Prostate cancer susceptibility genes: lessons learned and challenges posed
Prostate cancer susceptibility genes: lessons learned and challenges posed
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DOI：
10.1677/erc.0.0100225
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发表时间：
2003-06-01
影响因子：
3.9
通讯作者：
Tavtigian, SV
中科院分区：
文献类型：
--
作者：
Simard, J;Dumont, M;Tavtigian, SV
在大多数发达国家，前列腺癌是男性中最常诊断的恶性肿瘤。其发病率的明显种族/民族差异在多大程度上归因于筛查方法、环境、激素和/或遗传因素仍不清楚。阳性家族史是前列腺癌最强的流行病学风险因素之一。现在公认的是，这种多因素恶性肿瘤的候选遗传标记的作用比其他癌症易感基因的鉴定更难鉴定。事实上，尽管定位了几个易感基因座，但在识别乳腺癌和卵巢癌中类似于BRCA 1或BRCA 2的高危易感基因方面的成功有限。尽管如此，已经描述了三个强候选易感基因，即ELAC 2（染色体17 p11/HPC 2区域）、2 '-5'-寡腺苷酸依赖性核糖核酸酶L（RNASEL）（HPC 1区域中的基因）和巨噬细胞清道夫受体1（MSR 1）（染色体8 p上的连锁区域内的基因）。需要使用更大的队列进行额外的研究，以充分评估这些易感基因在前列腺癌风险中的作用。值得一提的是，相当比例的早发性前列腺癌男性在BRCA 2基因中存在种系突变，从而证实了其作为高风险前列腺癌易感基因的作用。虽然最初的分离分析支持了一个假设，即一些罕见的高度外显基因座有助于孟德尔遗传的前列腺癌，目前的实验证据更好地支持这一假设，一些家族性风险可能是由于遗传的多种中度风险的遗传变异。在这方面，毫不奇怪，对编码参与雄激素生物合成和作用的关键蛋白质的基因的分析导致观察到前列腺癌易感性与其中一些基因中的常见遗传变异之间的显著关联。
In most developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal and/or genetic factors remains unknown. A positive family history is among the strongest epidemiological risk factors for prostate cancer. It is now well recognized that the role of candidate genetic markers to this multifactorial malignancy is more difficult to identify than the identification of other cancer susceptibility genes. Indeed, despite the localization of several susceptibility loci, there has been limited success in identifying high-risk susceptibility genes analogous to BRCA1 or BRCA2 for breast and ovarian cancer. Nonetheless, three strong candidate susceptibility genes have been described, namely ELAC2 (chromosome 17p11/HPC2 region), 2'-5'-oligoadenylate-dependent ribonuclease L (RNASEL), a gene in the HPC1 region, and Macrophage Scavenger Receptor 1 (MSR1), a gene within a region of linkage on chromosome 8p. Additional studies using larger cohorts are needed to fully evaluate the role of these susceptibility genes in prostate cancer risk. It is also of interest to mention that a significant percentage of men with early-onset prostate cancer harbor germline mutation in the BRCA2 gene thus confirming its role as a high-risk prostate cancer susceptibility gene. Although initial segregation analyses supported the hypothesis that a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer, current experimental evidence better supports the hypothesis that some of the familial risks may be due to inheritance of multiple moderate-risk genetic variants. In this regard, it is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action led to the observation of a significant association between a susceptibility to prostate cancer and common genetic variants in some of those genes.