Georges Fournier

Predisposing Gene for Early-Onset Prostate Cancer, Localized on Chromosome 1q42.2-43

There is genetic predisposition associated with >=10% of all cancer of the prostate (CaP). By means of a genomewide search on a selection of 47 French and German families, parametric and nonparametric linkage (NPL) analysis allowed identification of a locus, on chromosome 1q42.2-43, carrying a putative predisposing gene for CaP (PCaP). The primary localization was confirmed with several markers, by use of three different genetic models. We obtained a maximum two-point LOD score of 2.7 with marker D1S2785. Multipoint parametric and NPL analysis yielded maximum HLOD and NPL scores of 2.2 and 3.1, respectively, with an associated P value of . 001. Homogeneity analysis with multipoint LOD scores gave an estimate of the proportion of families with linkage to this locus of 50%, with a likelihood ratio of 157/1 in favor of heterogeneity. Furthermore, the 9/47 families with early-onset CaP at age <60 years gave multipoint LOD and NPL scores of 3.31 and 3.32, respectively, with P = .001.

PTEN/MMAC1/TEP1 involvement in primary prostate cancers

The PTEN/MMAC1/TEP1 gene, located at 10q23.3, is a tumor suppressor gene responsible for the familial cancer syndromes Cowden disease and Bannayan-Zonana syndrome, and is commonly somatically mutated in several types of cancers. Mutations of the PTEN gene have been found in prostate cancer cell lines and LOH at 10q22-24 in prostate tumors have also been described with a high frequency. To determine the role of this gene in prostate tumorigenesis, we therefore analysed 22 primary tumors for loss of heterozygosity (LOH) within the 10q22-23 region such that tumors hemizygous at those loci may be examined for somatic PTEN mutations. Losses of heterozygosity of at least one locus was found in 12 (55%) of the 22 tumors DNAs. Among these, six tumors exhibited allele loss in the interval between D10S1765 and D10S541 wherein lies the PTEN gene. We searched the entire coding region of PTEN for somatic mutations in these six tumors. One somatic mutation (17%), a 1 bp deletion, was detected in exon 7 of the gene, in one tumor, indicating that somatic mutations of the PTEN gene may occur in primary prostate tumors.

Quantification of expression of netrins, slits and their receptors in human prostate tumors

Recently, DCC (Deleted in Colorectal Cancer) protein has been forwarded as a receptor for netrin. The Netrin/DCC complex is critical for axon guidance and cell migration. In the developing nervous system, netrin protein secreted by midline cells attracts commissural axons by activating the DCC receptor on growth cones. This attraction can be switched to repulsion or silenced completely, depending on the DCC binding partner. The potential suppressor function of DCC in prostate tumorigenesis, through a still unknown mechanism, prompted us to quantify the expression of several genes involved in this axon guidance pathway. The relative expression levels of DCC, NEO1, NTN1, NTN2L, NTN4, UNC5C, Slit1, Slit2, Slit3, Robo1 and Robo2 were simultaneous quantified in 48 tumors and 7 normal prostate tissues by using real‐time quantitative reverse transcriptase‐polymerase chain reaction (RT‐PCR). A reduction in DCC, NEO1, NTN1 and NTN4 expression was observed in prostate tumors, while many of the same prostate tumors over‐expressed either Slit genes or their receptors, Robo.

htert expression correlates with myc over-expression in human prostate cancer

Expression of the telomerase catalytic sub‐unit (htert) constitutes a key step in the development of human cancer. Although htert regulation is still unclear, several studies suggest that c‐myc may activate its expression. Prostate cancer is one of the most common malignancies among men in Western countries. Since de‐regulated expression of myc as well as telomerase activation may contribute to the pathogenicity of this cancer, we investigated this pathway in prostate tumorigenesis. For this purpose, myc‐ and htert‐mRNA expression was quantified in 33 sporadic prostate tumors using a real‐time quantitative PCR assay based on TaqMan methodology. myc over‐expression was observed in 19 (58%) of 33 tumors, whereas telomerase status evaluated by htert expression was observed in 22 (67%). There was no correlation between myc over‐expression or htert expression level and tumor stage or Gleason grade. A significant association (p = 0.0024) was found between myc over‐expression and elevated htert expression, indicating that the up‐regulation of telomerase activity often observed in prostate tumors might be conferred through transactivation of htert by myc. It is likely that the ability of c‐myc protein to stimulate expression of htert and thereby enhance telomerase activity represents an important step in prostate tumorigenesis. Int. J. Cancer (Pred. Oncol.) 89:172–176, 2000.

Combination of Polymorphisms From Genes Related to Estrogen Metabolism and Risk of Prostate Cancers: The Hidden Face of Estrogens

PURPOSE The association between common functional polymorphisms from the CYP17, CYP19, CYP1B1, and COMT genes involved in the estrogen metabolism and the risk of prostate carcinoma was evaluated. PATIENTS AND METHODS The study investigated 1,983 white French men (1,101 patients with prostate cancer and 882 healthy controls) aged between 40 and 98 years. The different alleles and genotypes were analyzed according to case-control status, aggressiveness pattern of the tumors, age at onset, and family history of cancers. RESULTS The VV (high activity) genotype of the V432L polymorphism from CYP1B1 (odds ratio [OR] = 1.36; 95% CI, 1.03 to 1.79; P = .031), and the long allele (> 175 bp) of the TTTA repeat from CYP19 (OR, 1.26; 95% CI, 1.08 to 1.47; P = .003) were significantly associated with the risk of prostate cancer. An additive effect was observed when we combined the two at-risk alleles (OR = 1.63; 95% CI, 1.24 to 2.13; P < .001). The association was stronger for the CYP1B1 VV genotype (OR = 1.55; 95% CI, 1.13 to 2.13; P = .007) among the group of patients with highly aggressive disease. Stratification by age at onset showed that the associations of CYP1B1 and CYP19 variants were largely confined to the younger prostate cancer patients. CONCLUSION This association between polymorphisms from genes related to estrogen metabolism and prostate cancer risk suggest new clinical considerations in the management of prostate cancer: the development of new prevention trials based on genetic profiling and the evaluation of specific inhibitors involving the estrogen pathways.

Early-onset hereditary prostate cancer is not associated with specific clinical and biological features.

Familial prostate cancer (CaP) accounts for 15–20% of all CaP, and hereditary CaP for 5–10% of patients. Few data are available concerning their clinical and biological features.

PCAP is the major known prostate cancer predisposing locus in families from south and west Europe

To date four prostate cancer predisposing loci have been mapped: HPC1 (Hereditary Prostate Cancer 1) on 1q24-25, PCaP (Predisposing for Cancer Prostate) on 1q42.2-43, CAPB (Cancer Prostate and Brain) on 1p36, and HPCX on Xq27-28. We examined evidence for linkage to those loci in 64 families from south and west Europe. Genotyping of three (six for PCaP) markers encompassing the candidate regions were performed on 221 individuals including 159 affected patients. The resulting data were analysed using both parametric and non parametric linkage methods. No significant evidence of linkage to HPC1, CAPB, or HPCX was found either in the whole population or when pedigrees were stratified according to criteria specific to each locus. By contrast, results in favour of linkage to PCaP locus were observed with maximum multipoint NPL and HLOD scores of 2.8 (P = 0.0026) and 2.65 respectively. Homogeneity analysis performed with multipoint LOD scores gave an estimated proportion of families with linkage to this locus up to 50%. Particularly, families with an earlier age at diagnosis (⩽65-years-old) contributed significantly to the evidence of linkage with a maximum multipoint NPL score of 2.03 (P = 0.024). Those results suggest that PCaP is the most frequent known locus predisposing to hereditary prostate cancer cases from families from south and west Europe.

Early onset and familial predisposition to prostate cancer significantly enhance the probability for breast cancer in first degree relatives.

Genetic predisposition accounts for ≥10% of all cancer of the prostate (CaP) and is therefore considered a major risk factor, together with age and ethnic origin. Several epidemiological studies have suggested that familial clustering of CaP may be associated with an increased frequency of breast and other cancers among relatives. In order to correlate the incidence of CaP with prevalence of breast and other cancers, we have performed uni‐ and multi‐variate analyses on 691 complete pedigrees including probands, who were consecutive patients with confirmed CaP treated in three French urological departments. We have shown a significantly higher risk (RR = 2.3, p = 0.01) to develop breast cancer in families with multiple than in those with a single CaP. Risk of observing other types of cancer within these families was not significant. We then calculated the breast cancer risk in early onset prostate cancer families, and observed a relative risk that is even more significant (RR = 5.5, p = 0.002). Furthermore, the risk was >30 times that a probands mother have breast cancer if CaP occurred below 55 years of age, rather than after 75 years (p = 0.003). This study has therefore shown for the first time, the relatively high penetrance for breast cancer in relatives of early onset CaP patients. Int. J. Cancer 86:883–887, 2000.

TARGETED SCREENING FOR PROSTATE CANCER IN HIGH RISK FAMILIES: EARLY ONSET IS A SIGNIFICANT RISK FACTOR FOR DISEASE IN FIRST DEGREE RELATIVES

PURPOSE Targeted screening for prostate cancer in high risk families is generally suggested by ages 40 to 45 years in first degree relatives. We support this concept by reporting higher risk and earlier onset of the disease in these families. MATERIALS AND METHODS We proposed serum prostate specific antigen (PSA) testing in 40 to 70-year-old first degree relatives of 435 patients with prostate cancer treated between July 1994 and June 1997. A previous systematic genealogical analysis allowed us to define the familial prostate cancer status of each patient as sporadic or familial. RESULTS Of the 747 potential candidates 442 (59%) accepted into the study have been screened, including 240 who were 40 to 49 years old (mean age 44.8) and 202 who were 50 to 70 years old (mean age 57.4). Two of the 240 subjects (0.8%) had PSA greater than 4 ng./ml. in the 40 to 49-year-old group. Prostate biopsies were negative in 1 relative but diagnostic for prostate cancer in the other. In the 50 to 70-year-old group 25 of 202 subjects (12.4%) had a PSA of greater than 4 ng./ml. Prostate cancer was diagnosed in 9 individuals (4.5%), 9 had negative biopsy results, 1 died before biopsy and 6 refused biopsy. The proportion of relatives with PSA greater than 4 ng./ml. and prostate cancer detection was not different according to familial status (sporadic or familial) but it was significantly higher in first degree relatives with early onset prostate cancer in the family at ages younger than 65 years (p = 0.037 and 0.012, respectively). CONCLUSIONS Our results emphasize the usefulness of PSA screening in high risk families, including those without obvious hereditary features. Furthermore, early onset prostate cancer is a significant risk factor for prostate cancer in first degree relatives.

Loss of heterozygosity at chromosome arm 13q and RB1 status in human prostate cancer.

Aberrations of the long arm of chromosome 13 are common in prostate cancer and were initially attributed to alterations of the RB1 gene in band q14 of the chromosome. However, prostate tumors generally yield normal p110RB1 nuclear staining despite loss of heterozygosity (LOH) at the RB1 locus. Our previous analysis of chromosome arm 13q showed allelic loss in 41% of primary prostate tumors. To refine our knowledge of 13q, we extended our previous LOH study by using more polymorphic markers to analyze more prostate tumors. Sixty human prostate carcinomas were screened for allelic loss on 13q by using 13 13q-specific markers. LOH on the long arm of chromosome 13 was found in 39 (65%) of the 60 tumors. Furthermore, 33 of these 39 tumors had evidence of allelic loss involving a region of 13q14 containing RB1. Because immunohistochemical assessment of pRb expression is controversial in prostate tumors, we used a quantitative reverse transcription polymerase chain reaction (RT-PCR) method to determine whether RB1 is the target tumor suppressor gene in this region. RB1 mRNA steady-state levels were determined in 12 prostate tumors preselected on the basis of presumed deletion at the RB1 locus and four prostate tumors without LOH at the RB1 locus; five normal prostate specimens were used as controls. One of the 12 assessable prostate tumors with presumed LOH at RB1 showed a corresponding decreased in RB1 mRNA expression, whereas none of the four tumors without LOH at RB1 locus showed such a decrease. This study, based on another technical approach, confirms that RB1 is not the main target of the observed LOH at 13q14.3, and raises the possibility that another tumor suppressor gene in this region plays a key role in prostate cancer.