早发性结直肠癌患者中 DNA 错配修复基因改变的发生率。
Prevalence of alterations in DNA mismatch repair genes in patients with young-onset colorectal cancer.
机构信息
Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
出版信息
Clin Gastroenterol Hepatol. 2011 Jun;9(6):497-502. doi: 10.1016/j.cgh.2010.10.021. Epub 2010 Nov 5.
BACKGROUND & AIMS: Direct germline analysis could be used to screen high-risk patients for mutations in DNA mismatch repair genes associated with Lynch Syndrome. We examined the prevalence of mutations in MLH1, MSH2, and MSH6 in a population-based sample of patients with young-onset (age <50 years) colorectal cancer (CRC).
METHODS
Young-onset CRC cases were randomly selected from 3 Colon Cancer Family Registry sites. DNA was extracted from peripheral blood leukocytes; MLH1, MSH2, and MSH6 were sequenced, and duplication and deletion analyses was performed for MLH1 and MSH2. Results were reported as deleterious or suspected deleterious, likely neutral, variant of uncertain significance, or no alteration detected. Germline data were compared to Amsterdam II criteria (ACII) and immunohistochemistry results in secondary analyses.
RESULTS
Among 195 subjects, 11 had deleterious/suspected deleterious mutations (5.6%; 95% confidence interval [CI], 2.8%-9.9%), 12 had likely neutral alterations (6.2%; 95% CI, 3.2%-10.5%), 14 had variants of uncertain significance (7.2%; 95% CI, 4.0%-11.8%), 2 had a likely neutral alteration and a variant of uncertain significance (1.0%; 95% CI, 0.1%-3.7%), and 156 had no alteration detected (80.0%; 95% CI, 73.7%-85.4%). Sensitivity, specificity, and positive and negative predictive values for detecting deleterious/suspected deleterious mutations, based on ACII, were 36.4% (4/11), 96.7% (178/184), 40.0% (4/10), and 96.2% (178/185), respectively; based on immunohistochemistry these values were 85.7% (6/7), 91.9% (136/148), 33.3% (6/18), and 99.3% (136/137), respectively.
CONCLUSIONS
In a population-based sample of young-onset CRC cases, germline mutations in MLH1, MSH, and/or MSH6 were more prevalent than reported for CRC patients overall. Because only about 5% of young-onset CRC cases had confirmed deleterious or suspected deleterious mutations, further comparative effectiveness research is needed to determine the most appropriate screening strategy for Lynch Syndrome in this high-risk group.
背景与目的
直接种系分析可用于筛选与林奇综合征相关的 DNA 错配修复基因的高危患者中的突变。我们在基于人群的年轻发病（<50 岁）结直肠癌（CRC）患者样本中检查了 MLH1、MSH2 和 MSH6 中突变的发生率。
方法
从 3 个结肠癌家族登记处随机选择年轻发病 CRC 病例。从外周血白细胞中提取 DNA；对 MLH1、MSH2 和 MSH6 进行测序，并对 MLH1 和 MSH2 进行重复和缺失分析。结果报告为有害/疑似有害、可能中性、意义不明的变异或未检测到的改变。种系数据与阿姆斯特丹 II 标准（ACII）和二次分析中的免疫组织化学结果进行比较。
结果
在 195 名受试者中，有 11 名有有害/疑似有害突变（5.6%；95%置信区间[CI]，2.8%-9.9%），12 名有可能中性改变（6.2%；95%CI，3.2%-10.5%），14 名有意义不明的变异（7.2%；95%CI，4.0%-11.8%），2 名有中性改变和意义不明的变异（1.0%；95%CI，0.1%-3.7%），156 名无改变（80.0%；95%CI，73.7%-85.4%）。基于 ACII，检测有害/疑似有害突变的检测灵敏度、特异性、阳性预测值和阴性预测值分别为 36.4%（4/11）、96.7%（178/184）、40.0%（4/10）和 96.2%（178/185）；基于免疫组织化学这些值分别为 85.7%（6/7）、91.9%（136/148）、33.3%（6/18）和 99.3%（136/137）。
结论
在基于人群的年轻发病 CRC 病例样本中，MLH1、MSH 和/或 MSH6 中的种系突变比总体 CRC 患者更为常见。由于只有约 5%的年轻发病 CRC 病例有明确的有害或疑似有害突变，因此需要进一步的比较有效性研究来确定在这个高风险人群中林奇综合征最适当的筛查策略。
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