prostate cancer discovery


Should We Rethink Gleason Pattern 3 Cancer?


It’s not “CSI,” but the same forensic autopsy approach that helps police capture a murderer has shed new light on the prostate cancer that proved lethal for a man who died 17 y ears after diagnosis, and the results have stunned Hopkins scientists.


When “John” died of high-grade, advanced prostate cancer, Hopkins pathologists performed an autopsy. Using highly sophisticated, wholegenome sequencing analysis, they were able to characterize multiple, distinct lesions of cancer. They were also able to compare the cancer obtained at the autopsy with earlier samples from a biopsy of a metas tatic lesion taken a few years before his death, and even earlier, from John’s radical prostatectomy specimen.


What they did was akin to tracing cancer, through its distinctive fingerprints, back in time. What they found has never been shown before.


What they did was akin to tracing cancer, through its distinctive fingerprints, back in time. What they found has never been shown before. “Molecular genome analysis revealed that 85 coding mutations and 226 structural rearrangements were shared by each of the metastatic lesions, indicating that the progeny of a single clone w ere responsible for the spread of lethal cancer,” says William Nelson, M.D, Ph.D., the Marion I. Knott Professor of Oncology and Director of the Sidney Kimmel Comprehensive Cancer Center.


Here’s the stunning part: That cancer was Gleason pattern 3. “This Gleason pattern 3 was in the radical prostatectomy specimen,” says Nelson. Although the predominant cancer in the tumor was Gleason pattern 4, the two types of cells did not shar e the same characteristics. “The Gleason pattern 3 disease had some high-risk features, including a p53 mutation and PTEN loss (covered in previous issues of Discovery; please see our w ebsite), that are otherwise rare in primary prostate cancer. They are rarer still in Gleason pattern 3 prostate cancer.” Those high-risk characteristics allowed John’s cancer to defy several treatments, including radical prostatectomy, vaccine immunotherapy, hormonal therapy, chemotherapy, and radiation therapy.


The fact that a pattern of cancer that is considered to be “good” can be lethal may mean scientists need to rethink Gleason pattern 3 — or at least, to stratify it based on whether these high-risk features are present — and that certain men with Gleason pattern 3 disease might need early, aggressive treatment. “The findings represent an interesting use of autopsy for lethal pr ostate cancer in a ‘forensic’ mode,” says Nelson, tracking its evolution “with the hope of ascertaining how cancer progresses despite available treatment, and discovering new ways to prevent prostate cancer deaths.”


This work was published in the Journal of Clinical Investigation. The study’s authors, besides Nelson, include Michael Haffner, Timothy Mosbruger, David Esopi, Helen Fedor, Christopher Heaphy, DA Walker, Nkosi Adejola, Bora Gurel, J. Hicks, Alan Meeker, Marc Halushka, Jonathan Simons, William Isaacs, Angelo De Marzo, and Srinivasan Yegnasubramanian.

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