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

Abstract

ImportanceSmall 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.ObjectiveTo 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 participantsA 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.InterventionAndrogen deprivation therapy for adenocarcinoma followed by multiagent chemotherapy for NePC.Main outcomes and measuresIdentification 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.ResultsA 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 relevanceNGS 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).Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0204-7) contains supplementary material, which is available to authorized users.

The Role of Epigenetics and Long Noncoding RNA MIAT in Neuroendocrine Prostate Cancer

“…Notably, the original hormone-sensitive adenocarcinoma and the derived NEPC exhibited matching genetic profiles [26]. Furthermore, an analysis of ERG rearrangement and TP53 status in clinical samples with mixed NEPC/adenocarcinoma phenotype suggested a single clonal origin for the two PCa subtypes, thereby supporting the trans-differentiation model [13,[27][28][29][30][31].Regardless of its cellular origin, NEPC will likely become a major clinical issue in the near future. Although the diagnosis of de novo NEPC is rare, sparse NEPC clones often coexist with more abundant adenocarcinoma cells.…”

Targeted next-generation sequencing of CIC-DUX4 soft tissue sarcomas demonstrates low mutational burden and recurrent chromosome 1p loss

“…DNA was isolated using the Qiagen Allprep FFPE DNA/RNA kit (Qiagen, Valencia, CA) as described[19, 20]. DNA was quantified using the Qubit 2.0 fluorometer (Life Technologies, Foster City, CA).…”

“…We performed targeted, multiplexed PCR based next generation sequencing (NGS) using the Ion Ampliseq Comprehensive Cancer Panel (CCP), which targets 1,688,650 bases from 15,992 amplicons representing 409 cancer genes, essentially as described [19, 20]. Barcoded libraries were generated from 40 ng of DNA per sample using the CCP and the Ion Ampliseq library kit 2.0 (Life Technologies, Foster City, CA) according to manufacturer’s instructions with barcode incorporation.…”

“…Data analysis was performed essentially as described [19, 20] using validated pipelines based on Torrent Suite 4.0.2, with alignment by TMAP using default parameters, and variant calling using the Torrent Variant Caller plugin (version 4.0-r76860) with low-stringency default somatic variant settings. Variants were annotated using Annovar [21].…”

The Role of Next-Generation Sequencing in Castration-Resistant Prostate Cancer Treatment

“…The increasing relevance of NePC (whether due to selection by more potent AR signaling therapies or increased survival of patients with CRPC beyond AR driven disease) has led to investigation on both the morphologic and molecular characterization of this disease subtype 4,12,40,41 . Importantly, both single gene and comprehensive NGS approaches support transdifferentiation as the typical mechanism of NePC development, where NePC is clonally related to preceding AR driven disease 4,42,43 . NePC, particularly small cell carcinoma, shows a unique transcriptional profile (typically AR signaling low, neuroendocrine gene expression high and proliferation high) as well as characteristic genomic alterations including RB1 and TP53 loss and MYCN (or MYCL ) amplification 40,44–46 .…”