Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Cancer J. 2011 Nov-Dec;17(6):416-22. doi: 10.1097/PPO.0b013e31823e5387.
One hundred years ago, decades before the discovery of the structure of DNA, debate raged regarding how human traits were passed from one generation to the next. Phenotypes, including risk of disease, had long been recognized as having a familial component. Yet it was difficult to reconcile genetic segregation as described by Mendel with observations exhaustively documented by Karl Pearson and others regarding the normal distribution of human characteristics. In 1918, R. A. Fisher published his landmark article, "The Correlation Between Relatives on the Supposition of Mendelian Inheritance," bridging this divide and demonstrating that multiple alleles, all individually obeying Mendel's laws, account for the phenotypic variation observed in nature.Since that time, geneticists have sought to identify the link between genotype and phenotype. Trait-associated alleles vary in their frequency and degree of penetrance. Some minor alleles may approach a frequency of 50% in the human population, whereas others are present within only a few individuals. The spectrum for penetrance is similarly wide. These characteristics jointly determine the segregation pattern of a given trait, which, in turn, determine the method used to map the trait. Until recently, identification of rare, highly penetrant alleles was most practical. Revolutionary studies in genomics reported over the past decade have made interrogation of most of the spectrum of genetic variation feasible.The following article reviews recent discoveries in the genetic basis of inherited cancer risk and how these discoveries inform cancer biology and patient management. Although this article focuses on prostate cancer, the principles are generic for any cancer and, indeed, for any trait.
一百年前，在发现 DNA 结构的几十年前，关于人类特征如何从上一代传递到下一代的争论就已经激烈了。表型，包括患病风险，长期以来一直被认为具有家族成分。然而，孟德尔描述的遗传分离很难与卡尔·皮尔逊（Karl Pearson）等人详尽记录的关于人类特征正态分布的观察结果相协调。1918 年，R.A.费希尔（R. A. Fisher）发表了他的里程碑式文章《在孟德尔遗传假设下亲属间的相关性》，弥合了这一鸿沟，并证明了多个等位基因，每个基因都单独遵循孟德尔定律，解释了自然界中观察到的表型变异。从那时起，遗传学家一直在试图确定基因型和表型之间的联系。与特征相关的等位基因在其频率和外显率方面存在差异。一些次要等位基因在人类群体中的频率可能接近 50%，而其他等位基因仅存在于少数个体中。外显率的范围也同样广泛。这些特征共同决定了特定特征的分离模式，而这反过来又决定了用于绘制特征的方法。直到最近，鉴定罕见的、高外显率的等位基因才是最实际的。过去十年中基因组学的革命性研究使得对大多数遗传变异谱的研究成为可能。本文综述了遗传性癌症风险的遗传基础的最新发现，以及这些发现如何为癌症生物学和患者管理提供信息。虽然本文主要关注前列腺癌，但这些原则对于任何癌症甚至任何特征都是通用的。
