The genomic landscape of unsuspected, incidentally detected Gleason 7 prostate cancer found on autopsy
Foucal, A. Livingstone, J. Salcedo, A. Kuk, C. Fraser, M. Pushkar, D. Govorov, A. Kovylina, M. Bristow, Robert G Fleshner, N. E.
Foucal, A.
Livingstone, J.
Salcedo, A.
Kuk, C.
Fraser, M.
Pushkar, D.
Govorov, A.
Kovylina, M.
Bristow, Robert G
Fleshner, N. E.
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Abstract
Introduction & Objectives: Changes in our way of thinking in medicine are sometimes driven by observations in a small number of patients. For
instance, when whole-genome sequencing used to track the lethal cell clone in a single patient who died of prostate cancer (PCa), surprisingly,
revealed that it arose from a small, low-grade PCa focus. The genomic landscape of unsuspected, incidentally detected PCa on autopsy in men
never found with the disease during their lifetime is virtually unknown. Intriguingly, while the field has anticipated that most autopsy-detected PCa
are of low tumor volume and low Gleason score (GS), we and others have shown that nearly 25% of unsuspected autopsy detected PCa in
Caucasian men were GSā„7.
Materials & Methods: We used prostate glands prospectively collected during autopsy from Caucasian men, deceased with no known history of
PCa, accrued by the University of Moscow, Russia and analyzed in Toronto, Canada. We limited the scope of our study to unifocal GS7 tumors
with good DNA quantity and quality. DNA was isolated from the autopsy-detected tumors using QIAamp DNA Mini Kit (Hilden, Germany). To profile
genome-wide copy number aberrations (CNAs), we used the OncoScanĀ® FFPE Express v3 platform, optimized for highly degraded samples.
BioDiscovery Nexus Express TM for OncoScan 3 was used to call CNAs using the SNP-FASST2 algorithm. We compared autopsy CNA data
to intermediate-risk prostate cancer cases from the Canadian Prostate Cancer Genome Network (CPC-GENE project), all of whom underwent
radiotherapy or radical prostatectomy for localized, non-indolent GS6-7 disease.
Results: Three autopsy incidentally detected tumors were analyzed (ages 63, 70, 80) and compared to 300 surgical and biopsy-specimens from
CPC-GENE. Driver gene hits were common in autopsy specimens: deletions in TP53 were observed in all three, BRCA2 in two and RB1 loss in
two. A TMPRSS2:ERG fusion, caused by a deletion of chr21:39988436-42859011, was observed in one sample. Two of the three autopsy samples
were indistinguishable from the diagnosed tumors in the CPC-GENE set. A limitation of this study is that although the three GS 7 were found
incidentally on autopsy, they were not necessarily indolent: These men could have died of something else before their PCa became diagnosed.
Conclusions: To our surprise, this study has shown, to the best of our knowledge, for the first time that unsuspected PCa GS7 detected incidentally
on autopsy is genomically indistinguishable from clinically detected tumors. Autopsy studies have revealed the presence of a large reservoir of
PCa, including GS7, which exist in the population and do not cause clinical symptoms or death. Most GS7 tumors found on autopsy in this study,
intriguingly displayed mutations usually observed in more aggressive forms of the disease. This may suggest that other factors such as epigenetics
could play an important role.
Description
Date
2021
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Foucal A, Livingstone J, Salcedo A, Kuk C, Fraser M, Pushkar D, et al. The genomic landscape of unsuspected, incidentally detected Gleason 7 prostate cancer found on autopsy. European Urology. 2021;79:S1436-S.