Gleason score 7 (GS7)
prostate cancer [
tumors with both Gleason patterns 3 (GP3) and 4 (
GP4)] portends a significantly more aggressive
tumor than Gleason score 6 (GS6). It is, therefore, critical to understand the molecular relationship of adjacent GP3 and
GP4 tumor cell populations and relate molecular abnormalities to
disease progression. To decipher molecular relatedness, we used
laser capture microdissection (LCM) and whole-genome amplification (WGA) to separately collect and amplify
DNA from adjacent GP3 and
GP4 cell populations from 14 cases of GS7
prostate cancer. We then carried out massively parallel mate-pair next generation sequencing (NGS) to examine the landscape of large chromosomal alterations. We identified four
to 115 DNA breakpoints in GP3 and 17 to 480 in
GP4. Our findings indicate that while GP3 and
GP4 from the same
tumor each possess unique breakpoints, they also share identical ones, indicating a common origin. Approximately 300 chromosomal breakpoints were localized to the regions affected in at least two
tumors, whereas more than 3,000 were unique within the set of 14
tumors. TMPRSS2-ERG was the most recurrent rearrangement present in eight cases, in both GP3 and
GP4. PTEN rearrangements were found in five of eight TMPRSS2-ERG fusion-positive cases in both GP3 and
GP4. Hierarchical clustering analysis revealed that GP3 has greater breakpoint similarity to its partner
GP4 compared with GP3 from different patients. We show evidence that LCM, WGA, and NGS of adjacent
tumor regions provide an important tool in deciphering lineage relationships and discovering chromosomal alterations associated with
tumor progression.