title: Intratumoral heterogeneity and chemoresistance in nonseminomatous germ cell tumor of the testis.
abstract: BACKGROUND
  Nonseminomatous germ cell tumor of the testis (NSGCT) is largely curable. However, a small group of patients develop refractory disease. We investigated the hypothesis that intratumoral heterogeneity contributes to the emergence of chemoresistance and the development of refractory tumor subtypes.
  
  
  RESULTS
  Our institution's records for January 2000 through December 2010 included 275 patients whose primary tumor showed pure embryonal carcinoma (pure E); mixed embryonal carcinoma, yolk sac tumor, and teratoma (EYT); or mixed embryonal carcinoma, yolk sac tumor, seminoma, and teratoma (EYST). Patients with EYST had the highest cancer-specific mortality rate (P = .001). They tended to undergo somatic transformation (P = .0007). Two of 5 patients with clinical stage I EYST who had developed recurrence during active surveillance died of their disease.
  
  
  METHODS
  In this retrospective study, we evaluated consecutive patients who had been diagnosed with the three most common histological phenotypes of NSGCT. Chemoresistance was defined as the presence of teratoma, viable germ cell tumor, or somatic transformation in the residual tumor or the development of progressive or relapsed disease after chemotherapy. In a separate prospective study, we performed next-generation sequencing on tumor samples from 39 patients to identify any actionable genetic mutations.
  
  
  CONCLUSIONS
  Our data suggest that patients with EYST in their primary tumor may harbor a potentially refractory NSGCT phenotype and are at increased risk of dying from disease. Despite intratumoral heterogeneity, improved patient selection and personalized care of distinct tumor subtypes may optimize the clinical outcome of patients with NSGCT.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
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, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.affiliation: Department of Genitourinary Medical Oncology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Campbell
authors.affiliation: Department of Genitourinary Medical Oncology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.affiliation: Department of Urology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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, USA.
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, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
authors.affiliation: Department of Radiation Oncology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Seungtaek L
authors.initials: SL
authors.lastname: Choi
authors.affiliation: Department of Pathology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Rao
authors.affiliation: Department of Pathology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Investigational Cancer Therapeutics the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: Department of Genitourinary Medical Oncology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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, USA.
authors.forename: Diana H
authors.initials: DH
authors.lastname: Cauley
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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, USA.
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, USA.
authors.forename: Louis L
authors.initials: LL
authors.lastname: Pisters
authors.affiliation: Department of Genitourinary Medical Oncology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Tu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019008:Drug Resistance, Neoplasm; D059472:Exome; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012189:Retrospective Studies; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D055815:Young Adult
keywords: chemoresistance; intratumoral heterogeneity; next-generation sequencing; nonseminomatous germ cell tumor; testicular cancer