The genetics of cancer risk.
The genetics of cancer risk.
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DOI：
10.1097/ppo.0b013e31823e5387
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Freedman ML
中科院分区：
文献类型：
--
作者：
Pomerantz MM;Freedman ML
一百年前，在发现DNA结构的几十年前，关于人类特征如何从一代传递到下一代的争论激烈。表型，包括患病风险，长期以来一直被认为具有家族性。然而，孟德尔所描述的遗传隔离与卡尔·皮尔逊和其他人关于人类特征正态分布的详尽记录的观察结果很难调和。1918年，RA Fisher发表了他的里程碑式的论文，“孟德尔遗传假设的亲属之间的相关性”，弥合了这一分歧，并证明了多个等位基因，所有个体都遵守孟德尔定律，解释了自然界中观察到的表型变异。从那时起，遗传学家就一直在寻找基因型和表型之间的联系。性状相关等位基因的频率和等位率的程度各不相同。一些次要等位基因可能在人类群体中接近50%的频率，而其他等位基因仅存在于少数个体中。类似地，催眠的范围也很广。这些特征共同决定了给定性状的分离模式，而分离模式又决定了用于定位该性状的方法。直到最近，鉴定罕见的、高外显的等位基因才是最实用的。在过去的十年中，基因组学的革命性研究报告已经使得对大多数遗传变异谱的询问变得可行。下面的文章将回顾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。虽然这篇文章的重点是前列腺癌，但这些原则对任何癌症都是通用的，事实上，对任何特征都是通用的。
One hundred years ago, decades prior to 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, RA Fisher published his landmark paper, “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 while 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 will review recent discoveries in the genetic basis of inherited cancer risk and how these discoveries inform cancer biology and patient management. While this article focuses on prostate cancer, the principles are generic for any cancer and, indeed, for any trait.