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The origin of metastatic disease: clues from genomics

The origin of metastatic disease: clues from genomics. 7/13/2011. Tumor evolution. Metastasis: Current questions. When do tumor cells leave the primary tumor? Are metastases clonal ? Do metastases evolve at the metastatic site? Do different tumor types have different metastatic origins?.

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The origin of metastatic disease: clues from genomics

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  1. The origin of metastatic disease: clues from genomics 7/13/2011

  2. Tumor evolution

  3. Metastasis: Current questions • When do tumor cells leave the primary tumor? • Are metastases clonal? • Do metastases evolve at the metastatic site? • Do different tumor types have different metastatic origins? Nguyen, D. J Pathol2011; 223:195-204

  4. Why do we care? • Treatment for metastasis is virtually non-existent • Some treatments increase the likelihood of metastasis • Analyzing the primary tumor may indicate the genetic make-up of metastases • Diagnostics do not exist for metastases, but may be required if metastases are genetically dissimilar to the primary tumor • CSCs might be a source of metastasis that are refractory to current treatment

  5. Genomic studies of metastases • How do we track the differences between primary tumors and mets? • Loss of heterozygosity: two distinct alleles exist in normal tissue, one is lost in tumor • Copy number: number of alleles or chromosomes increases or decreases • Epigenetic markers: methylation states

  6. Loss of heterozygosity • Caused by • Non-disjunction • Recombination • Double strand break repair • Deletion • Detect with SNPs or microsatelllites

  7. Copy Number • Measure of genomic instability • Detected by sequencing (single cell) or CGH (tissue)

  8. CGH • Comparative Genomic Hybridization • Label tumor vs. normal tissue

  9. Metastasis: Current questions • When do tumor cells leave the primary tumor? • Are metastases clonal? • Do metastases evolve at the metastatic site? • Do different tumor types have different metastatic origins? Nguyen, D. J Pathol2011; 223:195-204

  10. Metastasis: Current questions • When do tumor cells disseminate? • Early: DTCs or Mets have fewer or different mutations than the primary tumor • Late: DTCs or Mets look like aggressive primary tumor • Are metastases clonal? • The entire met or all mets in the body look the same • Do metastases evolve at the metastatic site? • No: Mets look like primary tumor • Yes: Mets show significant divergence from the primary tumor • Do different tumor types have different metastatic origins? • Mets look like primary tumor in some cancers • Mets look different than primary tumor in other cancers

  11. When do tumor cells disseminate?

  12. Disseminated tumor cells Metastasis Primary tumor

  13. DTCs often do not cluster with metastases or primary tumors

  14. Conclusions and Caveats • DTCs exist very early in tumor progression • Cytokeratin marker causes bias

  15. Are Metastases Clonal?

  16. Copy Number Analysis Liu et al. Nature Medicine 15, 559 - 565 (2009)

  17. Metastases are clonal in prostate cancer • Metastases found in different regions of the body are clonal, implying a single cell of origin Liu et al. Nature Medicine 15, 559 - 565 (2009)

  18. Metastases are not clonal in breast cancer Wu et al. Clin Cancer Res April 1, 2008 14; 1938

  19. Primary tumors are similar to metastases

  20. Copy number analysis of single cells 6% coverage Navin et al. Nature 472, 90–94 (07 April 2011)

  21. Copy number analysis of single cells in breast tumors Stromal cells Tumor cells Navin et al. Nature 472, 90–94 (07 April 2011)

  22. Copy number analysis of single cells Navin et al. Nature 472, 90–94 (07 April 2011)

  23. Clinical examples of tracing metastatic origin • Breast cancer • Her2-pos • 65 PTs with 42 macrometastases and 18 micrometastases • In HER-2-positive PTs, 26 of 29 metastases were HER-2-positive • HER-2 amplification and ER and PR status were conserved in mets in 71% of cases Strein et al. Pathol Res Pract. 2010 Apr 15;206(4):253-8

  24. Similarities between primary tumor and metastases in colorectal cancer Jones et al. PNAS March 18, 2008 vol. 105 no. 11 4283-4288

  25. Screened 233 known mutations in PTs and Mets • Only seven not found in both Jones et al. PNAS March 18, 2008 vol. 105 no. 11 4283-4288

  26. Implications of this data • Mets arise late from aggressive, advanced carcinoma cells • Implies that genes required for primary tumor growth might confer metastatic ability

  27. Primary tumors are significantly different than metastases

  28. Clinical examples of tracing metastatic origin Fehmet al.Breast Cancer Research 2009 11:R59

  29. Clinical examples of tracing metastatic origin Fehmet al.Breast Cancer Research 2009 11:R59

  30. Significant divergence of Mets from PTs in breast cancer Ramaswamy et al. Nature Genetics33, 49 - 54 (2002)

  31. Methylation states change between primary tumor and metastases in prostate cancer Prostate cancer cell lines Yegnasubramanian et al. Cancer Res March 15, 2004 64; 1975

  32. Methylation states change between primary tumor and metastases Yegnasubramanian et al. Cancer Res March 15, 2004 64; 1975

  33. Methylation states change between primary tumor and metastases Yegnasubramanian et al. Cancer Res March 15, 2004 64; 1975

  34. Hypermethylation occurs in breast cancer metastases Mehrotra et al. Clin Cancer Res. Vol. 10, 3104-3109, 2004.

  35. Interpretations of this data • Metastases require additional mutations to successfully grow at a distant site • Three possible scenarios: • Metastatic cells leave the primary tumor early on • Metastatic cells leave the primary tumor late but then require additional mutations to colonize a distant organ • Clones exist in primary tumor but are not detected

  36. The best current example of using genomics to understand metastatic origin

  37. Metastases occur late in pancreatic cancer Yachida et al. Nature 467, 1114–1117 (28 October 2010)

  38. Yachida et al. Nature 467, 1114–1117 (28 October 2010)

  39. Conclusions • Some metastases are genetically similar to the primary tumor, while others are not • Metastases can be clonal or heterogeneous • Information from primary tumor could help to determine characteristics about metastases • Primary tumor diagnostics may not be sufficient • Origin of metastatic precursor may be early or late in tumor progression • These studies imply that it may not be cancer-type dependent • Studies are limited…

  40. Stoecklein, N. H. and Klein, C. A. (2010). International Journal of Cancer, 126: 589–598.

  41. Conclusions Seems to be mostly patient or study dependent!

  42. Future directions • Next generation sequencing • Can get more accurate data • Single cell resolution • Analysis of CTCs and DTCs • “Personalized medicine”

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