Segregation analysis of 1,546 prostate cancer families in Finland shows recessive inheritance

Abstract

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.

Effect of Genetic Variability within 8q24 on Aggressiveness Patterns at Diagnosis and Familial Status of Prostate Cancer

“…Recently, Christensen et al (16) showed that a subset of Utah high-risk pedigrees with a familial history of prostate cancer showed nominal linkage evidence on chromosome 8q (heterogeneity LOD score, 1.67). Our results, which included a familial prostate cancer history but was not restricted to a high-penetrance model to a major gene (Carter's criteria), could be compatible with our previous observation of a brother-brother dependence inheritance (17) and the (18).…”

Prostate cancer segregation analyses using 4390 families from UK and Australian population‐based studies

“…This difference in risk has been found by other studies [Monroe et al, 1995;Narod et al, 1995;Woolf, 1960]. Some evidence for a recessive component was also reported in a previous publication using a subset of the Australian data [Cui et al, 2001], and more recently of Finnish prostate cancer families [Pakkanen et al, 2007].…”

“…The best-fitting model was a simple multifactorial non-genetic model. The recent study conducted in Finland also found a significant paternal regressive coefficient that is indicative of a polygenic component [Pakkanen et al, 2007]. There are several possible explanations for the differences in findings between these analyses.…”

“…More recent studies have reported that other models provide a better explanation for the familial aggregation. The best-fitting models include a recessive only model [Pakkanen et al, 2007], two mode of inheritance models (dominant and recessive; dominant and X-linked) [Cui et al, 2001], a simple multifactorial non-genetic model [Gong et al, 2002], and a heterogeneity model with two to three dominant genes [Conlon et al, 2003].…”

Fine mapping of familial prostate cancer families narrows the interval for a susceptibility locus on chromosome 22q12.3 to 1.36 Mb

“…Although the studies are in diverse populations, seven analyses report evidence for a single major gene with a rare autosomal dominant eVect, especially in families with early ages of onset (Carter et al 1992;Conlon et al 2003;Cui et al 2001;Gronberg et al 1997;Schaid et al 1998;Valeri et al 2003;Verhage et al 2001). Two studies provide evidence for recessive inheritance (Cui et al 2001;Pakkanen et al 2007), while Gong et al (2002) suggest that a multifactorial model best Wts the available data.…”