Department of Medical Oncology, Princess Margaret Hospital, 610 University Ave, Room 7-124, Toronto, Ontario, M5G 2M9 Canada.
J Clin Oncol. 2010 Sep 10;28(26):4029-37. doi: 10.1200/JCO.2009.27.2336. Epub 2010 Aug 2.
Studies of the role of germline or inherited genetic variation on cancer outcome can fall into three distinct categories. First, the impact of highly penetrant but lowly prevalent mutations of germline DNA on cancer prognosis has been studied extensively for BRCA1 and BRCA2 mutations as well as mutations related to hereditary nonpolyposis colorectal cancer syndrome. These mainly modest-sized analyses have produced conflicting results. Although some associations have been observed, they may not be independent of other known clinical or molecular prognostic factors. Second, the impact of germline polymorphisms on cancer prognosis is a burgeoning field of research. However, a deeper understanding of potentially confounding somatic changes and larger multi-institutional, multistage studies may be needed before consistent results are seen. Third, research examining the impact of germline genetic variation on differential treatment response or toxicity (pharmacogenetics) has produced some proof-of-principle results. Putative germline pharmacogenetic predictors of outcome include DPYD polymorphisms and fluorouracil toxicity, UGT1A1 variation and irinotecan toxicity, and CYP2D6 polymorphisms and tamoxifen efficacy, with emerging data on predictors of molecularly targeted or biologic drugs. Here we review data pertaining to these germline outcome and germline toxicity relationships.
研究种系或遗传基因突变对癌症结局的影响可以分为三个不同类别。首先，研究种系 DNA 中高外显但低流行的突变对 BRCA1 和 BRCA2 突变以及与遗传性非息肉病性结直肠癌综合征相关的突变对癌症预后的影响已广泛开展。这些主要是规模适度的分析得出了相互矛盾的结果。尽管观察到了一些关联，但它们可能与其他已知的临床或分子预后因素无关。其次，种系多态性对癌症预后的影响是一个新兴的研究领域。然而，在得出一致的结果之前，可能需要更深入地了解潜在的混杂性体细胞变化，并进行更大规模的多机构、多阶段研究。第三，研究种系遗传变异对治疗反应或毒性（药物遗传学）的影响已经产生了一些原理验证结果。潜在的种系药物遗传学预测因子包括 DPYD 多态性和氟尿嘧啶毒性、UGT1A1 变异和伊立替康毒性，以及 CYP2D6 多态性和他莫昔芬疗效，以及关于分子靶向或生物药物预测因子的新兴数据。在这里，我们回顾了与这些种系结局和种系毒性关系相关的数据。
