Genetic mapping of allelic loss on chromosome 6q within heterogeneous prostate carcinoma

Abstract

A number of genetic events have been reported in prostate carcinogenesis, including frequent loss of heterozygosity (LOH) on chromosomes 8q, 10q, 16q and 18q. In samples of heterogeneous, multifocal prostate carcinomas, we focused on chromosome 6q using PCR-based techniques with 15 microsatellite markers to identify the specific 6q deletion within tumors. LOH of one or more polymorphic markers was detected in 10 of 21 tumors (48%). Two of these 10 tumors demonstrated LOH in all cancerous foci at specific loci and 4 tumors showed deletion in one focus. Different deletion patterns were found in 3 tumors when different polymorphic markers were used. In 90% of tumors showing LOH in one or more foci, however, two common regions of LOH were identified; one at 1.81 cM on 6q15-16.3 between markers D6S1631 and D6S1056, and the other at 5.11 cM on 6q16-21 between markers D6S424 and D6S283. By RT-PCR analysis, the TAK1 gene located at these loci did not correlate with LOH status, indicating that TAK1 is not a target gene in prostate carcinoma. The 6q deletion occurs heterogeneously and LOH was more frequent in tumors of higher pathological stages, implying that this alteration is a late event in prostate carcinogenesis. ytogenetic studies of prostate carcinomas indicate that various chromosomal deletions containing tumor suppressor genes contribute to the development and progression of tumors. Recent intensive investigations using PCR of polymorphic microsatellite markers, fluorescent in situ hybridization (FISH), and comparative genomic hybridization (CGH) have shown consistent genetic alterations on chromosomes 2q, 3q, 5q, 6q, 7q, 8q, 9q, 10q, 13q, 16q and 18q.1, 2) Although malignant tumors are now believed to develop through a multi-step process involving both oncogene activation and tumor suppressor gene (TSG) inactivation, 3) putative TSG are postulated to be the primary targets of these carcinogenesis-associated events.Allelic losses on 6q have been described in a number of cancers including melanoma and breast, ovarian, and renal cancers. [4][5][6][7][8][9] Genes associated with prostate carcinoma in the 6q region have also been reported and, while the incidences varied, 6q alterations have been found to occur in up to 48% of prostate cancers.1, 2, 10, 11) However, the role of these chromosomal aberrations remains unclear. At least two common regions of 6q deletion have been identified in prostate carcinoma. Using 13 polymorphic markers, Srikantan et al.2) reported that 6q16, 6q3-21, and the distal region 6q23-24 were deleted. Hyytinen et al.11) examined two regions, 6q16-21 and 6q22, and claimed that deletion of 6q16-22 is a frequent event in prostate cancer. They further showed that loss of 6q24 was associated with androgen-independence and tumorigenicity.12) Several candidate genes, such as the insulin-like growth factor II receptor (IGF2R) at 6q26 or cyclin C (CCNC) at 6q21, may participate in prostate carcinogenesis.1) A novel gene located on chromosome 6q23-24 and designated UROC28 was recently identified as ...

Asynchronous Growth of Prostate Cancer Is Reflected by Circulating Tumor Cells Delivered from Distinct, Even Small Foci, Harboring Loss of Heterozygosity of the PTEN Gene

“…Primary tumors show a rather heterogeneous expression of proliferationassociated markers, such as Ki-67, and apoptosis-induced DNA fragmentation, showing the asynchronous growth of a prostate tumor (8). Microsatellite-based studies on microdissected tissue resulted in the identification of areas in the primary tumor with different alterations associated with a distinct histologic differentiation (3,4,9).…”

Genetic changes in pT2 and pT3 prostate cancer detected by comparative genomic hybridization

“…CGH and cytogenetic studies have shown that frequent genetic alterations occur in the 6q15-22 region and indicate that 1 or more TSGs are located there. [26][27][28][29][30] Three potential candidate genes are present in this region, and they encode cell-cycle regulatory protein cyclin C, thiol-specific antioxidant protein 1 and the glutamate receptor iontropic kainate 2.…”

HRK inactivation associated with promoter methylation and LOH in prostate cancer

“…We employed PCR-SSCP analysis to pre-screen for mutations in exons 5-8 of the p53 gene; sequencing primers used have been previously described [20]. Samples showing mobility shifts in SSCP analysis were further analyzed by DNA sequencing.…”

“…Only samples heterozygous for a given locus were regarded to be informative; loci homozygosity and/or microsatellite instability rendered any particular sample noninformative. Samples were considered to show LOH when a peak allele signal from tumor DNA was reduced by 50% compared with the normal tissue counterpart [20].…”