Germline polymorphisms in genes involved in the CD44 signaling pathway are associated with clinical outcome in localized gastric adenocarcinoma†‡
Thomas Winder
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorYan Ning
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorDongyun Yang
Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorWu Zhang
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorDerek G Power
Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, NY
Search for more papers by this authorPierre Bohanes
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorArmin Gerger
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorPeter M. Wilson
Department of Pathology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorGeorg Lurje
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorLaura H Tang
Department of Pathology, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, NY
Search for more papers by this authorManish Shah
Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, NY
Search for more papers by this authorCorresponding Author
Heinz-Josef Lenz
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Tel.: +1-323-865-3967, Fax: +1-323-865-0061
Sharon A. Carpenter Laboratory, Division of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90033, USASearch for more papers by this authorThomas Winder
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorYan Ning
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorDongyun Yang
Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorWu Zhang
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorDerek G Power
Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, NY
Search for more papers by this authorPierre Bohanes
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorArmin Gerger
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorPeter M. Wilson
Department of Pathology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorGeorg Lurje
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Search for more papers by this authorLaura H Tang
Department of Pathology, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, NY
Search for more papers by this authorManish Shah
Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, NY
Search for more papers by this authorCorresponding Author
Heinz-Josef Lenz
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
Tel.: +1-323-865-3967, Fax: +1-323-865-0061
Sharon A. Carpenter Laboratory, Division of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90033, USASearch for more papers by this authorThis work was done in memory of David Donaldson
This paper was presented at 2010 Gastrointestinal Cancers Symposium (oral presentation General Session II), ASCO 2010 (abstract #4047)
Abstract
The cluster of differentiation 44 (CD44) signaling pathway is crucial in cancer-cell growth, invasion, proliferation and metastasis. CD44 is a transmembrane receptor for hyaluronan and osteopontin, and has recently attracted attention as a gastric cancer stem cell marker. Previous studies showed that polymorphisms in the CD44 gene can influence both human cancer survival and determine cellular response to cytotoxic chemotherapeutics. In addition, CD44 protein overexpression has been associated with poor prognosis in gastric adenocarcinoma (GA). We tested the hypothesis whether polymorphisms involved in the CD44 pathway will predict clinical outcome in patients with localized GA. Either blood or formalin-fixed paraffin-embedded (FFPE) tissues were obtained from 137 patients with localized GA at University of Southern California and Memorial Sloan-Kettering Cancer Center medical facilities. DNA was isolated and polymorphisms within the CD44 pathway were determined by PCR-RFLP technique. In univariate analysis CD44 rs187116 and CD44 rs7116432 were significantly associated with time to tumor recurrence (TTR) and overall survival (OS). After adjusting for covariates, patients harboring at least one G allele of CD44 rs187116 remained significantly associated with TTR (adjusted p = 0.009) and OS (adjusted p = 0.045). Further, patients harboring CD44 T-A haplotype were at the lowest risk of developing tumor recurrence (HR: 0.255; 95% CI: 0.11–0.591; adjusted p = 0.001) and death (HR 0.198; 95% CI: 0.07–0.563; adjusted p = 0.002). These results provide the first evidence that CD44 polymorphisms predict clinical outcome in patients with localized GA. This may help to identify localized GA patients at high risk for tumor recurrence.
References
- 1 Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74–108.
- 2 Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin, in press.
- 3 Van Cutsem E, Kang Y, Chung H, Shen L, Sawaki A, Lordick F, Hill J, Lehle M, Feyereislova A, Bang Y. Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). In ASCO 2009; J Clin Oncol 2009; 27( suppl; abstr LBA4509): 18s.
- 4 Macdonald JS. Treatment of localized gastric cancer. Semin Oncol 2004; 31: 566–73.
- 5 D'Angelica M, Gonen M, Brennan MF, Turnbull AD, Bains M, Karpeh MS. Patterns of initial recurrence in completely resected gastric adenocarcinoma. Ann Surg 2004; 240: 808–16.
- 6 Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 1965; 64: 31–49.
- 7 Keller G, Hofler H, Becker KF. Molecular medicine of gastric adenocarcinomas. Expert Rev Mol Med 2005; 7: 1–13.
- 8 Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 2003; 4: 33–45.
- 9 Weber GF, Ashkar S, Glimcher MJ, Cantor H. Receptor-ligand interaction between CD44 and osteopontin (Eta-1). Science 1996; 271: 509–12.
- 10 Lin YH, Yang-Yen HF. The osteopontin-CD44 survival signal involves activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. J Biol Chem 2001; 276: 46024–30.
- 11 Bourguignon LY, Zhu H, Chu A, Iida N, Zhang L, Hung MC. Interaction between the adhesion receptor, CD44, and the oncogene product, p185HER2, promotes human ovarian tumor cell activation. J Biol Chem 1997; 272: 27913–8.
- 12 Bourguignon LY, Zhu H, Shao L, Zhu D, Chen YW. Rho-kinase (ROK) promotes CD44v(3,8-10)-ankyrin interaction and tumor cell migration in metastatic breast cancer cells. Cell Motil Cytoskeleton 1999; 43: 269–87.
- 13 Lesley J, English NM, Gal I, Mikecz K, Day AJ, Hyman R. Hyaluronan binding properties of a CD44 chimera containing the link module of TSG-6. J Biol Chem 2002; 277: 26600–8.
- 14 Tsukita S, Oishi K, Sato N, Sagara J, Kawai A. ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons. J Cell Biol 1994; 126: 391–401.
- 15 Gotley DC, Fawcett J, Walsh MD, Reeder JA, Simmons DL, Antalis TM. Alternatively spliced variants of the cell adhesion molecule CD44 and tumour progression in colorectal cancer. Br J Cancer 1996; 74: 342–51.
- 16 Naor D, Sionov RV, Ish-Shalom D. CD44: structure, function, and association with the malignant process. Adv Cancer Res 1997; 71: 241–319.
- 17 Liu YJ, Yan PS, Li J, Jia JF. Expression and significance of CD44s, CD44v6, and nm23 mRNA in human cancer. World J Gastroenterol 2005; 11: 6601–6.
- 18
Yoo CH,
Noh SH,
Kim H,
Lee HY,
Min JS.
Prognostic significance of CD44 and nm23 expression in patients with stage II and stage IIIA gastric carcinoma.
J Surg Oncol
1999;
71:
22–8.
10.1002/(SICI)1096-9098(199905)71:1<22::AID-JSO5>3.0.CO;2-I CAS PubMed Web of Science® Google Scholar
- 19 Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R, Gordon SA, Shimada Y, Wang TC. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 2009; 27: 1006–20.
- 20 Shukla SJ, Duan S, Wu X, Badner JA, Kasza K, Dolan ME. Whole-genome approach implicates CD44 in cellular resistance to carboplatin. Hum Genomics 2009; 3: 128–42.
- 21 Vazquez A, Grochola LF, Bond EE, Levine AJ, Taubert H, Muller TH, Wurl P, Bond GL. Chemosensitivity profiles identify polymorphisms in the p53 network genes 14-3-3tau and CD44 that affect sarcoma incidence and survival. Cancer Res 2010; 70: 172–80.
- 22 Zhou J, Nagarkatti PS, Zhong Y, Creek K, Zhang J, Nagarkatti M. Unique SNP in CD44 intron 1 and its role in breast cancer development. Anticancer Res 2010; 30: 1263–72.
- 23 Suga T, Ishikawa A, Kohda M, Otsuka Y, Yamada S, Yamamoto N, Shibamoto Y, Ogawa Y, Nomura K, Sho K, Omura M, Sekiguchi K, et al. Haplotype-based analysis of genes associated with risk of adverse skin reactions after radiotherapy in breast cancer patients. Int J Radiat Oncol Biol Phys 2007; 69: 685–93.
- 24 Han S, Guthridge JM, Harley IT, Sestak AL, Kim-Howard X, Kaufman KM, Namjou B, Deshmukh H, Bruner G, Espinoza LR, Gilkeson GS, Harley JB, et al. Osteopontin and systemic lupus erythematosus association: a probable gene-gender interaction. PLoS One 2008; 3: e0001757.
- 25 Neuberger J, Altman DG, Christensen E, Tygstrup N, Williams R. Use of a prognostic index in evaluation of liver transplantation for primary biliary cirrhosis. Transplantation 1986; 41: 713–6.
- 26 Ghaffarzadehgan K, Jafarzadeh M, Raziee HR, Sima HR, Esmaili-Shandiz E, Hosseinnezhad H, Taghizadeh-Kermani A, Moaven O, Bahrani M. Expression of cell adhesion molecule CD44 in gastric adenocarcinoma and its prognostic importance. World J Gastroenterol 2008; 14: 6376–81.
- 27 Huh JW, Kim HR, Kim YJ, Lee JH, Park YS, Cho SH, Joo JK. Expression of standard CD44 in human colorectal carcinoma: association with prognosis. Pathol Int 2009; 59: 241–6.
- 28 Screaton GR, Bell MV, Jackson DG, Cornelis FB, Gerth U, Bell JI. Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc Natl Acad Sci USA 1992; 89: 12160–4.
- 29 Skelton TP, Zeng C, Nocks A, Stamenkovic I. Glycosylation provides both stimulatory and inhibitory effects on cell surface and soluble CD44 binding to hyaluronan. J Cell Biol 1998; 140: 431–46.
- 30 Barbour AP, Reeder JA, Walsh MD, Fawcett J, Antalis TM, Gotley DC. Expression of the CD44v2-10 isoform confers a metastatic phenotype: importance of the heparan sulfate attachment site CD44v3. Cancer Res 2003; 63: 887–92.
- 31 Gunthert U, Hofmann M, Rudy W, Reber S, Zoller M, Haussmann I, Matzku S, Wenzel A, Ponta H, Herrlich P. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 1991; 65: 13–24.
- 32 Heider KH, Dammrich J, Skroch-Angel P, Muller-Hermelink HK, Vollmers HP, Herrlich P, Ponta H. Differential expression of CD44 splice variants in intestinal- and diffuse-type human gastric carcinomas and normal gastric mucosa. Cancer Res 1993; 53: 4197–203.
- 33 Klingbeil P, Marhaba R, Jung T, Kirmse R, Ludwig T, Zoller M. CD44 variant isoforms promote metastasis formation by a tumor cell-matrix cross-talk that supports adhesion and apoptosis resistance. Mol Cancer Res 2009; 7: 168–79.
- 34 Wielenga VJ, Heider KH, Offerhaus GJ, Adolf GR, van den Berg FM, Ponta H, Herrlich P, Pals ST. Expression of CD44 variant proteins in human colorectal cancer is related to tumor progression. Cancer Res 1993; 53: 4754–6.
- 35 Pagani F, Baralle FE. Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 2004; 5: 389–96.
- 36 Narla G, Difeo A, Reeves HL, Schaid DJ, Hirshfeld J, Hod E, Katz A, Isaacs WB, Hebbring S, Komiya A, McDonnell SK, Wiley KE, et al. A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer Res 2005; 65: 1213–22.
- 37 Borjesson PK, Postema EJ, Roos JC, Colnot DR, Marres HA, van Schie MH, Stehle G, de Bree R, Snow GB, Oyen WJ, van Dongen GA. Phase I therapy study with (186)Re-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with head and neck squamous cell carcinoma. Clin Cancer Res 2003; 9: 3961S–72S.
- 38 Colnot DR, Ossenkoppele GJ, Roos JC, Quak JJ, de Bree R, Borjesson PK, Huijgens PC, Snow GB, van Dongen GA. Reinfusion of unprocessed, granulocyte colony-stimulating factor-stimulated whole blood allows dose escalation of 186Relabeled chimeric monoclonal antibody U36 radioimmunotherapy in a phase I dose escalation study. Clin Cancer Res 2002; 8: 3401–6.
- 39 Marangoni E, Lecomte N, Durand L, de Pinieux G, Decaudin D, Chomienne C, Smadja-Joffe F, Poupon MF. CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts. Br J Cancer 2009; 100: 918–22.
- 40 Rupp U, Schoendorf-Holland E, Eichbaum M, Schuetz F, Lauschner I, Schmidt P, Staab A, Hanft G, Huober J, Sinn HP, Sohn C, Schneeweiss A. Safety and pharmacokinetics of bivatuzumab mertansine in patients with CD44v6-positive metastatic breast cancer: final results of a phase I study. Anticancer Drugs 2007; 18: 477–85.
- 41 Tijink BM, Buter J, de Bree R, Giaccone G, Lang MS, Staab A, Leemans CR, van Dongen GA. A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. Clin Cancer Res 2006; 12: 6064–72.
Citing Literature
