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Thomas Winder, M.D. University of Southern California Norris Comprehensive Cancer Center

Germline polymorphisms in the CD44 gene are associated with clinical outcome in localized gastric adenocarcinoma. Thomas Winder, M.D. University of Southern California Norris Comprehensive Cancer Center USC Keck School of Medicine Sharon A. Carpenter Laboratory Los Angeles, CA. Background.

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Thomas Winder, M.D. University of Southern California Norris Comprehensive Cancer Center

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  1. Germline polymorphisms in the CD44 gene are associated with clinical outcome in localized gastric adenocarcinoma. Thomas Winder, M.D. University of Southern California Norris Comprehensive Cancer Center USC Keck School of Medicine Sharon A. Carpenter Laboratory Los Angeles, CA

  2. Background • Gastric Cancer is the 4th most common cancer type worldwide • 21.130 newly diagnosed patients in the US in 2009 • 2nd cause of cancer death worldwide • 10.620 deaths in the US in 2009 • Prognosis depends on: • Stage • Pathological differentiation National Cancer institute http://www.cancer.gov/cancertopics/types/stomach

  3. Genetic alterations in gastric cancer Diffuse type Intestinal type Normal gastric mucosa MSI-H (0-6%) MSI-H (13-20%) Telomerase activation/ TERT expression Metaplasia E-cadherin mutation (41-45%) p53 mutation (25-63%) K-ras mutation (10%) Reduced p27 expression p53 mutation (0-33%) (Adenoma) APC mutation (40-60%) Bcl-3 loss (43%) c-met amplification (19%) CD44 Cyclin E overexpression (10 %) CDC25B overexpression Early cancer Cyclin E overexpression (14-20%) 18q (DCC) loss (50%) ß-Catenin mutation (27%) N-cadherin overexpression (43%) Twist 1 overexpression (39%) C-erbB2 amplification (20%) CD44 E-cadherin reduction (60%) SIP1 overexpression (55%) Carcinoma K-sam amplification (33%) c-met amplification (39%) Metastasis Reduced nm23 (˂52%) Reduced nm23 (52%) Adapted from Keller et al. 2005 Expert Rev in Mol Medicine 7;17

  4. CD44 - Background • CD44 is a glycoprotein encoded on the short arm of chromosome 11. • CD44 was first isolated in haemopoietic cells and has since been found on a wide range of tissues (e.g. gastric, lung, liver, pancreas) • The main ligands of CD44 are hyaluronan and osteopontin. • The protein isoforms are encoded by a single gene by alternative splicing and post-translational modification.

  5. CD44 and its function • Cellular adhesion (transmembrane link between extracellular matrix and cytoskeleton) • CD44 positive cells are tumor initiating cells in gastric cancer • Immune System (e.g. lymphocyte homeing, T cell activation) • High CD44 protein expression has been associated with poor prognosis in gastric adenocarcinoma* *Ghaffarzadehgan K et al. World J Gastroenterol 2008;14(41):6376-6381

  6. Cell membrane TM Cyto 3´UTR Extracellular domain 1 2 3 4 5 16 17 18 19 20 s1 s2 s3 s4 s5 s6 s7 s8 s9 s10 5´ 3´ 6 7 8 9 10 11 12 13 14 15 v1 v2 v3 v4 v5 v6 v7 v8 v9 v10 CD44 gene structure CD44 Receptor CD44 gene structure

  7. CD44 - pathways Hyaluronan, Osteopontin Feedback loop CD44 Hsp90/cdc37 ErbB2 pY PI3-kinase pY Grb2 Vav2 Gab-1 PTEN Ras PDK1 Raf-1 Akt MEK Erk Anti-apoptosis Gene transcription Cell-cycle progression Cell survival Invasion Proliferation Drug resistance

  8. Hyaluronan, Osteopontin CD44 Ezrin Radixin Moesin Ankyrin Filamentous actin network CD44 and cellular adhesion Cell motility Migration

  9. CD44 gastric stem cell marker • Property of self-renewal, longevity and multipotency. • High CD44 protein-expression correlates with the presence of dysplasia in murine and human gastric cancer. • CD44 overexpression is associated with chemo- and radio-resistance Takaishi S et al. Stem Cells 2009:27:106-1020 Al-Hajj M et al. Proc. Natl Acad. Sci. USA 2003;100:3983-3988

  10. Location of gastric stem cells • Gastric stem cells has been localized • to the isthmus. • Migrate bidirectionally to differentiate • into gastric surface mucus cells that • coat the • Gastric pits • Gastric parietal and • Zymogenic cells Quante M et al. Nat Rev Gastroenterol Hepatol. 2009 Dec;6(12):724-37

  11. CD44 as a gastric cancer stem cell marker CD44 positive gastric cancer cell line in the stomach and skin of SCID mice Takaishi S et al. Stem Cells 2009:27:106-1020

  12. Objectives • Identifying germline polymorphisms within the CD44 gene for clinical outcome in patients with localized gastric adenocarcinoma.

  13. Patient Characteristics

  14. Methods • gDNA was isolated either from blood or from formalin-fixed paraffin-embeddedtissue samples. • PCR-RFLP was used to determine the polymorphisms

  15. s1 s2 s3 s4 s5 Transcriptional regulation Selected germline polymorphisms CD44 rs4755392 CD44 rs187116 16 17 20 1 18 19 2 3 4 5 s6 s7 s8 s9 s10 3´UTR 5´ 6 7 8 9 10 15 11 12 13 14 CD44 rs8193 v1 v2 v3 v4 v5 v6 v7 v8 v9 v10 CD44 rs7116432

  16. CD44 rs187116 predicts tumor recurrence Estimated Recurrence-Free Probability Log-Rank P value = 0.022 CD44 A/A (n=30) CD44 A/G or G/G (n=94) TTR: 2.1 yrs TTR: 7.0 yrs Years since Diagnosis of Resectable Gastric Cancer

  17. Estimated Probability of Survival Years since Diagnosis of Resectable Gastric Cancer CD44 rs187116 is associated with overall survival Log-Rank P value = 0.079 CD44 A/A (n=30) CD44 A/G or G/G (n=94) OS: 4.1 yrs OS: 7.0 yrs

  18. Estimated Recurrence-Free Probability Years since Diagnosis of Resectable Gastric Cancer CD44 rs7116432 predicts tumor recurrence Log-Rank P value = 0.045 CD44 G/G (n=36) CD44 A/G or A/A (n=91) TTR: 2.2 yrs TTR: 7.0 yrs

  19. Estimated Probability of Survival Years since Diagnosis of Resectable Gastric Cancer CD44 rs7116432 predicts overall survival Log-Rank P value = 0.018 CD44 G/G (n=36) CD44 A/G or A/A (n=91) OS: 3.8 yrs OS: 7.3 yrs

  20. Estimated Recurrence-Free Probability Years since Diagnosis of Resectable Gastric Cancer Combined analysis of risk alleles for time to recurrence Adjusted P value = 0.016 CD44 1-2 Favorable alleles (n=55) CD44 0 Favorable alleles (n=67) TTR: 7.0 yrs TTR: 1.7 yrs

  21. Estimated Probability of Survival Years since Diagnosis of Resectable Gastric Cancer Combined analysis of risk alleles for overall survival Adjusted P value = 0.019 CD44 1–2 Favorable alleles (n=55) CD44 0 Favorable alleles (n=67) OS: 3.6 yrs OS: 7.3 yrs

  22. Time to recurrence Overall survival N* Relative risk (95% CI) P value † Relative risk (95% CI) P value † CD44rs187116 A/A 30 1 (Reference) 1 (Reference) A/G,G/G 92 3.81 (1.45, 9.98) 0.007 3.52 (1.16, 10.65) 0.026 CD44rs7116432 G/G 34 1 (Reference) 1 (Reference) A/G,A/A 88 1.49 (0.66, 3.36) 0.34 2.31 (0.81, 6.60) 0.12 Combined 1-2 Favorable 55 1 (Reference) 1 (Reference) * Patients with incomplese genotyping were excluded in the multivatiate analysis † adjusted for T category, N category, race and type of therapy 0 Favorable 67 2.41 (1.18, 4.92) 0.016 2.74 (1.18, 6.38) 0.019 Multivariate Analysis

  23. Conclusions • CD44 gene polymorphisms are associated with TTR and OS in the multivariate analysis • CD44 polymorphisms may identify patients at high risk for tumor recurrence • CD44 might be a promising target for drug development

  24. Future directions • These results need to be validated in large, prospective biomarker embedded clinical trials. • Mechanistic studies need to explore the function of these polymorphisms. • The pharmacogenetic analysis should be expanded to the CD44 pathway.

  25. Acknowledgements Medical Oncology: Heinz-Josef Lenz, Syma Iqbal Anthony El-Khoueiry, Statistics: Dongyun Yang, Susan Groshen Dr. Lenz´ Lab: Georg Lurje, Wu Zhang, Yan Ning, Pierre Bohanes, Siwen Hu, Rita El-Khoueiry Memorial Sloan-Kettering Cancer Center: Derek G. Power, Laura H. Tang, Manish Shah Grants: Dhont Foundation Austrian Society of Hematology and Oncology

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