TY - JOUR
T1 - Genotype-to-Phenotype Associations in the Aggressive Variant Prostate Cancer Molecular Profile (AVPC-m) Components
AU - Soundararajan, Rama
AU - Viscuse, Paul
AU - Pilie, Patrick
AU - Liu, Jingjing
AU - Logotheti, Souzana
AU - Fernández, Caddie Laberiano
AU - Lorenzini, Daniele
AU - Hoang, Anh
AU - Lu, Wei
AU - Soto, Luisa Maren Solis
AU - Wistuba, Ignacio I.
AU - Xu, Mingchu
AU - Song, Xingzhi
AU - Shepherd, Peter D.A.
AU - Navone, Nora M.
AU - Tidwell, Rebecca S.S.
AU - Lozano, Guillermina
AU - Logothetis, Christopher
AU - Zhang, Jianhua
AU - Long, James P.
AU - Estecio, Marcos R.
AU - Tzelepi, Vasiliki
AU - Aparicio, Ana M.
N1 - Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - The aggressive variant prostate cancer molecular profile (AVPC-m), composed of combined defects in TP53, RB1 and PTEN, characterizes a subset of prostate cancers linked to androgen in-difference and platinum sensitivity. To contribute to the optimization of the AVPC-m assessment for inclusion in prospective clinical trials, we investigated the status of the AVPC-m components in 28 patient tumor-derived xenografts (PDXs) developed at MDACC. We subjected single formalin-fixed, paraffin-embedded (FFPE) blocks from each PDX to immunohistochemistry (IHC), targeted next-generation genomic sequencing (NGS) and Clariom-S Affymetrix human microarray expression profiling. Standard validated IHC assays and a 10% labeling index cutoff resulted in high repro-ducibility across three separate laboratories and three independent readers for all tumor suppressors, as well as strong correlations with loss-of-function transcriptional scores (LOF-TS). Adding intensity assessment to labeling indices strengthened the association between IHC results and LOF-TS for TP53 and RB1, but not for PTEN. For TP53, genomic alterations determined by NGS had slightly higher agreement scores with LOF-TS than aberrant IHC, while for RB1 and PTEN, NGS and IHC determinations resulted in similar agreement scores with LOF-TS. Nonetheless, our results indicate that the AVPC-m components can be assessed reproducibly by IHC using various widely available standardized assays.
AB - The aggressive variant prostate cancer molecular profile (AVPC-m), composed of combined defects in TP53, RB1 and PTEN, characterizes a subset of prostate cancers linked to androgen in-difference and platinum sensitivity. To contribute to the optimization of the AVPC-m assessment for inclusion in prospective clinical trials, we investigated the status of the AVPC-m components in 28 patient tumor-derived xenografts (PDXs) developed at MDACC. We subjected single formalin-fixed, paraffin-embedded (FFPE) blocks from each PDX to immunohistochemistry (IHC), targeted next-generation genomic sequencing (NGS) and Clariom-S Affymetrix human microarray expression profiling. Standard validated IHC assays and a 10% labeling index cutoff resulted in high repro-ducibility across three separate laboratories and three independent readers for all tumor suppressors, as well as strong correlations with loss-of-function transcriptional scores (LOF-TS). Adding intensity assessment to labeling indices strengthened the association between IHC results and LOF-TS for TP53 and RB1, but not for PTEN. For TP53, genomic alterations determined by NGS had slightly higher agreement scores with LOF-TS than aberrant IHC, while for RB1 and PTEN, NGS and IHC determinations resulted in similar agreement scores with LOF-TS. Nonetheless, our results indicate that the AVPC-m components can be assessed reproducibly by IHC using various widely available standardized assays.
KW - AVPC-m
KW - PTEN
KW - RB1
KW - TP53
KW - molecular heterogeneity
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U2 - 10.3390/cancers14133233
DO - 10.3390/cancers14133233
M3 - Article
C2 - 35805010
AN - SCOPUS:85133133896
SN - 2072-6694
VL - 14
JO - Cancers
JF - Cancers
IS - 13
M1 - 3233
ER -