Syngal S, Fox E A, Li C, Dovidio M, Eng C, Kolodner R D, Garber J E
Brigham and Women's Hospital, Department of Population Sciences, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Mass 02115, USA.
JAMA. 1999 Jul 21;282(3):247-53. doi: 10.1001/jama.282.3.247.
Genetic testing for cancer predisposition is evolving from purely research applications to affecting clinical management.
To determine how often genetic test results for hereditary nonpolyposis colorectal cancer (HNPCC) can be definitively interpreted and used to guide clinical management.
Case-series study conducted in 1996 to 1998 in which a complete sequence analysis of hMSH2 and hMLH1 coding sequence and flanking intronic regions was performed. Mutations were categorized as protein truncating and missense. In the case of missense alterations, additional analyses were performed in an effort to assess pathogenicity.
Families were identified by self-referral or health care provider referral to a cancer genetics program. Participants and kindreds were classified into 1 of 4 categories: (1) Amsterdam criteria for HNPCC, (2) modified Amsterdam criteria for HNPCC, (3) young age at onset, or (4) HNPCC-variant. In addition, each proband was classified according to the Bethesda guidelines for identification of individuals with HNPCC.
Alterations of hMSH2 and hMLH1 genes.
Twenty-seven alterations of hMSH2 and hMLH1 were found in 24 of 70 families (34.3%). Of these, deleterious mutations that could be used with confidence in clinical management were identified in 25.7% (18/70) of families. The rates of definitive results for families fulfilling Amsterdam criteria, modified Amsterdam criteria, young age at onset, HNPCC-variant, and Bethesda guidelines were 27 (39.3%), 13 (18.2%), 12 (16.7%), 11 (15.8%), and 21 (30.4%), respectively. The prevalence of missense mutations, genetic heterogeneity of the syndrome, and limited availability of validated functional assays present a challenge in the interpretation of genetic test results of HNPCC families.
The identification of pathogenic mutations in a significant subset of families for whom the results may have marked clinical importance makes genetic testing an important option for HNPCC and HNPCC-like kindreds. However, for the majority of individuals in whom sequence analysis of hMSH2 and hMLH1 does not give a definitive result, intensive follow-up is still warranted.
癌症易感性基因检测正从单纯的研究应用发展到影响临床管理。
确定遗传性非息肉病性结直肠癌（HNPCC）基因检测结果能够明确解读并用于指导临床管理的频率。
1996年至1998年进行的病例系列研究，对hMSH2和hMLH1编码序列及侧翼内含子区域进行了完整序列分析。突变分为蛋白截短突变和错义突变。对于错义改变，进行了额外分析以评估其致病性。
通过自我推荐或医疗服务提供者转诊至癌症遗传学项目来识别家庭。参与者及其亲属被分为以下4类之一：（1）HNPCC的阿姆斯特丹标准，（2）HNPCC的改良阿姆斯特丹标准，（3）发病年龄较轻，或（4）HNPCC变异型。此外，根据贝塞斯达指南对每个先证者进行分类，以识别HNPCC个体。
hMSH2和hMLH1基因的改变。
在70个家庭中的24个（34.3%）发现了27处hMSH2和hMLH1的改变。其中，在25.7%（18/70）的家庭中鉴定出了可在临床管理中放心使用的有害突变。符合阿姆斯特丹标准、改良阿姆斯特丹标准、发病年龄较轻、HNPCC变异型和贝塞斯达指南的家庭中明确结果的比例分别为27（39.3%）、13（18.2%）、12（16.7%）、11（15.8%）和21（30.4%）。错义突变的普遍性、该综合征的遗传异质性以及经过验证的功能检测方法的有限可用性，给HNPCC家庭基因检测结果的解读带来了挑战。
在相当一部分结果可能具有显著临床重要性的家庭中鉴定出致病突变，使得基因检测成为HNPCC和HNPCC样亲属的重要选择。然而，对于大多数hMSH2和hMLH1序列分析未得出明确结果的个体，仍需进行密切随访。
