A novel genomic alteration of LSAMP associates with aggressive prostate cancer in African American men

Abstract

Evaluation of cancer genomes in global context is of great interest in light of changing ethnic distribution of the world population. We focused our study on men of African ancestry because of their disproportionately higher rate of prostate cancer (CaP) incidence and mortality. We present a systematic whole genome analyses, revealing alterations that differentiate African American (AA) and Caucasian American (CA) CaP genomes. We discovered a recurrent deletion on chromosome 3q13.31 centering on the LSAMP locus that was prevalent in tumors from AA men (cumulative analyses of 435 patients: whole genome sequence, 14; FISH evaluations, 101; and SNP array, 320 patients). Notably, carriers of this deletion experienced more rapid disease progression. In contrast, PTEN and ERG common driver alterations in CaP were significantly lower in AA prostate tumors compared to prostate tumors from CA. Moreover, the frequency of inter-chromosomal rearrangements was significantly higher in AA than CA tumors. These findings reveal differentially distributed somatic mutations in CaP across ancestral groups, which have implications for precision medicine strategies.

Keywords: African American; ERG; Genome; LSAMP; PTEN; Prostate cancer.

Fig. 1

Similarities and differences in the landscape of primary prostate cancer genomic alterations between AA and CA men. (a) Mutations identified in AA and CA genomes in this study are also found at higher frequencies in the TCGA prostate cancer mutation dataset (highlighted in red). (b) Affected loci or cytogenetic band (cb) of high confidence somatic structural variations (SV) and copy number variations (CNV) identified in AA or in CA genomes or in both ethnic group. Asterisk marks previously published somatic alterations.

Fig. 2

Significantly higher number of inter-chromosomal rearrangements and exclusive association of chromosome LSAMP deletion/rearrangement in prostate cancer of AA men. (a) Circos plots of AA and CA whole genomes indicate chromoplexy characteristic of prostate cancer genomes. Inter-chromosomal translocations are marked with purple. Inter-chromosomal rearrangements are marked by green. (b) Inter-chromosomal translocations are significantly more frequent events in AA prostate cancer genomes. (c) Wild type (WT), LSAMP locus rearrangements by large deletion (patient GP04), small deletion (GP2) or by duplication generating a ZBTB20-LSAMP gene fusion (GP10). (d) Confirmation of ZBTB20-LSAMP gene fusion by Sanger sequencing of the genomic fusion junction.

Fig. 3

LSAMP deletion is more prevalent in AA tumors correlating with rapid disease progression. Moreover, (a) SNP deletion frequencies in AA (red, n = 41) and CA (blue, n = 279) genomes indicate LSAMP within the minimum deletion region of 3q13.31 in AA patients. PTEN and TMPRSS2-ERG (T2-ERG) loci are more often deleted in CA patients. Deletion frequencies are marked on the Y-axis. (b) LSAMP deletion (red tiles) is associated with biochemical recurrence (BCR, marked by black dots) and is a more frequent event in AA patients. PTEN deletion (blue tiles) is a rare event in AA patients. Inset shows representative images of FISH assays of hemizygous LSAMP (red) and PTEN (red) deletions relative to centromeres (green), scale bar is 2 μm. (c) Rapid disease progression of AA patients harboring LSAMP deletion shown by the Kaplan–Meier biochemical recurrence free survival curves. Number of AA patients in BCR curves with deletion (red) or without deletion (blue) is marked above the X-axis.