ABSTRACT
Recently, variants in CHEK2 gene were shown to associate with sporadic prostate cancer in the USA. In the present study from Finland, we found that the frequency of 1100delC, a truncating variant that abrogates the kinase activity, was significantly elevated among 120 patients with hereditary prostate cancer (HPC) (four out of 120 (3.3%); odds ratio 8.24; 95% confidence interval 1.49-45.54; P=0.02) compared to 480 population controls. Suggestive evidence of segregation between the 1100delC mutation and prostate cancer was seen in all positive families. In addition, I157T variant had significantly higher frequency among HPC patients (13 out of 120 (10.8%); odds ratio 2.12; 95% confidence interval 1.06-4.27; P=0.04) than the frequency 5.4% seen in the population controls. The results suggest that CHEK2 variants are low-penetrance prostate cancer predisposition alleles that contribute significantly to familial clustering of prostate cancer at the population level.
Subject(s)
Genetic Predisposition to Disease , Prostatic Neoplasms/genetics , Protein Serine-Threonine Kinases/genetics , Adult , Aged , Aged, 80 and over , Checkpoint Kinase 2 , DNA Mutational Analysis , DNA Replication , Epidemiologic Studies , Finland/epidemiology , Fungal Proteins , Genes, Tumor Suppressor , Humans , Male , Middle Aged , Odds Ratio , Pedigree , Prevalence , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/pathologySubject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Genes, BRCA1 , Genes, BRCA2 , Genetic Predisposition to Disease/genetics , Mutation , Prostatic Neoplasms/genetics , Aged , Aged, 80 and over , BRCA1 Protein/physiology , BRCA2 Protein/physiology , Finland , Genetic Testing , Humans , Male , Middle Aged , Prostatic Neoplasms/diagnosisSubject(s)
Fumarate Hydratase/genetics , Prostatic Neoplasms/genetics , Chromatography, High Pressure Liquid/methods , Chromosomes, Human, Pair 1/genetics , DNA Mutational Analysis , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , Genetic Predisposition to Disease/genetics , Humans , Male , Microsatellite Repeats , Mutation , Prostatic Neoplasms/enzymologyABSTRACT
The genetic mechanisms of prostate cancer recurrence during hormonal therapy are largely unknown. So far, data from conventional karyotype analysis on hormone-refractory prostate carcinomas have not been published, mainly because of the difficulties in obtaining fresh hormone-refractory prostate carcinoma samples and getting metaphases from them. Here, we have studied chromosomal changes in 12 locally recurrent, hormone-refractory prostate carcinomas using karyotyping and CGH that revealed genetic aberrations in all tumors. Loss of the Y chromosome was the most common (89%) finding, and tetraploidy or near-tetraploidy was detected in all tumors. Also non-random translocations were found in 56% of the tumors. The present study indicates that clonal chromosomal aberrations in hormone-refractory prostate carcinomas are more common than in untreated primary tumors, and also, further studies on the frequency and significance of translocations in prostate carcinoma progression during hormonal therapy are warranted.
Subject(s)
Androgens/pharmacology , Chromosome Aberrations , Neoplasm Recurrence, Local/genetics , Prostatic Neoplasms/genetics , Humans , Karyotyping , Male , Neoplasm Recurrence, Local/classification , Neoplasm Recurrence, Local/pathology , Nucleic Acid Hybridization , Prostatic Neoplasms/classification , Prostatic Neoplasms/pathology , Tumor Cells, CulturedABSTRACT
The ELAC2/HPC2 gene at 17p11 is the first candidate gene identified for human prostate cancer (PRCA) based on linkage analysis and positional cloning (S. V. Tavtigian et al. Nat. Genet., 27:172-180, 2001). A truncating mutation was found in one hereditary prostate cancer (HPC) family, whereas two missense variants, Ser217Leu and Ala541Thr, were reported to be associated with increased PRCA risk in the general population. Here, we screened for mutations of the ELAC2/HPC2 gene in 66 Finnish HPC families. Several sequence variants, including a new exonic variant (Glu622Val) were found, but none of the mutations were truncating. We then analyzed the frequency of the three found missense variants in 1365 individuals, including hereditary (n = 107) and unselected (n = 467) PRCA, benign prostatic hyperplasia (n = 223), and population controls (568 healthy male blood donors). Ser217Leu and Ala541Thr variants carried no significantly elevated risk for HPC or PRCA, although the latter variant was associated with benign prostatic hyperplasia. The previously undescribed Glu622Val variant had a 1.0% population prevalence, but a significantly higher frequency in PRCA cases (3.0% odds ratio, 2.94; 95% confidence interval, 1.05-8.23). We conclude that ELAC2/HPC2 truncating mutations are rare in HPC, but that rare variants of the ELAC2/HPC2 require additional study as risk factors for PRCA in the general population.
Subject(s)
Neoplasm Proteins/genetics , Prostatic Neoplasms/genetics , Aged , Aged, 80 and over , DNA/genetics , DNA, Neoplasm/genetics , Exons/genetics , Finland , Genetic Predisposition to Disease/genetics , Genetic Variation , Humans , Male , Middle Aged , Mutation, Missense , Polymorphism, Restriction Fragment Length , Polymorphism, Single-Stranded ConformationalABSTRACT
BACKGROUND: Germline mutations in recessive cancer predisposition genes are uncovered by somatic genetic deletions during tumor development. Analysis of genetic changes in tumor tissues from patients with an inherited predisposition may therefore highlight regions of the genome containing susceptibility or modifier genes. Our aim was to characterize genetic changes in familial prostate cancer METHODS: Twenty-one primary prostate cancers from 19 Finnish prostate cancer families were analyzed for somatic genetic changes by comparative genomic hybridization (CGH). RESULTS: The average number of genetic alterations per tumor was 4.0 +/- 1.9, distributed equally among losses and gains. The most common losses were found at chromosomal regions 13q14-q22 (29%), 8p12-pter (24%), and 6q13-q16 (14%), and the most common gains at 19p (25%), 19q (14%) and 7q (14%). CONCLUSIONS: These results suggest that prostate cancers in genetically predisposed individuals arise for the most part through similar somatic genetic progression pathways as sporadic prostate cancers. This also implies that the biological properties of tumors from the two groups may not be different from one another.
