Somatic Allelic Loss at the DCC, APC, nm23-H1 and P53 Tumor Suppressor Gene Loci in Human Prostatic Carcinoma

Abstract

We present a restriction fragment length polymorphism (RFLP) analysis of 29 benign and 30 malignant prostatic tumors, using polymorphic DNA probes to the putative tumor suppressor genes DCC (Deleted in Colorectal Carcinoma; chromosome 18q21.3), nm23-H1 (17q21.3), APC (Adenomatous Polyposis Coli; 5q21) and p53 (17p13). Six of 23 evaluable cancers (26%) showed loss of heterozygosity (LOH) at DCC; 5 were advanced stage and one was clinically localized (p < 0.05). Mapping 18q deletions, another (advanced) cancer showed LOH at a locus distal to DCC (18q22), but no LOH at DCC. Three of 15 evaluable cancers (20%), all advanced, showed LOH at APC. Three of eight (38%) cancers, of which 2 were advanced, showed LOH at p53. One high grade/stage cancer of 21 (5%) showed LOH at nm23-H1 (and also at DCC). Combining data, allelic losses at either DCC, APC, or p53 genes were seen in 13% of localized cancers, but in 71% of advanced cancers (p < 0.002). Allelic loss involving nm23-H1 is rare in prostatic carcinoma. We suggest that loss of tumor suppressor genes DCC and/or an unidentified gene located distally on chromosome 18q, APC, or p53 may influence progression in prostatic carcinoma.

Genetic changes associated with the acquisition of androgen-independent growth, tumorigenicity and metastatic potential in a prostate cancer model

“…The overall number of genetic aberrations almost doubled in all LNCaP sublines compared with the parental line suggesting that clonal evolution and an accumulation of genetic changes underlies tumour progression in this model system. A similar increase in the overall number of genetic changes has also been reported during the progression of human prostate cancer in vivo (Kunimi et al, 1991;Lundgren et al, 1992;Brewster et al, 1994;Koivisto et al, 1995;Visakorpi et al, 1995a) consistent with the multistep progression model of human cancer (Fearon and Vogelstein, 1990). All sublines shared most if not all genetic changes seen in the previous generation.…”

Stabilization of β-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdifferentiation of other secretory epithelia

“…Circumstantial evidence from studies on subsets of human prostate cancers documents the overexpression of the Wnt-5A (Iozzo et al, 1995), APC gene mutations (Brewster et al, 1994;Phillips et al, 1994;Suzuki et al, 1994;Watanabe et al, 1996), and mutations a ecting the stability of b-catenin (Chesire et al, 2000;Voeller et al, 1998) in tumors. Deletion of critical sequences of the b-catenin third exon was reported in each of nine separate metastases examined from a single patient, indicating that this mutation may represent an early and perhaps clonal event (Chesire et al, 2000).…”

Comparative mutational analysis of DPC4 (Smad4) in prostatic and colorectal carcinomas

“…Chromosome arm 18q in particular is reported to su er loss of heterozygosity (LOH) in 17 ± 45% of prostate cancers (Carter et al, 1990;Kunimi et al, 1991;Gao et al, 1993;Latil et al, 1994;Brewster et al, 1994;Cunningham et al, 1996). A candidate tumor suppressor gene at subband 18q21.1, deleted in colorectal carcinoma (DCC), was shown to have decreased or loss of expression in the majority of prostate cancers, and reduced expression was often associated LOH at the DCC locus (Gao et al, 1993).…”

“…Allelic imbalance (AI) of at least one informative marker was observed in three of 29 primary prostatic cases. Imbalance of 18q21 markers was interpreted as allelic loss based on Southern blotting or comparative genomic hybridisation (CGH) data which suggested genetic loss rather than gain at 18q in prostate cancers (Carter et al, 1990;Kunimi et al, 1991;Latil et al, 1994;Brewster et al, 1994;Visakorpi et al, 1995;Joos et al, 1995;Cher et al, 1996). In two cases, imbalance was observed at all informative loci; one tumor (#12) displayed a pattern consistent with allelic loss of D18S851 and retention of alleles at D18S454 ( Figure 1).…”

“…The discrepancy with previous reports of moderate to high levels of allelic loss at 18q21 may be attributed to di erences in tumor stage or grade. It has been suggested that chromosome 18q21 LOH is associated with advanced disease; of 6/23 (26%) cancers with allelic loss of the DCC locus, ®ve were of advanced stage and one was clinically localised (Brewster et al, 1994). However, another study showing six (33%) of 18 informative stage B cases with allelic loss at DCC suggests otherwise (Latil et al, 1994).…”