Background: Genomic characterization of prostate cancer (PCa) biopsies may improve criteria for the selection of patients suitable for active surveillance (AS). Objective: To identify somatic genomic aberrations associated with adverse outcome as AS protocol exclusion indicators. Design, setting and participants: Whole-exome sequencing profiles were generated for Gleason score (GS) = 3 + 3 biopsies obtained from 54 PCa patients enrolled in two AS protocols. Patients were selected as representative of a nonindolent population, consisting of 27 patients who dropped out from AS due to upgrading (ie, finding of GS > 3 + 3 at a follow-up biopsy) within 2 yr, and a potentially indolent population, consisting of 27 patients in AS for ≥4 yr without any evidence of reclassification. Outcome measurements and statistical analysis: The genomic alteration landscape of core biopsies was analyzed using an integrated computational pipeline and correlated with patient reclassification due to upgrading. Results and limitations: Of all the GS = 3 + 3 biopsies of the study cohort, 34% showed clear evidence of somatic copy number aberrations along the genome. Of these, 39% came from the potentially indolent and 61% from the nonindolent population. Single-nucleotide variants demonstrated low allelic fractions and included a common F133C mutation in the SPOP gene. The minimally altered genomic landscape of the study cohort presented a distinct set of monoallelic deletions, including on 8p, 13q, 16q, and 21q, and rare amplifications of 8q, which were observed in both AS patient populations. Concerning lesions typically associated with adverse outcome, PTEN deletions and MYC amplification, though observed in a small number of cases, were detected exclusively or preferentially, respectively, in nonindolent patients. Such molecular findings were confirmed by immunohistochemistry on the same tissue blocks. The small sample size and the retrospective nature of the analysis represent the main study limitations. Conclusions: Genomic features enriched in aggressive tumors can be detected in GS = 3 + 3 core biopsies of AS patients. Patient summary: PTEN and MYC alterations at the time of diagnosis would deserve investigation in larger cohorts of AS patients to assess their potential as biomarkers for a more precise/earlier identification of patients at risk of reclassification. The presence of adverse outcome-related genomic lesions, such as PTEN deletion and MYC amplification, in GPS = 3 + 3 diagnostic core biopsies of prostate cancer patients could be considered for a more precise/earlier selection of patients not suitable for active surveillance.

Core Biopsies from Prostate Cancer Patients in Active Surveillance Protocols Harbor PTEN and MYC Alterations / Gandellini, P.; Casiraghi, N.; Rancati, T.; Benelli, M.; Doldi, V.; Romanel, A.; Colecchia, M.; Marenghi, C.; Valdagni, R.; Demichelis, F.; Zaffaroni, N.. - In: EUROPEAN UROLOGY ONCOLOGY. - ISSN 2588-9311. - ELETTRONICO. - 2:3(2019), pp. 277-285. [10.1016/j.euo.2018.08.010]

Core Biopsies from Prostate Cancer Patients in Active Surveillance Protocols Harbor PTEN and MYC Alterations

Casiraghi N.;Benelli M.;Romanel A.;Demichelis F.;
2019-01-01

Abstract

Background: Genomic characterization of prostate cancer (PCa) biopsies may improve criteria for the selection of patients suitable for active surveillance (AS). Objective: To identify somatic genomic aberrations associated with adverse outcome as AS protocol exclusion indicators. Design, setting and participants: Whole-exome sequencing profiles were generated for Gleason score (GS) = 3 + 3 biopsies obtained from 54 PCa patients enrolled in two AS protocols. Patients were selected as representative of a nonindolent population, consisting of 27 patients who dropped out from AS due to upgrading (ie, finding of GS > 3 + 3 at a follow-up biopsy) within 2 yr, and a potentially indolent population, consisting of 27 patients in AS for ≥4 yr without any evidence of reclassification. Outcome measurements and statistical analysis: The genomic alteration landscape of core biopsies was analyzed using an integrated computational pipeline and correlated with patient reclassification due to upgrading. Results and limitations: Of all the GS = 3 + 3 biopsies of the study cohort, 34% showed clear evidence of somatic copy number aberrations along the genome. Of these, 39% came from the potentially indolent and 61% from the nonindolent population. Single-nucleotide variants demonstrated low allelic fractions and included a common F133C mutation in the SPOP gene. The minimally altered genomic landscape of the study cohort presented a distinct set of monoallelic deletions, including on 8p, 13q, 16q, and 21q, and rare amplifications of 8q, which were observed in both AS patient populations. Concerning lesions typically associated with adverse outcome, PTEN deletions and MYC amplification, though observed in a small number of cases, were detected exclusively or preferentially, respectively, in nonindolent patients. Such molecular findings were confirmed by immunohistochemistry on the same tissue blocks. The small sample size and the retrospective nature of the analysis represent the main study limitations. Conclusions: Genomic features enriched in aggressive tumors can be detected in GS = 3 + 3 core biopsies of AS patients. Patient summary: PTEN and MYC alterations at the time of diagnosis would deserve investigation in larger cohorts of AS patients to assess their potential as biomarkers for a more precise/earlier identification of patients at risk of reclassification. The presence of adverse outcome-related genomic lesions, such as PTEN deletion and MYC amplification, in GPS = 3 + 3 diagnostic core biopsies of prostate cancer patients could be considered for a more precise/earlier selection of patients not suitable for active surveillance.
2019
3
Gandellini, P.; Casiraghi, N.; Rancati, T.; Benelli, M.; Doldi, V.; Romanel, A.; Colecchia, M.; Marenghi, C.; Valdagni, R.; Demichelis, F.; Zaffaroni, N.
Core Biopsies from Prostate Cancer Patients in Active Surveillance Protocols Harbor PTEN and MYC Alterations / Gandellini, P.; Casiraghi, N.; Rancati, T.; Benelli, M.; Doldi, V.; Romanel, A.; Colecchia, M.; Marenghi, C.; Valdagni, R.; Demichelis, F.; Zaffaroni, N.. - In: EUROPEAN UROLOGY ONCOLOGY. - ISSN 2588-9311. - ELETTRONICO. - 2:3(2019), pp. 277-285. [10.1016/j.euo.2018.08.010]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/257914
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