Oncotarget

Research Papers:

Intratumoral heterogeneity and chemoresistance in nonseminomatous germ cell tumor of the testis

Mehmet Asim Bilen, Kenneth R. Hess, Matthew T. Campbell, Jennifer Wang, Russell R. Broaddus, Jose A. Karam, John F. Ward, Christopher G. Wood, Seungtaek L. Choi, Priya Rao, Miao Zhang, Aung Naing, Rosale General, Diana H. Cauley, Sue-Hwa Lin, Christopher J. Logothetis, Louis L. Pisters and Shi-Ming Tu _

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Oncotarget. 2016; 7:86280-86289. https://doi.org/10.18632/oncotarget.13380

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Abstract

Mehmet Asim Bilen1, Kenneth R. Hess2, Matthew T. Campbell3, Jennifer Wang3, Russell R. Broaddus4, Jose A. Karam5, John F. Ward5, Christopher G. Wood5, Seungtaek L. Choi6, Priya Rao4, Miao Zhang4, Aung Naing7, Rosale General3, Diana H. Cauley3, Sue-Hwa Lin8, Christopher J. Logothetis3, Louis L. Pisters5, Shi-Ming Tu3

1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA

2Department of Biostatistics the University of Texas MD Anderson Cancer Center, Houston, Texas, USA

3Department of Genitourinary Medical Oncology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA

4Department of Pathology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA

5Department of Urology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA

6Department of Radiation Oncology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA

7Department of Investigational Cancer Therapeutics the University of Texas MD Anderson Cancer Center, Houston, Texas, USA

8Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Correspondence to:

Shi-Ming Tu, email: [email protected]

Keywords: testicular cancer, intratumoral heterogeneity, chemoresistance, nonseminomatous germ cell tumor, next-generation sequencing

Received: August 15, 2016     Accepted: November 07, 2016     Published: November 16, 2016

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.

Materials and 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.


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