Comprehensive serial molecular profiling of an “N of 1” exceptional non-responder with metastatic prostate cancer progressing to small cell carcinoma on treatment

Journal of Hematology & Oncology

Kathleen A. Cooney¹  Chia-Jen Liu²  Daniel H. Hovelson²  Kei Omata²  Andi K. Cani²  Saagar K. Sanghvi³  Scott A. Tomlins⁴  Kunal C. Kadakia¹ 

[1] Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, 7216 Cancer Center, SPC 5948, 1500 East Medical Center Drive, Ann Arbor 48109, MI, USA;Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor 48109, MI, USA;Boonshoft School of Medicine, Wright State University, Dayton, USA;Department of Pathology and Urology, Michigan Center for Translational Pathology; University of Michigan Comprehensive Cancer Center, Ann Arbor 48109, MI, USA

关键词: Next generation sequencing;    Transdifferentiation;    Small cell prostate cancer;    Neuroendocrine prostate cancer;   

Others  :  1232043
DOI  :  10.1186/s13045-015-0204-7

 received in 2015-07-22, accepted in 2015-09-28,  发布年份 2015

【 摘 要 】

Importance

Small cell carcinoma/neuroendocrine prostate cancer (NePC) is a lethal, poorly understood prostate cancer (PCa) subtype. Controversy exists about the origin of NePC in this setting.

Objective

To molecularly profile archived biopsy specimens from a case of early-onset PCa that rapidly progressed to NePC to identify drivers of the aggressive course and mechanisms of NePC origin and progression.

Design, setting, and participants

A 47-year-old patient presented with metastatic prostatic adenocarcinoma (Gleason score 9). After a 6-month response to androgen deprivation therapy, the patient developed jaundice and liver biopsy revealed exclusively NePC. Targeted next generation sequencing (NGS) from formalin-fixed paraffin-embedded (FFPE)-isolated DNA was performed from the diagnostic prostate biopsy and the liver biopsy at progression.

Intervention

Androgen deprivation therapy for adenocarcinoma followed by multiagent chemotherapy for NePC.

Main outcomes and measures

Identification of the mutational landscape in primary adenocarcinoma and NePC liver metastasis. Whether the NePC arose independently or was derived from the primary adenocarcinoma was considered based on mutational profiles.

Results

A deleterious somatic SMAD4 L535fs variant was present in both prostate and liver specimens; however, a TP53 R282W mutation was exclusively enriched in the liver specimen. Copy number analysis identified concordant, low-level alterations in both specimens, with focal MYCL amplification and homozygous PTEN, RB1, and MAP2K4 losses identified exclusively in the NePC specimen. Integration with published genomic profiles identified MYCL as a recurrently amplified in NePC.

Conclusions and relevance

NGS of routine biopsy samples from an exceptional non-responder identified SMAD4 as a driver of the aggressive course and supports derivation of NePC from primary adenocarcinoma (transdifferentiation).

【 授权许可】

   
2015 Kadakia et al.

【 图 表 】

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