SEGREGATION ANALYSIS OF BREAST-CANCER - A COMPARISON OF TYPE-DEPENDENT AGE-AT-ONSET VERSUS TYPE-DEPENDENT SUSCEPTIBILITY MODELS

Most segregation analyses of breast cancer susceptibility have modeled the effect of the major gene on the age-at-onset distribution. Howeve r, in families linked to BRCA1 or BRCA2, there is wide variation in th e age-at-onset among gene carriers. We performed a segregation analysi s of 544 Minnesota breast cancer families using models which parameter ized the putative major gene effect in two ways: earlier age-at-onset, with a common level of susceptibility (model I), and greater suscepti bility, with a common mean age-at-onset (model II). Five hypothetical modes of transmission and an unrestricted general hypothesis were fitt ed to the data. Twice the difference between the log, likelihood for t he data under the specified hypothesis (recessive, no major gene, etc. ) and the log(e) Likelihood under the general hypothesis is distribute d asymptotically as a chi-square statistic with the degrees of freedom equal to the difference in the number of parameters estimated. This d ifference was compared to the critical value for the chi-square distri bution to assess goodness-of-fit. Under model I, both Mendelian and no n-Mendelian hypotheses were rejected. When model II was used, the non- Mendelian hypotheses were rejected whereas all Mendelian hypotheses we re not. Mendelian recessive inheritance of a common allele (q(A) = 0.1 1) with a high penetrance (87%) provided the best fit to the data. We then stratified the families into two subsets based on the age at diag nosis of the proband [less than or equal to 55 years (n = 265) versus >55 years (n = 279)]; there was no evidence of heterogeneity under eit her model (I or II). These data suggest that, in some breast cancer fa milies, the effect of the putative susceptibility gene is better repre sented as increasing overall susceptibility to breast cancer rather th an as a shift in the age-at-onset distribution. (C) 1996 Wiley-Liss, I nc.