{"entity":{"id":"paper-aparicio-aggressive-variant-prostate-tumour-suppressors-ccr-2016","kind":"paper","name":"Combined tumour suppressor defects characterise clinically defined aggressive variant prostate cancers","aka":[],"tldr":"Prostate cancers that behave like small cell carcinoma without looking like it turn out to share the same broken genes, so the clinical description can be checked against the molecular one.","summary":"Morphologically heterogeneous prostate cancers that behave clinically like small cell prostate cancers share their chemotherapy responsiveness. Fifty-nine prostate cancer samples from 40 clinical trial participants meeting aggressive variant criteria, and 8 patient-derived xenografts from 6 of them, were stained for markers aberrantly expressed in small cell prostate cancer, and DNA from 36 samples and 8 xenografts was analysed for copy-number gains and losses. Irrespective of morphology, Ki67 and Tp53 stained in at least 10% of cells in 80% and 41% of samples; RB1 stained in fewer than 10% of cells in 61% and androgen receptor in 36%. MYC copy gain, a surrogate for 8q, and RB1 copy loss were each present in 54% of 44 samples and PTEN copy loss in 48%. All but 1 of 8 xenografts carried Tp53 missense mutations. RB1 copy loss was the strongest discriminator between unselected castration-resistant prostate cancer and the aggressive variant, and combined alterations in RB1, Tp53 and PTEN were more frequent in aggressive variant disease than in unselected castration-resistant disease or in TCGA samples.","asOf":"2026-09-25","links":[{"label":"Aparicio et al., Clin Cancer Res 2016: combined RB1, TP53 and PTEN defects characterise clinically defined aggressive variant prostate cancer (59 samples from 40 trial participants)","url":"https://doi.org/10.1158/1078-0432.CCR-15-1259"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26546118/"}],"tags":[],"related":[],"cancers":["prostate","prostate-mcrpc","prostate-nepc"],"sections":[],"technologies":["histopathology-ihc"],"targets":["rb1","tp53","pten","androgen-receptor","mki67"],"drugs":[],"companies":[],"institutions":[],"pathways":["lineage-plasticity-neuroendocrine","p53-cell-cycle","pi3k-akt-mtor","chromosomal-instability"],"terms":["histologic-transformation","ihc","copy-number-variation-term","castration-resistance"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["clinical-cancer-research"],"dependsOn":[],"notes":[],"journal":"Clinical Cancer Research","year":2016,"doi":"10.1158/1078-0432.CCR-15-1259","pmid":"26546118","authors":"Aparicio AM, Shen L, Tapia ELN, et al.","paperType":"translational","findings":["RB1 loss the strongest single discriminator between unselected castration-resistant disease and the aggressive variant.","MYC copy gain and RB1 copy loss each in 54% of 44 samples, PTEN copy loss in 48%.","RB1 staining in under 10% of cells in 61% of samples and androgen receptor in 36%.","Combined RB1, TP53 and PTEN alterations enriched in aggressive variant disease."],"whatItMeans":"It validates a clinical definition against a molecular one, which is unusual and useful: a man whose disease behaves like small cell carcinoma can be treated as such even when his biopsy does not look like it, because the underlying genotype is the same.","caveats":["Fifty-nine samples from 40 trial participants, a selected population.","Copy-number analysis on archival material rather than sequencing.","The aggressive variant criteria are clinical and were defined by the same group."],"changedPractice":false,"participants":40},"route":"/key-papers/paper-aparicio-aggressive-variant-prostate-tumour-suppressors-ccr-2016/","neighbours":{"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate-nepc","kind":"cancer","name":"Neuroendocrine and small-cell prostate cancer","route":"/cancers/prostate-nepc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"technology":[{"id":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"mki67","kind":"target","name":"Ki-67 (MKI67)","route":"/targets/mki67/"},{"id":"pten","kind":"target","name":"PTEN","route":"/targets/pten/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"pathway":[{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/"},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"}],"term":[{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"copy-number-variation-term","kind":"term","name":"Copy number alteration (CNA)","route":"/terms/copy-number-variation-term/"},{"id":"histologic-transformation","kind":"term","name":"Histologic transformation","route":"/terms/histologic-transformation/"},{"id":"ihc","kind":"term","name":"Immunohistochemistry (IHC)","route":"/terms/ihc/"}],"journal":[{"id":"clinical-cancer-research","kind":"journal","name":"Clinical Cancer Research","route":"/journals/clinical-cancer-research/"}],"biomarker":[{"id":"nepc-transformation","kind":"biomarker","name":"Treatment-emergent neuroendocrine transformation (recognising it)","route":"/biomarkers/nepc-transformation/"}]}}