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de Kouchkovsky et al. J Transl Genet Genom 2021;5:265-77 https://dx.doi.org/10.20517/jtgg.2021.32 Page 267

mCRPC-adenocarcinoma). The presence of visceral or predominantly lytic bone metastases, bulky tumors,
low prostate-specific antigen levels relative to tumor burden, and short response to androgen deprivation
[4]
therapy (ADT) have been used to select patients for platinum-based chemotherapy . However, the
sensitivity and specificity of these clinical features have not been established. Our group has demonstrated
that the combined finding of a serum neuron-specific enolase concentration > 6.05 ng/mL and
chromogranin A level > 3.1 ng/mL showed high sensitivity and negative predictive value (95% and 98%,
respectively), but low specificity (50%) and positive predictive value (22%) for the finding of t-SCNC on
biopsy. Although commonly seen at the time of t-SCNC diagnosis, the presence of liver metastases does not
predict histology .
[11]

GENOMIC ALTERATIONS IN T-SCNC
Unlike other small cell neuroendocrine carcinomas and their non-small cell histologic counterparts , there
[13]
is a surprising overlap in the spectrum of genomic alterations seen in t-SCNC and mCRPC-
adenocarcinoma. Similar numbers of single nucleotide and copy number variants are observed across t-
SCNC and mCRPC-adenocarcinoma specimens [3,14] , and most of the common PC alterations (such as ERG
gene rearrangements and PTEN deletions) are detected in similar frequencies across the two histologic
subtypes [15-17] . This genomic overlap supports a divergent model of clonal evolution, whereby t-SCNC arises
through transdifferentiation of an mCRPC-adenocarcinoma subclone - rather than treatment selection of a
pre-existing independent neuroendocrine subclone. The paucity of genomic differences between mCRPC-
adenocarcinoma and t-SCNC also underscores the potential role of epigenetic reprogramming in mediating
lineage plasticity and establishing tumor phenotype, discussed below. In the context of this broad genomic
overlap, however, the few genomic differences that have been described across the two histologic subtypes
provide important insights into the pathogenesis of t-SCNC.

RB1 loss and inactivating TP53 mutations have long been implicated in cancer development through the
activation of E2F transcription factors required for cell cycle progression and downregulation of pro-
apoptotic genes, respectively [18,19] . Among PC patients, the incidence of these alterations increases as the
disease progresses from non-metastatic adenocarcinoma to mCRPC . Heterogeneous levels of RB1
[17]
depletion within individual metastatic biopsies further suggest that RB1 loss constitutes a late subclonal
event in mCRPC . Both TP53 mutations and RB1 loss are significantly enriched in patients with t-SCNC:
[20]
Whole-exome sequencing of 81 mCRPC samples (including 30 t-SCNC tumors) thus detected RB1 loss in
70% of t-SCNC tumors, compared to only 32% of mCRPC-adenocarcinoma samples (P = 0.003) . In
[3]
another cohort of 101 mCRPC patients, RB1 loss was present in all five t-SCNC samples (with the biallelic
loss occurring in 60% of cases), compared to only 9.4% of mCRPC-adenocarcinoma tumors . TP53
[14]
alterations, which are found in approximately 30% of mCRPC-adenocarcinomas, are detected in up to two-
thirds of t-SCNC cases (P = 0.043) [3,14,21] . Finally, combined TP53 alteration and RB1 loss (seen in only 4%-
5% of mCRPC) [15,21] have been reported in more than 50% of t-SCNC .
[3]

Although RB1 loss and TP53 mutations constitute key genomic hallmarks of t-SCNC, these alterations
alone are not sufficient to drive neuroendocrine differentiation or to make a diagnosis of t-SCNC. Indeed,
persistent adenocarcinoma phenotype can still be seen in a subset of TP53/RB1 deficient mCRPC
samples . Similarly, among patients treated with neoadjuvant AR-targeted therapy, the presence of an RB1
[21]
loss predicts increased tumor proliferation and treatment resistance but is not itself associated with the
expression of neuroendocrine markers . Rather than directly inducing neuroendocrine differentiation,
[22]
RB1 loss and TP53 alterations more likely cooperate to promote lineage plasticity - thereby allowing cancer
cells to undergo a phenotypic switch following additional genomic and epigenetic events. Consistent with
this model, combined RB1/TP53 loss in PTEN-deficient mouse models of PC has been shown to induce