Distinct genomic alterations in prostate cancers in Chinese and Western populations suggest alternative pathways of prostate carcinogenesis

Abstract

Prostate cancer is significantly more common in Western men than in Asian men, but the basis for this difference remains unknown. Because genomic studies of Asian prostate cancer are very limited, we used a genome-wide approach to reveal the genomic alterations in Chinese prostate cancers. We found a significant reduction in the frequency of certain somatic genomic changes that are commonly found in Western prostate cancers, including the 21q22.2-22.3 deletion, which involves the TMPRSS2:ERG fusion gene, and 10q deletion, which causes PTEN inactivation. Array results were confirmed by PCR-based molecular copy-number counting in selected samples. The different frequencies of these genomic changes were further evaluated by fluorescent in situ hybridization and immunohistochemistry analyses of tissue microarray samples. These alterations might be key genetic changes underlying the regional/ethnic difference in clinical incidence and might be induced by specific environmental and/or genetic risk factors that Western men are exposed to. Our findings suggest that tumors arise in Western and Chinese populations by alternative pathogenetic mechanisms.

Figure 1

Lack of 10q23 and 21q22.2-22.3 deletions in Chinese prostate cancer detected by SNP array analysis. (A) Summary of SNP Array 6.0 results of 39 Chinese prostate cancer cases. Red and blue bars on the right of each chromosome represent regions of copy-number gains and losses, respectively. (B) SNP intensity profile of Chromosome 10 and 21 in UK and Chinese samples. The purple bar indicates the location of PTEN (chr 10), ERG (chr 21, left bar) and TMPRSS2 (chr 21, right bar) respectively, which mark the regions deleted in UK but not Chinese samples. In each SNP intensity plot, the middle horizontal line represents a log2 ratio of 0 compared with normal controls. The bottom and upper lines represent log2 ratios of −1 and +1, respectively.

Figure 2

Representative ERG and PTEN FISH images. A-C: FISH analysis of ERG gene status using probes for ERG 3′ undeleted region (red signal) and ERG 5′ deleted region (green signal) shows a UK case with ERG deletion (A), a UK case with ERG split signals (B) and a Chinese case with no ERG deletion (C). D-F: The detection of PTEN copy-number using probes for the PTEN locus (red signal) and chromosome 10 centromere (green signal) shows homozygous (D) and heterozygous (E) PTEN loss in UK samples and no PTEN loss in a Chinese sample (F). G-I: Immunohistochemistry analysis shows loss of PTEN expression in cancer cells and positive stromal cells in a UK PTEN homozygous deletion case (G), lack of PTEN expression in a proportion of cancer cells from a UK partial PTEN deletion case (H) and strong PTEN expression (+++) in a Chinese sample without PTEN deletion (I).