Deletion of a Small Consensus Region at 6q15, Including the MAP3K7 Gene, Is Significantly Associated with High-Grade Prostate Cancers

Johns Hopkins Medicine, Baltimore, Maryland, United States
Clinical Cancer Research (Impact Factor: 8.72). 09/2007; 13(17):5028-33. DOI: 10.1158/1078-0432.CCR-07-0300
Source: PubMed


Chromosome 6q14-21 is commonly deleted in prostate cancers, occurring in approximately 22% of all tumors and approximately 40% of metastatic tumors. However, candidate prostate tumor suppressor genes in this region have not been identified, in part due to the large and broad nature of the deleted region implicated in previous studies.
We first used high-resolution Affymetrix single nucleotide polymorphism arrays to examine DNA from malignant and matched nonmalignant cells from 55 prostate cancer patients. We identified a small consensus region on 6q14-21 and evaluated the deletion status within the region among additional 40 tumors and normal pairs using quantitative PCR and fluorescence in situ hybridization. We finally tested the association between the deletion and Gleason score using the Fisher's exact test.
Tumors with small, interstitial deletions at 6q14-21 defined an 817-kb consensus region that is affected in 20 of 21 tumors. The MAP3K7 gene is one of five genes located in this region. In total, MAP3K7 was deleted in 32% of 95 tumors. Importantly, deletion of MAP3K7 was highly associated with higher-grade disease, occurring in 61% of tumors with Gleason score >or=8 compared with only 22% of tumors with Gleason score <or=7. The difference was highly significant (P = 0.001).
Our study provides strong evidence for the first time that a small deletion at 6q15, including the MAP3K7 gene and four other genes, is associated with high-grade prostate cancers. Although the deletion may be a marker for high-grade prostate cancer, additional studies are needed to understand its molecular mechanisms.

1 Read
  • Source
    • "Loss of heterozygosity for BACH2, a transcription repressor gene, has been detected in non-Hodgkin's lymphomas [35]. Deletion of a small region at 6q15 including the MAP3K7/TAK1 gene, which encodes the TAK1 protein, involved in transforming growth factor-β-induced signalling pathways, has been associated with high-grade prostate cancers [36]. EPHA7 encodes an ephrin/Eph receptor, which is a positive regulator of apoptosis during forebrain neurogenesis and could potentially be involved in oncogenesis [37]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Desmoid tumours (also called deep or aggressive fibromatoses) are potentially life-threatening fibromatous lesions. Hereditary desmoid tumours arise in individuals affected by either familial adenomatous polyposis (FAP) or hereditary desmoid disease (HDD) carrying germline mutations in APC. Most sporadic desmoids carry somatic mutations in CTNNB1. Previous studies identified losses on 5q and 6q, and gains on 8q and 20q as recurrent genetic changes in desmoids. However, virtually all genetic changes were derived from sporadic tumours. To investigate the somatic alterations in FAP-associated desmoids and to compare them with changes occurring in sporadic tumours, we analysed 17 FAP-associated and 38 sporadic desmoids by array comparative genomic hybridisation and multiple ligation-dependent probe amplification. Overall, the desmoids displayed only a limited number of genetic changes, occurring in 44% of cases. Recurrent gains at 8q (7%) and 20q (5%) were almost exclusively found in sporadic tumours. Recurrent losses were observed for a 700 kb region at 5q22.2, comprising the APC gene (11%), a 2 Mb region at 6p21.2-p21.1 (15%), and a relatively large region at 6q15-q23.3 (20%). The FAP-associated desmoids displayed a significantly higher frequency of copy number abnormalities (59%) than the sporadic tumours (37%). As predicted by the APC germline mutations among these patients, a high percentage (29%) of FAP-associated desmoids showed loss of the APC region at 5q22.2, which was infrequently (3%) seen among sporadic tumours. Our data suggest that loss of region 6q15-q16.2 is an important event in FAP-associated as well as sporadic desmoids, most likely of relevance for desmoid tumour progression.
    PLoS ONE 09/2011; 6(9):e24354. DOI:10.1371/journal.pone.0024354 · 3.23 Impact Factor
  • Source
    • "In cancer studies, Affymetrix SNP arrays provide new insight into the mechanisms of tumor progression; they can be used to pinpoint new candidate genes for tumor-suppressor genes (Liu et al., 2007) and oncogenes (thought to be present in loss and gain regions, respectively), and to classify tumors, improving diagnosis for new patients and the evaluation of prognosis. Like all microarrays, Affymetrix SNP arrays are affected by systematic non-relevant sources of experimental variation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Affymetrix SNP arrays can be used to determine the DNA copy number measurement of 11 000-500 000 SNPs along the genome. Their high density facilitates the precise localization of genomic alterations and makes them a powerful tool for studies of cancers and copy number polymorphism. Like other microarray technologies it is influenced by non-relevant sources of variation, requiring correction. Moreover, the amplitude of variation induced by non-relevant effects is similar or greater than the biologically relevant effect (i.e. true copy number), making it difficult to estimate non-relevant effects accurately without including the biologically relevant effect. We addressed this problem by developing ITALICS, a normalization method that estimates both biological and non-relevant effects in an alternate, iterative manner, accurately eliminating irrelevant effects. We compared our normalization method with other existing and available methods, and found that ITALICS outperformed these methods for several in-house datasets and one public dataset. These results were validated biologically by quantitative PCR. The R package ITALICS (ITerative and Alternative normaLIzation and Copy number calling for affymetrix Snp arrays) has been submitted to Bioconductor.
    Bioinformatics 04/2008; 24(6):768-74. DOI:10.1093/bioinformatics/btn048 · 4.98 Impact Factor
  • Source

Show more

Similar Publications