Clinical and biological relevance of the transcriptomic‐based prostate cancer metastasis subtypes MetA‐C

Abstract

To improve treatment of metastatic prostate cancer, the biology of metastases needs to be understood. We recently described three subtypes of prostate cancer bone metastases (MetA-C), based on differential gene expression. The aim of this study was to verify the clinical relevance of these subtypes and to explore their biology and relations to genetic drivers. Freshly-frozen metastasis samples were obtained as hormone-naive (n = 17), short-term castrated (n = 21), or castration-resistant (n = 65) from a total of 67 patients. Previously published sequencing data from 573 metastasis samples were also analyzed. Through transcriptome profiling and sample classification based on a set of predefined MetA-C-differentiating genes, we found that most metastases were heterogeneous for the MetA-C subtypes. Overall, MetA was the most common subtype, while MetB was significantly enriched in castration-resistant samples and in liver metastases, and consistently associated with poor prognosis. By gene set enrichment analysis, the phenotype of MetA was described by high androgen response, protein secretion and adipogenesis, MetB by high cell cycle activity and DNA repair, and MetC by epithelial-to-mesenchymal transition and inflammation. The MetB subtype demonstrated single nucleotide variants of RB transcriptional corepressor 1 (RB1) and loss of 21 genes at chromosome 13, including RB1, but provided independent prognostic value to those genetic aberrations. In conclusion, a distinct set of gene transcripts can be used to classify prostate cancer metastases into the subtypes MetA-C. The MetA-C subtypes show diverse biology, organ tropism, and prognosis. The MetA-C classification

Epithelial and Stromal Characteristics of Primary Tumors Predict the Bone Metastatic Subtype of Prostate Cancer and Patient Survival after Androgen-Deprivation Therapy

“…The volume density of ERG+ endothelial cells, SDF-1+ stroma, SMA+ stroma, and PDGFRβ+ stroma was quantified using a square-lattice mounted in the eyepiece of the microscope counting grid-intersection falling on the stained tissue component and on reference space. The morphological data of bone metastases and their relations to the transcriptomic subtypes MetA-C (see below) and patient prognosis after ADT have, to some extent, been described and are here complemented with additional data and cases, and then related to morphological data of the primary tumors [ 4 , 5 ].…”

“…The duration of the initially favorable response is highly variable between patients. We have shown that human PC bone metastases can be separated into different subgroups with different transcriptome, proteome, metabolome, genetics, epigenetics, immune phenotypes, clinical behavior, and response to standard treatments [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Or in other words, there are different types of aggressive PC.…”

“…The most common transcriptomic subtype (approximately 70–80% of cases), by us named MetA, is characterized by high expression of androgen-regulated genes (including the prostate specific antigen, PSA), relatively low cell proliferation, a luminal cell phenotype, and a relatively favorable response to ADT. The most aggressive metastasis subtype (approximately 10–20% of cases), named MetB, is characterized by high cell proliferation, a dedifferentiated luminal cell phenotype with low PSA secretion, and the poorest response to ADT [ 4 , 5 ]. The smallest subtype (up to approximately 10% of cases), named MetC, is characterized by high expression of stroma-related genes, high immune cell response, and an intermediate to good ADT response [ 4 , 5 ].…”

“…The most aggressive metastasis subtype (approximately 10–20% of cases), named MetB, is characterized by high cell proliferation, a dedifferentiated luminal cell phenotype with low PSA secretion, and the poorest response to ADT [ 4 , 5 ]. The smallest subtype (up to approximately 10% of cases), named MetC, is characterized by high expression of stroma-related genes, high immune cell response, and an intermediate to good ADT response [ 4 , 5 ]. The diverse gene expression patterns in MetA-C indicate that their clinical behaviors are driven by different molecular mechanism and that they thereby should be treated differently [ 4 , 5 ].…”

“…The smallest subtype (up to approximately 10% of cases), named MetC, is characterized by high expression of stroma-related genes, high immune cell response, and an intermediate to good ADT response [ 4 , 5 ]. The diverse gene expression patterns in MetA-C indicate that their clinical behaviors are driven by different molecular mechanism and that they thereby should be treated differently [ 4 , 5 ].…”