Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Precision medicine based on epigenomics: the paradigm of carcinoma of unknown primary

Nature Reviews Clinical Oncology volume 14, pages 682–694 (2017)Cite this article

Subjects

Key Points

  • The identification of the tissue of origin leads to improved management and prognosis of patients with cancer of unknown primary (CUP)

  • Advances in the development of molecular platforms have enabled the achievement of higher sensitivity and specificity in the diagnosis of CUP

  • DNA methylation is a valid biomarker for clinical diagnosis, which enables discrimination between different tissues of origin

  • An epigenetic-guided prediction of tissue of origin provides a more robust CUP diagnosis than that achieved with other molecular-based platforms

  • The prediction of tissue of origin can provide preliminary evidence indicating the presence of particular genetic alterations for which specific treatments exist (drug-actionable targets)

Abstract

Epigenetic alterations are a common hallmark of human cancer. Single epigenetic markers are starting to be incorporated into clinical practice; however, the translational use of these biomarkers has not been validated at the 'omics' level. The identification of the tissue of origin in patients with cancer of unknown primary (CUP) is an example of how epigenomics can be incorporated in clinical settings, addressing an unmet need in the diagnostic and clinical management of these patients. Despite the great diagnostic advances made in the past decade, the use of traditional diagnostic procedures only enables the tissue of origin to be determined in ∼30% of patients with CUP. Thus, development of molecularly guided diagnostic strategies has emerged to complement traditional procedures, thereby improving the clinical management of patients with CUP. In this Review, we present the latest data on strategies using epigenetics and other molecular biomarkers to guide therapeutic decisions involving patients with CUP, and we highlight areas warranting further research to engage the medical community in this unmet need.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Biopsy sites and frequencies of tumour types predicted by EPICUP.
Figure 2: Examples of histopathological validation of patients with CUP with an EPICUP-predicted tissue of origin.
Figure 3: Determination of the primary site in patients with CUP can enable the right selection of tailored-treatment.
Figure 4: Example of a patients with CUP who received EPICUP-predicted matching site-specific treatment.

Similar content being viewed by others

References

  1. Forbes, S. A. et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 39, D945–D950 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Bell, D. et al. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

    Article  CAS  Google Scholar 

  3. Boehm, J. S. & Hahn, W. C. Towards systematic functional characterization of cancer genomes. Nat. Rev. Genet. 12, 487–498 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Hanahan, D. & Weinberg, R. A. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Carmona, F. J. & Esteller, M. Epigenomics of human colon cancer. Mutat. Res. 693, 53–60 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Ushijima, T. Detection and interpretation of altered methylation patterns in cancer cells. Nat. Rev. Cancer 5, 223–231 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Esteller, M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat. Rev. Genet. 8, 286–298 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Esteller, M., Corn, P. G., Baylin, S. B. & Herman, J. G. A gene hypermethylation profile of human cancer. Cancer Res. 61, 3225–3229 (2001).

    CAS  PubMed  Google Scholar 

  9. Fernandez, A. F. et al. A DNA methylation fingerprint of 1628 human samples. Genome Res. 22, 407–419 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Moran, S. et al. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol. 17, 1386–1395 (2016).

    Article  PubMed  Google Scholar 

  11. Löffler, H., Neben, K. & Krämer, A. CUP-Syndrom [German]. Radiologe 54, 107–111 (2014).

    Article  PubMed  Google Scholar 

  12. Stewart, J., Tattersall, M., Woods, R. & Fox, R. Unknown primary adenocarcinoma: incidence of over investigation and natural history. Br. Med. J. 1, 1530–1533 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. van de Wouw, A. J., Janssen-Heijnen, M. L. G., Coebergh, J. W. W. & Hillen, H. F. P. Epidemiology of unknown primary tumours; incidence and population-based survival of 1285 patients in Southeast Netherlands, 1984–1992. Eur. J. Cancer 38, 409–413 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Fizazi, K. et al. Cancers of unknown primary site: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 26, 3479–3482 (2015).

    Article  Google Scholar 

  15. Fizazi, K., Greco, F. A., Pavlidis, N. & Pentheroudakis, G. Cancers of unknown primary site: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 22, 64–68 (2011).

    Article  Google Scholar 

  16. Collado Martin, R., Garcia Palomo, A., de la Cruz Merino, L., Borrega Garcia, P. & Baron Duarte, F. J. Clinical guideline SEOM: cancer of unknown primary site. Clin. Transl Oncol. 16, 1091–1097 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Brewster, D. H., Lang, J., Bhatti, L. A., Thomson, C. S. & Oien, K. A. Descriptive epidemiology of cancer of unknown primary site in Scotland, 1961–2010. Cancer Epidemiol. 38, 227–234 (2014).

    Article  PubMed  Google Scholar 

  18. Ferlay, J. et al. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11. GLOBOCAN http://globocan.iarc.fr (2013).

    Google Scholar 

  19. Parkin, D. M., Whelan, S. L., Ferlay, J., Thomas, T. & Thomas, D. B. Cancer Incidence in Five Continents. IARC Sci. Publication 143 (IARC Sci. Publications, 1997).

  20. Varadhachary, G. R. & Raber, M. N. Cancer of unknown primary site. N. Engl. J. Med. 371, 757–765 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Riihimäki, M., Hemminki, A., Sundquist, K. & Hemminki, K. Time trends in survival from cancer of unknown primary: small steps forward. Eur. J. Cancer 49, 2403–2410 (2013).

    Article  PubMed  Google Scholar 

  22. Bevier, M., Sundquist, J. & Hemminki, K. Incidence of cancer of unknown primary in Sweden: analysis by location of metastasis. Eur. J. Cancer Prev. 21, 596–601 (2012).

    Article  PubMed  Google Scholar 

  23. Shu, X., Sundquist, K., Sundquist, J. & Hemminki, K. Time trends in incidence, causes of death, and survival of cancer of unknown primary in Sweden. Eur. J. Cancer Prev. 21, 281–288 (2012).

    Article  PubMed  Google Scholar 

  24. Brustugun, O. T. & Helland, Å. Rapid reduction in the incidence of cancer of unknown primary. A population-based study. Acta Oncol. 53, 134–137 (2014).

    Article  PubMed  Google Scholar 

  25. Luke, C. et al. Exploring the epidemiological characteristics of cancers of unknown primary site in an Australian population: implications for research and clinical care. Aust. N. Z. J. Public Health 32, 383–389 (2008).

    Article  PubMed  Google Scholar 

  26. Mnatsakanyan, E., Tung, W.-C., Caine, B. & Smith-Gagen, J. Cancer of unknown primary: time trends in incidence, United States. Cancer Causes Control 25, 747–757 (2014).

    Article  PubMed  Google Scholar 

  27. Pentheroudakis, G., Golfinopoulos, V. & Pavlidis, N. Switching benchmarks in cancer of unknown primary: from autopsy to microarray. Eur. J. Cancer 43, 2026–2036 (2007).

    Article  PubMed  Google Scholar 

  28. Pavlidis, N. & Pentheroudakis, G. Cancer of unknown primary site. Lancet 379, 1428–1435 (2012).

    Article  PubMed  Google Scholar 

  29. Hainsworth, J. D., Schnabel, C. A., Erlander, M. G., Haines, D. W. & Greco, F. A. A retrospective study of treatment outcomes in patients with carcinoma of unknown primary site and a colorectal cancer molecular profile. Clin. Colorectal Cancer 11, 112–118 (2012).

    Article  PubMed  Google Scholar 

  30. Hainsworth, J. D. et al. Paclitaxel/carboplatin with or without belinostat as empiric first-line treatment for patients with carcinoma of unknown primary site: a randomized, phase 2 trial. Cancer 121, 1654–1661 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Hainsworth, J. D. et al. Treatment for patients with unknown primary cancer and favorable prognostic factors. Semin. Oncol. 36, 44–51 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Culine, S. et al. Development and validation of a prognostic model to predict the length of survival in patients with carcinomas of an unknown primary site. J. Clin. Oncol. 20, 4679–4683 (2002).

    Article  PubMed  Google Scholar 

  33. van de Wouw, A. J., Jansen, R. L., Griffioen, A. W. & Hillen, H. F. Clinical and immunohistochemical analysis of patients with unknown primary tumour. A search for prognostic factors in UPT. Anticancer Res. 24, 297–301 (2004).

    PubMed  Google Scholar 

  34. Abbruzzese, J. L. et al. Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients. J. Clin. Oncol. 12, 1272–1280 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Green, A. C. Cancer of unknown primary: does the key lie in molecular diagnostics? Cytopathology 26, 61–63 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Ariza, A. et al. Update on the diagnosis of cancer of unknown primary (CUP) origin. Clin. Transl Oncol. 13, 434–441 (2011).

    Article  PubMed  Google Scholar 

  37. Kandalaft, P. L. & Gown, A. M. Practical applications in immunohistochemistry: carcinomas of unknown primary site. Arch. Pathol. Lab. Med. 140, 508–523 (2016).

    Article  CAS  PubMed  Google Scholar 

  38. Onofre, A. S. C., Pomjanski, N., Buckstegge, B. & Böcking, A. Immunocytochemical diagnosis of hepatocellular carcinoma and identification of carcinomas of unknown primary metastatic to the liver on fine-needle aspiration cytologies. Cancer 111, 259–268 (2007).

    Article  PubMed  CAS  Google Scholar 

  39. Hashimoto, K. et al. Immunohistochemical profile for unknown primary adenocarcinoma. PLoS ONE 7, e31181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Conner, J. R. & Hornick, J. L. Metastatic carcinoma of unknown primary. Adv. Anat. Pathol. 22, 149–167 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Rubin, B. P., Skarin, A. T., Pisick, E., Rizk, M. & Salgia, R. Use of cytokeratins 7 and 20 in determining the origin of metastatic carcinoma of unknown primary, with special emphasis on lung cancer. Eur. J. Cancer Prev. 10, 77–82 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Gunia, S., Koch, S. & May, M. Is CDX2 immunostaining useful for delineating anorectal from penile/vulvar squamous cancer in the setting of squamous cell carcinoma with clinically unknown primary site presenting with histologically confirmed inguinal lymph node metastasis? J. Clin. Pathol. 66, 109–112 (2012).

    Article  PubMed  Google Scholar 

  43. Anderson, G. G. & Weiss, L. Determining tissue of origin for metastatic cancers. Appl. Immunohistochem. Mol. Morphol. 18, 3–8 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Ruiz-Ruiz, F. J., Saenz-Abad, D., Hualde-Enguita, A. M. & Morales-Rull, J. L. Positron emission tomography: useful in detecting metastatic cancer of unknown primary site. Singapore Med. J. 46, 302–303 (2005).

    CAS  PubMed  Google Scholar 

  45. Karapolat, I. & Kumanlıog˘lu, K. Impact of FDG-PET/CT for the detection of unknown primary tumours in patients with cervical lymph node metastases. Mol. Imaging Radionucl. Ther. 21, 63–68 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Rades, D. et al. Localised disease in cancer of unknown primary (CUP): the value of positron emission tomography (PET) for individual therapeutic management. Ann. Oncol. 12, 1605–1609 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Lee, J. R. et al. Detection of occult primary tumors in patients with cervical metastases of unknown primary tumors: comparison of (18)F FDG PET/CT with contrast-enhanced CT or CT/MR imaging-prospective study. Radiology 274, 764–771 (2015).

    Article  PubMed  Google Scholar 

  48. Gutzeit, A. et al. Unknown primary tumors: detection with dual-modality PET/CT—initial experience. Radiology 234, 227–234 (2005).

    Article  PubMed  Google Scholar 

  49. Fencl, P. et al. Prognostic and diagnostic accuracy of [18F]FDG-PET/CT in 190 patients with carcinoma of unknown primary. Eur. J. Nucl. Med. Mol. Imaging 34, 1783–1792 (2007).

    Article  PubMed  Google Scholar 

  50. Nanni, C. et al. Role of 18F-FDG PET-CT imaging for the detection of an unknown primary tumour: preliminary results in 21 patients. Eur. J. Nucl. Med. Mol. Imaging 32, 589–592 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Delgado-Bolton, R. C., Fernández-Pérez, C., González-Maté, A. & Carreras, J. L. Meta-analysis of the performance of 18F-FDG PET in primary tumor detection in unknown primary tumors. J. Nucl. Med. 44, 1301–1314 (2003).

    PubMed  Google Scholar 

  52. Kwee, T. C. & Kwee, R. M. Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and meta-analysis. Eur. Radiol. 19, 731–744 (2009).

    Article  PubMed  Google Scholar 

  53. Beisenayeva, A. et al. The importance of immunohistochemical studies in the diagnosis of cancer of unknown primary origin. Georgian Med. News 249, 73–80 (2015).

    Google Scholar 

  54. Biernacka, A. et al. A case of S-100 negative melanoma: a diagnostic pitfall in the workup of a poorly differentiated metastatic tumor of unknown origin. Cytojournal 13, 21 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Tothill, R. W. et al. An expression-based site of origin diagnostic method designed for clinical application to cancer of unknown origin. Cancer Res. 65, 4031–4040 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Horlings, H. M. et al. Gene expression profiling to identify the histogenetic origin of metastatic adenocarcinomas of unknown primary. J. Clin. Oncol. 26, 4435–4441 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Varadhachary, G. R. et al. Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. J. Clin. Oncol. 26, 4442–4448 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. van Laar, R. K. et al. Implementation of a novel microarray-based diagnostic test for cancer of unknown primary. Int. J. Cancer 125, 1390–1397 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Handorf, C. R. et al. A multicenter study directly comparing the diagnostic accuracy of gene expression profiling and immunohistochemistry for primary site identification in metastatic tumors. Am. J. Surg. Pathol. 37, 1067–1075 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Yoon, H. H. et al. Gene expression profiling identifies responsive patients with cancer of unknown primary treated with carboplatin, paclitaxel, and everolimus: NCCTG N0871 (alliance). Ann. Oncol. 27, 339–344 (2016).

    Article  CAS  PubMed  Google Scholar 

  61. Greco, F. A., Lennington, W. J., Spigel, D. R. & Hainsworth, J. D. Molecular profiling diagnosis in unknown primary cancer: accuracy and ability to complement standard pathology. J. Natl Cancer Inst. 105, 782–790 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Varadhachary, G. R. et al. Prospective gene signature study using microRNA to identify the tissue of origin in patients with carcinoma of unknown primary. Clin. Cancer Res. 17, 4063–4070 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Ferracin, M. et al. MicroRNA profiling for the identification of cancers with unknown primary tissue-of-origin. J. Pathol. 225, 43–53 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 358, 1148–1159 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Heyn, H. & Esteller, M. DNA methylation profiling in the clinic: applications and challenges. Nat. Rev. Genet. 13, 679–692 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Rando, O. J. Daddy issues: paternal effects on phenotype. Cell 151, 702–708 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Schubeler, D. Epigenetic islands in a genetic ocean. Science 338, 756–757 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Portela, A. & Esteller, M. Epigenetic modifications and human disease. Nat. Biotechnol. 28, 1057–1068 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Vizoso, M. et al. Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. Nat. Med. 21, 741–750 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sakatani, T. et al. Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science 25, 1976–1978 (2005).

    Article  CAS  Google Scholar 

  71. Sandoval, J. et al. A prognostic DNA methylation signature for stage I non-small-cell lung cancer. J. Clin. Oncol. 31, 4140–4147 (2013).

    Article  PubMed  Google Scholar 

  72. Esteller, M. et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N. Engl. J. Med. 343, 1350–1354 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Veeck, J. et al. BRCA1 CpG island hypermethylation predicts sensitivity to poly(adenosine diphosphate)-ribose polymerase inhibitors. J. Clin. Oncol. 28, e563–564 (2010).

    Article  PubMed  Google Scholar 

  75. Ter Brugge, P. et al. Mechanisms of therapy resistance in patient-derived xenograft models of BRCA1-deficient breast cancer. J. Natl Cancer Inst. 108, djw148 (2016).

    Article  CAS  Google Scholar 

  76. Lopez-Serra, P. et al. A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect. Nat. Commun. 5, 3608 (2014).

    Article  PubMed  CAS  Google Scholar 

  77. Nogales, V. et al. Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in human cancer confers resistance to platinum drugs. Oncotarget 7, 3084–3097 (2016).

    Article  PubMed  Google Scholar 

  78. Moutinho, C. et al. Epigenetic inactivation of the BRCA1 interactor SRBC and resistance to oxaliplatin in colorectal cancer. J. Natl Cancer Inst. 106, djt322 (2014).

    Article  PubMed  CAS  Google Scholar 

  79. Roll, J. D. et al. Dysregulation of the epigenome in triple-negative breast cancers: basal-like and claudin-low breast cancers express aberrant DNA hypermethylation. Exp. Mol. Pathol. 95, 276–287 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Stefansson, O. A. et al. CpG island hypermethylation of BRCA1 and loss of pRb as co-occurring events in basal/triple-negative breast cancer. Epigenetics 6, 638–649 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Alvarez, S. et al. DNA methylation profiles and their relationship with cytogenetic status in adult acute myeloid leukemia. PLoS ONE 5, e12197 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Wilop, S. et al. Array-based DNA methylation profiling in acute myeloid leukaemia. Br. J. Haematol. 155, 65–72 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Ibragimova, I. et al. Genome-wide promoter methylome of small renal masses. PLoS ONE 8, e77309 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lenhard, K. et al. Analysis of promoter methylation in stool: a novel method for the detection of colorectal cancer. Clin. Gastroenterol. Hepatol. 3, 142–149 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Sabbioni, S. et al. Multigene methylation analysis of gastrointestinal tumors: TPEF emerges as a frequent tumor-specific aberrantly methylated marker that can be detected in peripheral blood. Mol. Diagn. 7, 201–207 (2003).

    PubMed  Google Scholar 

  86. Sameer, A. S. & Nissar, S. Epigenetics in diagnosis of colorectal cancer. Mol. Biol. Res. Commun. 5, 49–57 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Lee, B. Bin et al. Aberrant methylation of APC, MGMT, RASSF2A, and Wif-1 genes in plasma as a biomarker for early detection of colorectal cancer. Clin. Cancer Res. 15, 6185–6191 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Lee, W. H., Isaacs, W. B., Bova, G. S. & Nelson, W. G. CG island methylation changes near the GSTP1 gene in prostatic carcinoma cells detected using the polymerase chain reaction: a new prostate cancer biomarker. Cancer Epidemiol. Biomarkers Prev. 6, 443–450 (1997).

    CAS  PubMed  Google Scholar 

  89. Goessl, C. et al. Fluorescent methylation-specific polymerase chain reaction for DNA-based detection of prostate cancer in bodily fluids. Cancer Res. 1, 5941–5945 (2000).

    Google Scholar 

  90. Peng, X. et al. Accumulated promoter methylation as a potential biomarker for esophageal cancer. Oncotarget 8, 679–691 (2017).

    Article  PubMed  Google Scholar 

  91. Su, Y., Fang, H. & Jiang, F. Integrating DNA methylation and microRNA biomarkers in sputum for lung cancer detection. Clin. Epigenetics 8, 109 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Wei, J. et al. Integrated analysis of genome-wide DNA methylation and gene expression profiles identifies potential novel biomarkers of rectal cancer. Oncotarget 7, 62547–62558 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Toyota, M. et al. CpG island methylator phenotype in colorectal cancer. Proc. Natl Acad. Sci. USA 96, 8681–8686 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kanai, Y., Ushijima, S., Kondo, Y., Nakanishi, Y. & Hirohashi, S. DNA methyltransferase expression and DNA methylation of CPG islands and peri-centromeric satellite regions in human colorectal and stomach cancers. Int. J. Cancer 91, 205–212 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Ogino, S. et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 58, 90–96 (2009).

    Article  PubMed  Google Scholar 

  96. Abe, M. et al. CpG island methylator phenotype is a strong determinant of poor prognosis in neuroblastomas. Cancer Res. 1, 828–834 (2005).

    Google Scholar 

  97. Asada, K. et al. Stronger prognostic power of the CpG island methylator phenotype than methylation of individual genes in neuroblastomas. Jpn. J. Clin. Oncol. 43, 641–645 (2013).

    Article  PubMed  Google Scholar 

  98. Sandoval, J. et al. Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics 6, 692–702 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Moran, S., Arribas, C. & Esteller, M. Validation of a DNA methylation microarray for 850,000 CpG sites of the human genome enriched in enhancer sequences. Epigenomics 8, 389–399 (2016).

    Article  CAS  PubMed  Google Scholar 

  100. Heyn, H., Méndez-González, J. & Esteller, M. Epigenetic profiling joins personalized cancer medicine. Expert Rev. Mol. Diagn. 13, 473–479 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Moran, S. et al. Validation of DNA methylation profiling in formalin-fixed paraffin-embedded samples using the Infinium HumanMethylation450 Microarray. Epigenetics 9, 829–833 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Varadhachary, G. R., Raber, M. N., Matamoros, A. & Abbruzzese, J. L. Carcinoma of unknown primary with a colon-cancer profile-changing paradigm and emerging definitions. Lancet Oncol. 9, 596–599 (2008).

    Article  PubMed  Google Scholar 

  103. Hainsworth, J. D. et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute. J. Clin. Oncol. 31, 217–223 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Greco, F. A. Improved diagnosis, therapy and outcomes for patients with CUP. Nat. Rev. Clin. Oncol. 14, 5–6 (2016).

    Article  PubMed  CAS  Google Scholar 

  105. Varadhachary, G. R. et al. Carcinoma of unknown primary with gastrointestinal profile: immunohistochemistry and survival data for this favorable subset. Int. J. Clin. Oncol. 19, 479–484 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Pavlidis, N., Petrakis, D., Golfinopoulos, V. & Pentheroudakis, G. Long-term survivors among patients with cancer of unknown primary. Crit. Rev. Oncol. Hematol. 84, 85–92 (2012).

    Article  PubMed  Google Scholar 

  107. Tothill, R. W. et al. Massively-parallel sequencing assists the diagnosis and guided treatment of cancers of unknown primary. J. Pathol. 231, 413–423 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Ross, J. S. et al. Comprehensive genomic profiling of carcinoma of unknown primary site: new routes to targeted therapies. JAMA Oncol. 1, 40–49 (2015).

    Article  PubMed  Google Scholar 

  109. Stella, G. M. et al. MET mutations in cancers of unknown primary origin (CUPs). Hum. Mutat. 32, 44–50 (2011).

    Article  CAS  PubMed  Google Scholar 

  110. Gatalica, Z. et al. Comprehensive tumor profiling identifies numerous biomarkers of drug response in cancers of unknown primary site: analysis of 1806 cases. Oncotarget 5, 12440–12447 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Varadhachary, G. Carcinoma of unknown primary site: the poster child for personalized medicine? JAMA Oncol. 1, 19–21 (2015).

    Article  PubMed  Google Scholar 

  112. Amatu, A. et al. Promoter CpG island hypermethylation of the DNA repair enzyme MGMT predicts clinical response to dacarbazine in a phase II study for metastatic colorectal cancer. Clin. Cancer Res. 15, 2265–2272 (2013).

    Article  CAS  Google Scholar 

  113. Amatu, A. et al. Tumor MGMT promoter hypermethylation changes over time limit temozolomide efficacy in a phase II trial for metastatic colorectal cancer. Ann. Oncol. 27, 1062–1067 (2016).

    Article  CAS  PubMed  Google Scholar 

  114. Palma, N. A. et al. Durable response to crizotinib in a MET-amplified, KRAS-mutated carcinoma of unknown primary. Case Rep. Oncol. 7, 503–508 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Chung, J. H. et al. A poorly differentiated malignant neoplasm lacking lung markers harbors an EML4-ALK rearrangement and responds to crizotinib. Case Rep. Oncol. 7, 7628–7632 (2014).

    Article  Google Scholar 

  116. Petrakis, D., Pentheroudakis, G., Voulgaris, E. & Pavlidis, N. Prognostication in cancer of unknown primary (CUP): development of a prognostic algorithm in 311 cases and review of the literature. Cancer Treat. Rev. 39, 701–708 (2013).

    Article  PubMed  Google Scholar 

  117. Martinez-Cardús, A. et al. Epigenetic homogeneity within colorectal tumors predicts shorter relapse-free and overall survival times for patients with locoregional cancer. Gastroenteroogy 151, 961–972 (2016).

    Article  Google Scholar 

  118. Stelzer, Y., Shivalila, C. S., Soldner, F., Markoulaki, S. & Jaenisch, R. Tracing dynamic changes of DNA methylation at single-cell resolution. Cell 163, 218–229 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kantlehner, M. et al. A high-throughput DNA methylation analysis of a single cell. Nucleic Acids Res. 39, e44 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Komine, K. et al. Utility of measuring circulating tumor cell counts to assess the efficacy of treatment for carcinomas of unknown primary origin. Anticancer Res. 34, 3165–3168 (2014).

    PubMed  Google Scholar 

  121. Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat. Genet. 37, 391–400 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Seligson, D. B. et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435, 1262–1266 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Schmidl, C., Rendeiro, A. F., Sheffield, N. C. & Bock, C. ChIPmentation: fast, robust, low-input ChIP-seq for histones and transcription factors. Nat. Methods 12, 963–965 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Rotem, A. et al. Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state. Nat. Biotechnol. 33, 1165–1172 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hyun, B. R., McElwee, J. L. & Soloway, P. D. Single molecule and single cell epigenomics. Methods 72, 41–50 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Buenrostro, J. D. et al. Single-cell chromatin accessibility reveals principles of regulatory variation. Nature 523, 486–490 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Rendeiro, A. F. et al. Chromatin accessibility maps of chronic lymphocytic leukaemia identify subtype-specific epigenome signatures and transcription regulatory networks. Nat. Commun. 7, 11938 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Esteller, M. et al. Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. Cancer Res. 59, 67–70 (1999).

    CAS  PubMed  Google Scholar 

  129. Wong, I. H. et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res. 59, 71–73 (1999).

    CAS  PubMed  Google Scholar 

  130. Kristensen, L. S. et al. Aberrant methylation of cell-free circulating DNA in plasma predicts poor outcome in diffuse large B cell lymphoma. Clin. Epigenetics 8, 95 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Vaca-Paniagua, F. et al. Targeted deep DNA methylation analysis of circulating cell-free DNA in plasma using massively parallel semiconductor sequencing. Epigenomics 7, 353–362 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Lehmann-Werman, R. et al. Identification of tissue-specific cell death using methylation patterns of circulating DNA. Proc. Natl Acad. Sci. USA 113, E1826–E1834 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Guo, S. et al. Identification of methylation haplotype blocks aids in deconvolution of heterogeneous tissue samples and tumor tissue-of-origin mapping from plasma DNA. Nat. Genet. 49, 635–642 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01540058 (2016).

  135. [No authors listed.] CancerTYPE ID. CancerTYPE ID https://www.cancertypeid.com (2017).

  136. Gracia, A. et al. Economic analysis of epicup, an epigenetic test to predict the tissue of origin in cancer of unknown primary site, from USA payors perspective. Value Health 18, A356 (2015).

    Google Scholar 

  137. Gracia, A. et al. Economic analysis of epicup, an epigenetic test to predict the tissue of origin in cancer of unknown primary site, from the spanish NHS perspective. Value Health 18, A356–A357 (2015).

    Google Scholar 

  138. Lin, F. & Liu, H. Immunohistochemistry in undifferentiated neoplasm/tumor of uncertain origin. Arch. Pathol. Lab. Med. 138, 1583–1610 (2014).

    Article  PubMed  Google Scholar 

  139. Alaggio, R., Coffin, C. M. & Vargas, S. O. Soft tissue tumors of uncertain origin. Pediatr. Dev. Pathol. 15, 267–305 (2012).

    Article  PubMed  Google Scholar 

  140. Licciardello, J. T., Spitz, M. R. & Hong, W. K. Multiple primary cancer in patients with cancer of the head and neck: second cancer of the head and neck, esophagus, and lung. Int. J. Radiat. Oncol. Biol. Phys. 17, 467–476 (1989).

    Article  CAS  PubMed  Google Scholar 

  141. Chao, A. et al. Implication of genomic characterization in synchronous endometrial and ovarian cancers of endometrioid histology. Gynecol. Oncol. 143, 60–67 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Tothill, R. W. et al. Development and validation of a gene expression tumour classifier for cancer of unknown primary. Pathology 47, 7–12 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors have received funding from the AGAUR 2014SGR633 grant (to M.E.), the Cellex Foudation (to M.E.), the European Development Regional Fund 'A way to achieve Europe' (grants ERDF.CIBER 2016. CB16/12/00312, PIE13/00022 (ONCOPROFILE) and SAF2014-55000-R; to M.E.), the European Union's Horizon 2020 research and innovation programme under grant agreements No 640696 and No 727264 (to M.E.), the Health and Science Departments of the Catalan regional government (Generalitat de Catalunya), Instituto de Salud Carlos III (ISCIII), and the Ministerio de Economía y Competitividad (MINECO).

Author information

Author notes

  1. Sebastián Moran and Anna Martinez-Cardús: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Avinguda Gran Via 199–203, L'Hospitalet del Llobregat, Barcelona, 08908, Spain

    Sebastián Moran, Anna Martinez-Cardús & Manel Esteller

  2. Department of Medical Oncology, Ioannina University Hospital, Niarxou Avenue, Ioannina, 45110, Greece

    Stergios Boussios

  3. Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Carrer de la Feixa Llarga, s/n, L'Hospitalet, 08908, Spain

    Manel Esteller

  4. Institucio Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, Barcelona, 08010, Spain

    Manel Esteller

Authors
  1. Sebastián Moran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Martinez-Cardús
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stergios Boussios
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manel Esteller
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article, contributed to discussions of content, wrote, reviewed, and edited the manuscript before submission.

Corresponding author

Correspondence to Manel Esteller.

Ethics declarations

Competing interests

A.M-C. has received honoraria from Ferrer International. M.E. has received grant support and is named in a patent from Ferrer International. S.M. and S.B. declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moran, S., Martinez-Cardús, A., Boussios, S. et al. Precision medicine based on epigenomics: the paradigm of carcinoma of unknown primary. Nat Rev Clin Oncol 14, 682–694 (2017). https://doi.org/10.1038/nrclinonc.2017.97

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2017.97

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer