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The Association of Gleason Score and Tumor Stage in the Prevalence of DNA Repair Gene Mutations in Localized Prostate Cancer

To speak with Bob Dylan, ‘’..times they are a changing..’’, particularly when it comes to our insight in the genetic changes in prostate cancer. In the early days of molecular genetics studies of prostate cancer, scientists often referred to prostate cancer as being very different from other cancers, e.g. mutations in TP53 were rarely found in this malignancy. With the large scale introduction of next-generation sequencing and the impressive SU2C initiative, focusing on metastatic/advanced cancers, it was shown that prostate cancer was not that of a ‘’cancer genetic outlier’’. TP53-, Rb mutations ánd a rather high frequency of aberrations in genes encoding DNA repair proteins were found in advanced prostate cancer (metastatic CRPC).

A straight forward hypothesis is that these mutations have prognostic significance, i.e. mutations in pivotal cancer pathways are associated with clinical-, pathological stage, and grade, which in turn are a good proxy/surrogate for the outcome of the disease. Marshall and colleagues1 focussed on DNA repair gene mutations and ‘mined’ existing DNA sequencing information (TCGA, NatureGenetics via cBioportal) to test this hypothesis. There appeared to be a clear correlation between pathological stage (pT3/4 versus pT2) and Gleason Grade groups (GG ≥ 3 versus GG 1-2). In the cT≥3 ánd GG ≥3 tumors in >20% DNA repair gene mutations were identified. Interestingly there appeared to be a remarkable difference between GG2 and GG3 (5,2 % vs 10,5 % carrying DNA repair gene mutations). This may, in fact, illustrate that a very significant fraction of GG2 patients have in fact a rather indolent disease, and can be considered for active surveillance).

At the other end of the spectrum, the category of cT≥3/GG≥2 is quite enriched in DNA repair gene mutations information that can be used in stratification in genomically targeted clinical trials. This study nicely shows how much information can be mined from the available data sources, provided the clinical and pathological annotation is available and of high quality. It remains to be studied whether these rather high mutation frequencies reflect the typical ‘’real world’ setting.


Written by: Jack A. Schalken, Ph.D., Biochemist, Director of urological research, and Professor of experimental urology at Radboud University Medical Center, Nijmegen 

References:
1. Marshall CH, Fu W, Wang H, Baras AS, Lotan TL, Antonarakis ES. Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage. Prostate Cancer Prostatic Dis. 2019 Mar;22(1):59-65.

Read the Full-Text Article: Prevalence of DNA Repair Gene Mutations in Localized Prostate Cancer According to Clinical and Pathologic Features: Association of Gleason Score and Tumor Stage