有3名或3名以上亲属患这种病再加上基因突变会提高侵袭性前列腺癌的风险。
近日，美国人类遗传学会于波士顿举行，年会上报告的一项研究说，患前列腺癌的男性有3名或者更多的患前列腺癌的亲属，而这些男性的8个DNA修复基因之中如果有1个发生了突变，那么他们就可能出现侵袭性的前列腺癌。
“在我们研究的22个DNA修复基因中，我们发现了其中8个基因的14种失去了功能的变种；这导致蛋白质不能完全发挥作用。在我们的研究中，携带了这些类型的基因突变的男性与没有携带这些突变的男性相比，他们患转移性前列腺癌的几率要显着更高，”报告了这项研究的英国癌症研究所的研究生Daniel Leongamornlert说。
该研究让参与英国遗传前列腺癌研究项目的大约200名患家族前列腺癌的英国男性参与其中。Leongamornlert和他在英国癌症研究所（ICR）的同事搜索了为参与DNA修复路径的蛋白质编码的22个基因的遗传突变的序列。
这组科研人员在前列腺癌病人的血样DNA序列中发现了14种失去功能的基因变种。在BRCA2肿瘤抑制基因中发现了4个突变。这些科学家还在另一种肿瘤抑制基因BRCA1以及另外6种已知在DNA修复中发挥作用的基因中发现了突变。这些基因分别是：ATM，CHEK2，BRIP1，MUTYH，PALB2 和PMS2。其中几个DNA修复基因的突变与其他类型的癌症有联系。
“拥有失去功能的突变的DNA修复基因带来了4.64 的前列腺癌高相对风险。这些新发现的罕见基因变种可能作为开发药物的靶标，用于出现侵袭性前列腺癌的风险高的前列腺癌男性病人，”英国癌症研究所（ICR）领导了这项研究的资深科学家Zsofia Kote-Jarai博士说。
“这些发现可能在实施家族前列腺癌的新型筛查和治疗策略方面有临床用途，” 该研究的资深作者、英国癌症研究所（ICR）肿瘤遗传学研究组组长、肿瘤遗传学教授Rosalind Eeles M.D.补充说。Eeles博士还是英国遗传前列腺癌研究项目的创始人和研究组长，该研究是在1993年建立的，有170家医院参与。
这组科学家在美国人类遗传学会上公布的论文摘要的题目是《家族前列腺癌病例的DNA修复基因的常见种系突变》。(生物谷Bioon.com)
生物谷推荐的英文摘要
American Society of Human Genetics
http://www.ashg.org/2013meeting/abstracts/fulltext/f130120218.htm
Frequent germline mutations in DNA repair genes in familial prostate cancer cases
D. Leongamornlert, E. Saunders, T. Dadaev, M. Tymrakiewicz, C. Goh, S. Jugurnauth-Little, I. Kozarewa, K. Fenwick, I. Assiotis, D. Barrowdale, K. Govindasami, M. Guy, E. Sawyer, R. Wilkinson, A. Antoniou3, R. Eeles, Z. Kote-Jarai
Prostate cancer (PrCa) is one of the most common diseases to affect men worldwide and the underlying aetiology is poorly understood compared with other complex diseases. Many common variants have been identified over the last few years which are associated with PrCa risk but very few rare, higher risk alleles have been found. To investigate if rare variants in 22 DNA repair genes have a role in PrCa predisposition, we analysed these genes in a UK collection of familial prostate cancer cases. Germline DNA samples were obtained from 191 PrCa cases which had 3 or more relatives affected with PrCa. These samples were deeply re-sequenced using Agilent Sureselect target capture and Illumina HiSeq systems. The exonic and intronic sequences of 22 tumour suppressor DNA repair genes were analysed for genomic variation using a pipeline consisting of BWA, GATK and Annovar. We identified 14 loss-of-function (LoF) mutations (7.3%) with the highest fraction contributed by BRCA2 (4 mutations). Mutations were also found in ATM, CHEK2, BRIP1, BRCA1, MUTYH, PALB2 and PMS2. In addition, 13 missense variants which are likely to modify protein function were also identified. LoF mutation carriers had significantly higher odds of nodal involvement, metastasis or death from PrCa OR 11.32 (95% CI: 2.27-69.56; P=0.00421). Using a modified segregation analysis approach, we estimate that LoF mutations in any of the studied genes confer a relative risk of PrCa of 4.64, (95% confidence interval 3.84-5.61). In summary we present evidence that mutations in DNA repair genes may have a significant role in familial PrCa predisposition and that carriers of LoF mutations in these genes are more likely to have aggressive disease. This may have clinical utility in the implementation of new screening and treatment strategies.
