title: Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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. Cancer 2016;122:1836-43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Tu
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mehmet Asim
authors.initials: MA
authors.lastname: Bilen
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chongjuan
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lance C
authors.initials: LC
authors.lastname: Pagliaro
authors.affiliation: Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Karam
authors.affiliation: Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: John F
authors.initials: JF
authors.lastname: Ward
authors.affiliation: Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Priya
authors.initials: P
authors.lastname: Rao
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zachary H
authors.initials: ZH
authors.lastname: Tu
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rosale
authors.initials: R
authors.lastname: General
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Adrienne H
authors.initials: AH
authors.lastname: Chen
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yago L
authors.initials: YL
authors.lastname: Nieto
authors.affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sai-Ching J
authors.initials: SC
authors.lastname: Yeung
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sue-Hwa
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.affiliation: Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Louis L
authors.initials: LL
authors.lastname: Pisters
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002454:Cell Differentiation / Q000502:physiology; D002648:Child; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology; D010641:Phenotype; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D013736:Testicular Neoplasms / Q000235:genetics* / Q000473:pathology*; D055815:Young Adult
keywords: integrated therapy; intratumoral heterogeneity; lethal phenotype; precision medicine; testicular cancer; yolk sac tumor