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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.

Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors.

Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T(1)-T(2)) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 -34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3 -252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology.

Colon Interposition in the Treatment of Carcinoma of the Esophagus and Gastric Cardia

The stomach is the organ most used for restoring esophageal continuity after esophageal resection for malignancy. In the present series, we report our experience over a 20-year period (1965 through 1984) with an alternative method, colon interposition. Two hundred forty-eight patients (124 men and 124 women) underwent colon interposition. Seventy-one percent (175) of the tumors were squamous cell carcinomas, and 23% (58) were adenocarcinomas in the gastric cardia and lower esophagus. The left colon was the substitute of first choice and was used in 54% of the patients. Of the interpositions, 59% were antiperistaltic. Esophagectomy without thoracotomy was the method in 146 patients. The operative mortality was 16% (40 patients), and 3% (8 patients) sustained colon graft necrosis. Leakage in the upper anastomosis occurred in 4% (10). No dysphagia was experienced by 85%, 80%, and 76% of the patients during reexaminations 3, 6, and 12 months, respectively, after operation. The 1-year and 5-year survival for patients with squamous cell carcinoma was 40% and 10%, respectively, and for patients with adenocarcinoma, 50% and 12%, respectively. The data from this study suggest that colon interposition offers a good alternative for long-term relief of dysphagia in patients with carcinoma of the esophagus. The rate of complications is acceptable.

Lactase Persistence, Dietary Intake of Milk, and the Risk for Prostate Cancer in Sweden and Finland

Prostate carcinoma is the most common cancer in men. Its primary pathogenesis is mostly unknown. Dairy products containing lactose have been suggested to be risk factors for prostate cancer. Digestion of lactose is dependent on lactase activity in the intestinal wall. A single nucleotide polymorphism C to T residing 13,910 bp upstream of the lactase gene has been shown to associate with the developmental down-regulation of lactase activity underlying persistence/nonpersistence trait. To find out whether lactase persistence is related to the risk for prostate cancer, we genotyped 1,229 Finnish and 2,924 Swedish patients and their 473 Finnish and 1,842 Swedish controls using solid-phase minisequencing. To explore if dairy products have an association with prostate cancer, we analyzed the milk consumption in the Swedish study consisting of 1,499 prostate cancer patients and 1,130 controls (Cancer Prostate in Sweden I study) using a questionnaire. Only the consumption of low-fat milk was found to be associated with increased risk of prostate cancer [odds ratio (OR), 1.73; 95% confidence interval (95% CI), 1.16-2.39]. A statistically significantly higher (P < 0.01) lactose intake was observed among subjects with high lactase activity (C/T and T/T genotypes) compared with those with low lactase activity (C/C genotype). Lactase persistence did not associate with increased risk for prostate carcinoma in the Finnish (OR, 1.11; 95% CI, 0.83-1.47; P = 0.488) or in the Swedish populations (OR, 1.16; 95% CI, 0.91-1.46; P = 0.23). In conclusion, lactase persistence/nonpersistence contains no risk for prostate cancer. Analysis of different milk products showed some evidence for low-fat milk as a potential risk factor for prostate cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(5):956–61)

Role of the Nijmegen Breakage Syndrome 1 Gene in Familial and Sporadic Prostate Cancer

The Nijmegen breakage syndrome 1 (NBS1) gene, which participates in DNA double strand break repair, has been postulated to be a susceptibility factor for a number of cancers, including prostate cancer. Numerous mutations have been identified in NBS1, including the founder mutation 657del5. In this study, a number of analyses were done to determine whether mutations in NBS1 are associated with an increased risk for prostate cancer. The frequency of the 657del5 mutation in both familial prostate cancer cases (1,819 affected men among 909 families) and sporadic prostate cancer cases (1,218 affected men) collected from five centers participating in the International Consortium for Prostate Cancer Genetics were compared with that found in 697 normal controls. Seven individuals were identified to carry the mutation among the 3,037 cases screened: four in the familial group (three from one family and one from another) and three in the sporadic cases. The carrier frequency was 0.22% (2 of 909) for the probands and 0.25% (3 of 1,218) for the sporadic cases of prostate cancer. The 657del5 mutation was not detected in either the 293 unaffected members of the prostate cancer families or in the 697 control samples tested. The entire NBS1 gene was also sequenced in 20 of the youngest affected individuals from the Finnish group of familial cases to identify the presence of possible mutations in this high-risk group. One rare (D95N) and one common (E185Q) missense alteration was identified. More detailed analyses of the E185Q polymorphism, along with a third rare variant (R215W), failed to show an association with prostate cancer. Because the 657del5 mutation was absent from the control population, we are unable to determine if this alteration predisposes to prostate cancer. However, our data does suggest that mutations within NBS1, and in particular, 657del5, do not significantly contribute to the overall prostate cancer burden within our patient samples. (Cancer Epidemiol Biomarkers Prev 2006;15(5):935–8)

Elevated serum anti-I2 and anti-OmpW antibody levels in children with IBD

Background Bacteria are implicated as important factors in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to seek evidence of possible bacterial targets of the immune response related to IBD in children. Methods Seventy‐eight children referred to the Department of Paediatrics at Tampere University Hospital on suspicion of IBD were included in the study. Upper and lower gastrointestinal endoscopies with biopsies were performed on all children. Sera from 75 children were tested for antibodies to the Pseudomonas fluorescens‐associated sequence I2, a Bacteroides caccae TonB‐linked outer membrane protein, OmpW, anti‐Saccharomyces cerevisiae, and perinuclear anti‐neutrophil cytoplasmic antibodies. Results The IBD diagnosis was confirmed in 35 children (18 with Crohns disease [CD], 12 with ulcerative colitis [UC], and 5 with indeterminate colitis [IC]); 43 children were found to have no inflammation in the gut. Forty‐three percent (15 of 35) of those with IBD evinced positive seroreactivity to I2 and 46% (16 of 35) to OmpW. In CD, seroreactivity to I2 and OmpW was 50% (9 of 18) and 61% (11 of 18), respectively. Serum anti‐I2 and anti‐OmpW immunoglobulin A levels were significantly elevated in children with CD in comparison with the non‐IBD group (P = 0.007 and P = 0.001, respectively). A combination of OmpW, I2, and anti‐S cerevisiae tests identified 94% of CD patients, and a combination of OmpW, I2, and perinuclear anti‐neutrophil cytoplasmic antibodies detected 83% of UC cases. Conclusions Among children with IBD, strong serological responses to microbial antigens can be found, suggesting that P fluorescens and B caccae antigens have a potential role in the microbiology and immunology of the disease. Furthermore, serologic reactivity to the set of antigens studied here seems to be applicable in the initial differential diagnosis of children with CD and UC.

Hemochromatosis gene mutations among Finnish male breast and prostate cancer patients.

Hereditary hemochromatosis (HH), the most common genetic disease in northern Europeans, is an autosomal recessive disorder of iron metabolism. The association between hepatocellular carcinoma and HFE homozygosity is well documented, but recently HFE hetero‐ and homozygosity has also been linked to nonhepatocellular malignancies, including female breast cancer. We hypothesized that C282Y and H63D mutations in the HFE gene could contribute to male breast cancer (MBC) and prostate cancer (PC) susceptibility at the population level in Finland. We screened the 2 major HFE mutations, H63D and C282Y, from 116 MBC cases diagnosed in Finland between 1967 and 1996, 843 consecutive unselected PC cases diagnosed at the Pirkanmaa Hospital District between 1999 and 2001 and 480 anonymous blood donor controls by minisequencing. Our results indicate that the frequencies of the HFE mutations do not significantly differ between MBC and PC patients and the population‐based controls. No significantly altered risks for MBC or PC among carriers of the 2 variants were observed. However, HFE mutations were seen twice as often among carriers of a common BRCA2 mutation 9346(−2)A→G compared with the rest of the MBC cases, indicating that HFE may be an MBC risk modifier gene among BRCA2 mutation carriers. In conclusion, our results indicate a minor role for the HFE mutations C282Y and H63D in the causation of MBC and PC, but carriers of both BRCA2 9346(−2)A→G and an HFE mutation may be at an increased risk.

Voice Activity and Participation Profile (VAPP) in assessing the effects of voice disorders on patients' quality of life: validity and reliability of the Finnish version of VAPP.

The Voice Activity and Participation Profile (VAPP) is a self-assessment questionnaire describing the limitation of activities and participation of individuals with dysphonia. In this study, the validity and reliability of the Finnish translation of the VAPP was evaluated using 43 outpatients with various functional and organic voice disorders. A control group was formed consisting of 43 subjects matched according to age, gender, and profession, with normal voices. The VAPP was sensitive for voice disorders and items in the questionnaire had high internal consistency. The VAPP had a strong correlation with the Voice Handicap Index. The results showed that the questionnaire is a valid and reliable instrument to measure voice-related quality of life. It also showed that limitations in activity and participation levels should be examined separately.

Factors Associated with Physicians' Choice of Working Sector: A National Longitudinal Survey in Finland

ObjectiveTo analyse factors affecting physicians’ choice to work in either the public or the private sector.MethodWe undertook a longitudinal data analysis in the years 1988, 1993, 1998 and 2003 (n = 12 909) using a multilevel modelling technique. Factors related to economic factors, physician identity, appreciation as well as demographic factors were hypothesised to influence sector choice.ResultsPhysicians seem to make their career choices prior to graduation, at least to some extent. Wage levels, the physician’s personal characteristics and whether or not the physician knew his or her place of work before graduation were the key factors affecting the decision-making process in the years 1988, 1993, 1998 and 2003. Physicians for whom wages were important were less likely to choose the public sector. Also, physicians who regarded themselves as entrepreneurial preferred to work in the private sector. If a physician had worked in the public sector during his or her medical training before graduation, the probability of applying for a vacancy in the public sector was higher.ConclusionIt is not only economic factors, such as salary, that are involved in the physician’s decision to choose the working sector.