Segregation analyses of 1,476 population-based Australian families affected by prostate cancer

Segregation analyses aim to detect genetic factors that have a major effect on an individual's risk of disease and to describe them in terms of mode o f inheritance, age-specific cumulative risk (penetrance), and allele freque ncy. We conducted single- and two-locus segregation analyses of data from 1 ,476 men with prostate cancer diagnosed at age <70 years and ascertained th rough population registries in Melbourne, Sydney, and Perth, Australia, and from their brothers, fathers, and both maternal and paternal lineal uncles . Estimation and model selection were based on asymptotic likelihood theory and were performed through use of the software MENDEL. All two-locus model s gave better fits than did single- locus models, even if lineal uncles wer e excluded or if we censored data (age and disease status) for relatives at 1992, when prostate-specific-antigen testing started to have a major impac t on the incidence of prostate cancer in Australia. Among the genetic model s that we considered, the best-fitting ones included a dominantly inherited increased risk that was greater, in multiplicative terms, at younger ages, as well as a recessively inherited or X-linked increased risk that was gre ater, in multiplicative terms, at older ages. The recessive and X-linked ef fects were strongly confounded, and it was not possible to fit them togethe r. Penetrance to age 80 years was <similar to>70% (95% confidence interval [CI] 57%-85%) for the dominant effect and virtually 100% for the recessive and X-linked effects. Approximately 1/30 (95% CI 1/80-1/12) men would carry the dominant risk, and 1/140 (95% CI 1/220-1/90) would carry the recessive risk or 1/200 (95% CI 1/380-1/100) would carry the X-linked risk. Within d iscussed limitations, these analyses confirm the genetic heterogeneity, of prostate cancer susceptibility, that is becoming evident from linkage analy ses, and they may aid future efforts in gene discovery.