Annika Rökman

CHEK2 variants associate with hereditary prostate cancer

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.

Androgen receptor CAG polymorphism and prostate cancer risk

Abstract. Recent studies have suggested that polymorphisms of the androgen receptor gene (AR) may influence the risk of prostate cancer (PC) development and progression. Here, we analyzed the length of the CAG repeat of the AR gene in 1363 individuals, including patients with PC, benign prostate hyperplasia (BPH), and population controls. There was a tendency for short CAG repeats to be associated with PC. The Odds Ratio (OR) for PC was 1.47 (P=0.05) when individuals with short CAG repeats (≤18) were compared with those having long repeats (>18). CAG repeat length was not significantly associated with family history, disease stage, grade, age at diagnosis, prostate-specific antigen (PSA) level at diagnosis, or prognosis of the patients. Unexpectedly, short CAG repeats were significantly less common in patients with BPH compared with controls (OR=0.47, P=0.03). Our results suggest that the CAG polymorphism of the AR gene is unlikely to have a major role in the development or progression of PC in the Finnish population. The association of CAG repeats with the risk of BPH warrants further study.

Preservation of nucleic acids and tissue morphology in paraffin-embedded clinical samples: comparison of five molecular fixatives

Formalin fixation preserves tissue morphology at the expense of macromolecule integrity. Freshly frozen samples are the golden standard for DNA and RNA analyses but require laborious deep-freezing and frozen sectioning for morphological studies. Alternative tissue stabilisation methods are therefore needed. We analysed the preservation of nucleic acids, immunohistochemical staining properties and tissue morphology in paraffin-embedded clinical tissue samples fixed with Z7, RCL2, PAXgene, Allprotect and RNAlater. Formalin-fixed and deep-frozen samples were used as controls. Immunohistochemical analyses showed good preservation of antigenicity in all except Allprotect and RNAlater-fixed samples. RNA quality, based on RNA integrity number value by Bioanalyzer, was comparable with freshly frozen samples only in PAXgene-fixed samples. According to quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses, RNA from PAXgene samples yielded results similar to freshly frozen samples. No difference between fixatives was seen in DNA analyses (PCR and real-time PCR). In conclusion, PAXgene seems to be superior to other molecular fixatives and formaldehyde.

Genetic changes in familial prostate cancer by comparative genomic hybridization.

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

BRCA1 and BRCA2 mutations have no major role in predisposition to prostate cancer in Finland

A fter lung cancer, prostate cancer is the second leading cause of death from cancer in men in developed countries.1 Despite the substantial impact on public health of prostate cancer, the cause of the disease has remained poorly understood, with ethnicity, diet, and family history considered as the major risk factors.2,3 A fraction of patients with prostate cancer belong to families with hereditary prostate cancer (HPC). Recently, several loci have been implicated in predisposing to prostate cancer by genetic linkage studies in cancer families, including HPC1 at 1q24–q25, HPC2 at 17p11, PCAP at 1q42.2–q43, HPCX at Xq27–q28, CAPB at 1p36, and HPC20 at 20q13.4 Only two genes have been identified from these chromosomal regions, ELAC2 (MIM 605367) from the HPC2, locus5 and RNASEL (MIM 180435) from the HPC1, locus6 but none has so far been definitively confirmed. In Finland, neither of these genes alone explains disease segregation in Finnish families with HPC but they seem to have some modifying role in predisposition to cancer.7,8 Breast cancer predisposing genes BRCA1 (MIM 113705) and BRCA2 (MIM 600185) are involved in repair of DNA damage and transcriptional regulation.9 Clustering of breast, ovarian, and prostate cancer has been reported,10–14 suggesting a role for BRCA1 and BRCA2 in predisposition to prostate cancer. Several epidemiological studies have discovered an increased risk of prostate cancer among BRCA1 and BRCA2 families.15–19 Consistent with this view, loss of heterozygosity at the BRCA1 and BRCA2 loci is commonly encountered in prostate cancer.20–22 Edwards et al 23 implicated BRCA2 as a high risk gene for early onset prostate cancer. In a recent study in BRCA1 and BRCA2 mutation positive and mutation negative Finnish breast cancer families, the only increased standardised incidence ratio (SIR), besides breast and …

Chromosomal changes in locally recurrent, hormone-refractory prostate carcinomas by karyotyping and comparative genomic hybridization

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.