Lustbader E d, Rebbeck T R, Buetow K H
Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania. 19111, USA.
Genet Epidemiol. 1995;12(4):339-50. doi: 10.1002/gepi.1370120402.
Linkage analysis can be used to test the hypothesis that a marker locus of known location segregates independently from a presumed disease gene. One way to test this hypothesis is to measure the similarity of marker alleles among pairs of relatives affected with the disease. When the disease under consideration is cancer, it is possible to take advantage of the marker alleles in tumors to revise the similarity measure obtained from the observations made in constitutional tissue. Only cancers that arise through the model of recessive oncogenesis are amenable to this revised analysis. This model postulates that cancer is caused by somatic genetic changes which result in the loss of one or both copies of a normal allele at a tumor suppressor locus. If an individual's inherited genotype is heterozygous at the marker locus, the model of recessive oncogenesis suggests that we may observe loss of constitutional heterozygosity at the marker locus in the tumor. In this report, we how how to incorporate this loss of heterozygosity data into affected pedigree member linkage tests. The revised procedure is illustrated using data obtained from relatives with breast cancer. Substantial improvement in the power to reject the different chromosome hypothesis is obtained when loss of heterozygosity is observed in multiple relatives with the same marker alleles retained in the tumors.
已知位置的标记基因座与假定的疾病基因独立分离。检验该假设的一种方法是测量患该疾病的亲属对之间标记等位基因的相似性。当所考虑的疾病为癌症时，有可能利用肿瘤中的标记等位基因来修正从构成组织的观察中获得的相似性度量。只有通过隐性肿瘤发生模型产生的癌症才适合这种修正分析。该模型假定癌症是由体细胞遗传变化引起的，这些变化导致肿瘤抑制基因座上一个或两个正常等位基因的丢失。如果个体在标记基因座上的遗传基因型是杂合的，隐性肿瘤发生模型表明我们可能在肿瘤中观察到标记基因座上的构成性杂合性丢失。在本报告中，我们展示了如何将这种杂合性丢失数据纳入受影响家系成员连锁检验中。使用从乳腺癌亲属获得的数据说明了修正后的程序。当在多个亲属的肿瘤中观察到杂合性丢失且保留相同标记等位基因时，拒绝不同染色体假设的能力有显著提高。
