, Rammohan K, Lin S, Robinson N, Li O, Liu X, X-f Bai, Yin L, Scarberry B, Du P, You M, Guan K, Zheng P, Liu Y (2003) CD24 is a genetic modifier for risk and progression of multiple sclerosis. PNAS 100:15041-15046
53. Zitvogel L, Apetoh L, Ghiringhelli F, Andre F, Tesniere A, Kroemer G (2008) The anticancer immune response: indispensable for therapeutic success? J Clin Invest 118:1991-2001. doi: 10.1172/JCI35180