Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer

Shi Ming Tu, Mehmet Asim Bilen, Kenneth R. Hess, Russell R. Broaddus, Scott Kopetz, Chongjuan Wei, Lance C. Pagliaro, Jose A. Karam, John F. Ward, Christopher G. Wood, Priya Rao, Zachary H. Tu, Rosale General, Adrienne H. Chen, Yago L. Nieto, Sai Ching J. Yeung, Sue Hwa Lin, Christopher J. Logothetis, Louis L. Pisters

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


BACKGROUND Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype. METHODS In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next-generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations. RESULTS Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P =.0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac-seminoma subgroup had the poorest clinical outcome (P =.0015). These tumors tended to undergo somatic transformation (P <.0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected. CONCLUSIONS The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT.

Original languageEnglish (US)
Pages (from-to)1836-1843
Number of pages8
Issue number12
StatePublished - Jun 15 2016


  • integrated therapy
  • intratumoral heterogeneity
  • lethal phenotype
  • precision medicine
  • testicular cancer
  • yolk sac tumor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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