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Glinsky Genetic signatures of lethal disease in early stage prostate cancer

Most importantly, there are no genetic or molecular cancer. All men in this study were determined at the
methods prospectively defining low-risk or indolent time of diagnosis to have clinical stage T1 and T2,
prostate cancer at diagnosis with sufficient specificity Mx, and N0, according to the 2002 American Joint
and selectivity to ensure the safety of patients and Commission Committee TNM staging system. [5-7,14]
allow physicians to make informed, ethical, evidence- The prospective follow-up time in this cohort is now
based disease management decision of not treating up to 30 years and the study cohort was followed for
prostate cancer. Given the natural history of early cancer-specific and all-cause mortality until March
prostate cancer and long-term survival data from 1, 2006. Deaths were classified as cancer-specific
[11]
watchful waiting cohorts, conclusive prospective when prostate cancer was the primary cause of
validation of laboratory methods defining low-risk death as determined through a complete review of
indolent disease in Gleason 6 and 7 patients would medical records by a study end-point committee. [5-7,14]
require at least 10 years. Based on the analysis Importantly, that in addition to the histopathological
of the long-term survival data of prostate cancer examination at the time of diagnosis, slides and
patients from watchful waiting cohorts with up to 30 corresponding paraffin-embedded formalin-fixed
years follow-up, we reasoned that more feasible and blocks were subsequently retrieved and re-reviewed
clinically-relevant approach would be an attempt to to confirm cancer status and to assess Gleason scores
identify genetic markers of lethal prostate cancer in using review, examination, and grading procedures
patients with Gleason 6 and 7 tumors which would blinded with regard to disease outcome. [14]
capture a vast majority of all cancer-related death
events 4-6 years after diagnosis. Here we report Gene expression analysis, evaluation, and
identification of gene expression signatures (GES) of selection of GES
lethal prostate cancer in biopsy specimens obtained GES were developed based on a publicly available
at the time of diagnosis from patients with Gleason microarray analysis of a Swedish Watchful Waiting
6 and 7 tumors in a Swedish watchful waiting cohort cohort with up to 30 years of clinical follow up using
with up to 30 years follow-up. In retrospective a novel method for gene expression profiling (cDNA-
analysis, best-performing GES of lethal prostate mediated annealing, selection, ligation, and extension
cancer identify 89% and 100% of all death events method) which enabled the use of formalin-fixed
4 years after diagnosis in Gleason 7 and Gleason paraffin-embedded transurethral resection of prostate
6 patients, respectively. GES appear to perform (TURP) samples taken at the time of the initial
successfully in patients’ stratification with as little as diagnosis. Details of the experimental procedure
2% of cancer cells in a specimen. In Gleason 6 and 7 can be found in a recent publication and in Gene
[14]
prostate cancer patients of age 65 or younger, GES Expression Omnibus (GEO: http://www.ncbi.nlm.nih.
identifies 86% of all death events during the follow-up. gov/geo/) with platform accession number: GPL5474.
In Gleason 6 and 7 prostate cancer patients of age 70 Full data set and associated clinical information is
or younger, GES identifies 90% of all death events 6 available at GEO with accession number: GSE16560.
years after diagnosis. Reported in this study GES of
lethal prostate cancer in biopsy specimens of Gleason Feature selection was performed without assessment
6 and 7 tumors should help practicing physicians of differential gene expression between deceased and
to identify at the time of diagnosis prostate cancer surviving patients. All 6,144 genes were evaluated for
patients who should be considered for exclusion from association with clinical and pathological variables
the active surveillance programs and who would most (except survival status) using correlation analysis.
likely benefit from immediate curative interventions. Different thresholds on the P-values (0.05; 0.01; 0.001)
were used for selection of gene sets with common
METHODS patterns of association and concordance analysis
was performed using expression profiling data of
Patients snpRNA-driven cell line-based models of prostate
This study is based on prostate cancer patients from cancer predisposition [15,16] to identify concordant and
the population-based Swedish Watchful Waiting discordant GES in cell lines and clinical samples. [17-20]
cohort of men with localized prostate cancer. [5-7,14] GES were built based on selection of co-regulated
Distinguishing feature of this cohort is that it represents transcripts in various experimental conditions and
patients diagnosed with symptomatic early prostate clinically-relevant models, including prostate cancer
cancer at the time when no PSA screening programs predisposition and longevity models. [16-20] Underlying
were in place: these men had symptoms of benign concept at this stage of the analysis was to identify
prostatic hyperplasia (lower urinary tract symptoms) GES with concordant expression profiles across
and were subsequently diagnosed with prostate multiple data sets. [17-20] Cox regression analysis was
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ September 21, 2017 179