Prostate cancer (PCa) is the most frequently diagnosed cancer in men worldwide. As PCa is a complex, multigenic disease, it has been challenging to establish its genetic basis, with strong risk factors obscured by the genetically heterogeneous patient populations often available for analysis. Worldwide the PCa phenotype has been further complicated based on the frequent inclusion of cases in which prostate specific antigen (PSA)-tests allow early diagnosis of possibly latent disease. Thus, previous segregation analyses have variously suggested that the familial aggregation of PCa follows autosomal dominance, recessive or X-linked inheritance, but remain inconclusive. The objective of this study was to assess the familial aggregation of PCa in a sample of 1,546 nuclear families ascertained through an affected father and diagnosed during [1988][1989][1990][1991][1992][1993] NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript segregation analysis on two cohorts of 557 early-onset and 989 late-onset families with clinically diagnosed PCa cases, uncomplicated by predictions from PSA screening. We evaluated residual paternal effects, assuming that age at diagnosis followed a logistic distribution after logtransformation. Our results indicate that Mendelian recessive inheritance consistent with the sexlimited X-linked region previously mapped in Finnish families to the HPCX locus best fit the data in each cohort. With a putative high-risk allele frequency qA of 0.09 in the combined analysis, genotype-specific mean ages at diagnosis of 63.6 years for AA and 71.0 years for AB/BB, respectively, were obtained. The significant paternal regressive coefficient was also indicative of a polygenic multifactorial component, suggesting that environmental factors may contribute to the rising incidence of PCa in Finland.

BackgroundPALB2 1592delT mutation is associated with increased breast cancer and suggestive prostate cancer (PRCA) risk in Finland. In this study we wanted to assess if any other PALB2 variants associate to increased PRCA risk and clinically describe patients with formerly found PALB2 1592delT mutation.MethodsFinnish families with two or more PRCA cases (n = 178) and unselected cases (n = 285) with complete clinical data were initially screened for variants in the coding region and splice sites of PALB2. Potentially interesting variants were verified in additional set of unselected cases (n = 463).ResultsFrom our clinically defined sample set we identified total of six variants in PALB2. No novel variants among Finnish PRCA cases were found. Clinical characteristics of the variant carriers, including the previously described family carrying PALB2 1592delT, revealed a trend towards aggressive disease, which also applied to a few non-familial cases. Hypersensitivity to mitomycin C (MMC) of lymphoblasts from individuals from the family with 1592delT revealed haploinsufficiency among carriers with altered genotype.ConclusionsThough any of the detected PALB2 variants do not associate to PRCA in population level in Finland it cannot be ruled out that some of these variants contribute to cancer susceptibility at individual level.

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• A population-based cohort of 3011 hospital district Pirkanmaa PCa patients was used as a control group. RESULTS• The mean (range) year of diagnosis of PCa was 1993PCa was (1962PCa was -2006 and the mean (range) age at diagnosis was 68 (43-98 years).• The median (range) primary PSA level was 12.0 (0.8-11 000) ng/mL. After regrading, the Gleason score was ≤ 6 in 38%, 7 in 37% and ≥ 8 in 25% of men.• The subset of familial PCa men diagnosed after 1995 had higher PSA levels ( P = 9.9 × 10 − 6) and an earlier age of onset ( P = 1.7 × 10 − 6 ) than men in the control group, although there were no differences in cancer-specific survival.

Background: Clinical features of familial prostate cancer (PCa) and other malignancies associated with PCa are poorly described. Using a large family-based data registry of histologically confirmed cancers with a 40-year follow-up, we sought to determine incidence of cancer in Finnish PCa families, separately for clinically aggressive and clinically nonaggressive PCa. Methods: We calculated standardized incidence ratios (SIR) for 5,523 members of 202 families by dividing the number of observed cancers (altogether 497 cases) by the number of expected cancers. The number of expected cancers is based on the national cancer incidence rates. Results: SIR for overall cancer risk, excluding PCa, for male relatives in clinically nonaggressive families was