Familial cancer of unknown primary

  • Elie Rassy
  • Joseph Kattan
  • Nicholas PavlidisEmail author
Letter to the Editor


Cancer of unknown primary site (CUP) is a deadly disease diagnosed through metastases at various organs without primary tumor identification. Despite the major molecular and technological advances, the carcinogenesis of CUP remains enigmatic which hampers adequate study design of treatments leading to survival improvement. To date, the pathogenesis of CUP is still debatable with one hypothesis considering CUP simply a group of metastatic tumors with unidentified primaries and another considering it a distinct entity with specific genetic and phenotypic aberrations. Familial CUP seems to favor the first hypothesis due to common genetic predisposition factors between known primaries and CUP. Two clinical implications may be withdrawn from the pathogenesis of familial clustering of CUP. The detailed family history and environmental risk factors may orient towards the primary tumor identification. Smoking avoidance and adherence to general population guidelines for cancer screening would be strongly encouraged.


Cancer of unknown primary CUP Familial Genetics 


Compliance with ethical standards

Conflict of interest

No author has any conflict of interest.


  1. 1.
    Pavlidis N, Khaled H, Gaafar R (2015) A mini review on cancer of unknown primary site: a clinical puzzle for the oncologists. J Adv Res 6:375–382. CrossRefGoogle Scholar
  2. 2.
    Pavlidis N, Pentheroudakis G (2012) Cancer of unknown primary site. Lancet Lond Engl 379:1428–1435. CrossRefGoogle Scholar
  3. 3.
    Urban D, Rao A, Bressel M et al (2013) Cancer of unknown primary: a population-based analysis of temporal change and socioeconomic disparities. Br J Cancer 109:1318–1324. CrossRefGoogle Scholar
  4. 4.
    Fizazi K, Greco FA, Pavlidis N et al (2015) Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol 26(Suppl 5):v133–v138. CrossRefGoogle Scholar
  5. 5.
    Pentheroudakis G, Briasoulis E, Pavlidis N (2007) Cancer of unknown primary site: missing primary or missing biology? Oncologist 12:418–425. CrossRefGoogle Scholar
  6. 6.
    El Rassy E, Khaled H, Pavlidis N (2018) Liquid biopsy: a new diagnostic, predictive and prognostic window in cancers of unknown primary. Eur J Cancer 105:28–32. CrossRefGoogle Scholar
  7. 7.
    Hainsworth JD, Rubin MS, Spigel DR et al (2013) 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. CrossRefGoogle Scholar
  8. 8.
    Moran S, Martínez-Cardús A, Sayols S et al (2016) Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol 17:1386–1395. CrossRefGoogle Scholar
  9. 9.
    El Rassy E, Pavlidis N (2018) The current evidence for a biomarker-based approach in cancer of unknown primary. Cancer Treat Rev 67:21–28. CrossRefGoogle Scholar
  10. 10.
    Pavlidis N (2007) Forty years experience of treating cancer of unknown primary. Acta Oncol 46:592–601. CrossRefGoogle Scholar
  11. 11.
    Economopoulou P, Mountzios G, Pavlidis N et al (2015) Cancer of unknown primary origin in the genomic era: elucidating the dark box of cancer. Cancer Treat Rev 41:598–604. CrossRefGoogle Scholar
  12. 12.
    Hemminki K, Ji J, Sundquist J et al (2011) Familial risks in cancer of unknown primary: tracking the primary sites. J Clin Oncol 29:435–440. CrossRefGoogle Scholar
  13. 13.
    Samadder NJ, Smith KR, Hanson H et al (2016) Familial risk in patients with carcinoma of unknown primary. JAMA Oncol 2:340–346. CrossRefGoogle Scholar
  14. 14.
    Vikeså J, Møller AKH, Kaczkowski B et al (2015) Cancers of unknown primary origin (CUP) are characterized by chromosomal instability (CIN) compared to metastasis of know origin. BMC Cancer 15:151. CrossRefGoogle Scholar
  15. 15.
    Hemminki K, Chen B, Kumar A et al (2016) Germline genetics of cancer of unknown primary (CUP) and its specific subtypes. Oncotarget 7:22140–22149. CrossRefGoogle Scholar
  16. 16.
    Lynch HT, Slostad B, Silberstein P (2016) Familial carcinoma of unknown primary. JAMA Oncol 2:346–347. CrossRefGoogle Scholar
  17. 17.
    Linnebacher M, Gebert J, Rudy W et al (2001) Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens. Int J Cancer 93:6–11CrossRefGoogle Scholar
  18. 18.
    Hemminki K, Sundquist K, Sundquist J et al (2016) Location of metastases in cancer of unknown primary are not random and signal familial clustering. Sci Rep. Google Scholar
  19. 19.
    Hemminki K, Bevier M, Sundquist J et al (2012) Cancer of unknown primary (CUP): does cause of death and family history implicate hidden phenotypically changed primaries? Ann Oncol 23:2720–2724. CrossRefGoogle Scholar
  20. 20.
    Oskarsson T, Batlle E, Massagué J (2014) Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell 14:306–321. CrossRefGoogle Scholar
  21. 21.
    Kaaks R, Sookthai D, Hemminki K et al (2014) Risk factors for cancers of unknown primary site: results from the prospective EPIC cohort. Int J Cancer 135:2475–2481. CrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2019

Authors and Affiliations

  1. 1.Department of Cancer MedicineGustave Roussy InstitutVillejuifFrance
  2. 2.Department of Hematology-Oncology, Hotel Dieu de France University Hospital, Faculty of MedicineSaint Joseph UniversityBeirutLebanon
  3. 3.Emeritus ProfessorUniversity of IoanninaIoanninaGreece

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