Department of Medical Genetics, Mayo Foundation, 200 First Street SW, Rochester, MN 55905, USA.
J Med Genet. 2011 Aug;48(8):530-4. doi: 10.1136/jmedgenet-2011-100082. Epub 2011 Jun 2.
Carriers of a germline mutation in a DNA mismatch repair (MMR) gene--that is, persons with Lynch syndrome--have substantially high risks of colorectal (CRC), endometrial, and several other cancers. The proportion of carriers who have de novo mutations (not inherited from either parent) is not known. This study reports a case series of de novo mutations in MMR genes and estimates the frequency of de novo mutation in MMR genes using the Colon Cancer Family Registry.
Screening for germline MLH1, MSH2, MSH6, and PMS2 mutations was performed for all incident CRC cases recruited from cancer registries (population based probands) displaying microsatellite instability (MSI) or loss of expression of MMR genes by immunohistochemistry (IHC) and probands with CRC in multi-case families recruited from clinics (clinic based probands), regardless of MSI or IHC status. All relatives of probands with a pathogenic mutation who donated a blood sample underwent testing for the mutation identified in the proband.
Of 261 probands (202 clinic based, 59 population based) with MMR gene mutations for whom it was possible to determine the origin of the mutation, six (2.3%, 95% CI 0.9% to 5.0%) were confirmed as de novo, and the remaining 255 (97.7%, 95% CI 95.0% to 99.1%) were inherited. Of the de novo mutation carriers, three were clinic based probands (1.5%, 95% CI 0.3% to 4.5%) and three were population based probands (5.1%, 95% CI 1.2% to 14.5%). Two were in MLH1, three in MSH2, and one in MSH6.
De novo MMR gene mutations are uncommon causes of Lynch syndrome.
携带 DNA 错配修复 (MMR) 基因种系突变的个体——即林奇综合征患者——结直肠癌 (CRC)、子宫内膜癌和其他几种癌症的风险显著升高。种系突变并非来自父母遗传的新突变（de novo mutation）的比例尚不清楚。本研究报告了 MMR 基因中发生的一系列新突变病例，并使用结肠癌家族登记处（Colon Cancer Family Registry）估计了 MMR 基因中新突变的频率。
对所有从癌症登记处招募的表现出微卫星不稳定（MSI）或 MMR 基因免疫组化（IHC）表达缺失的新发 CRC 病例（基于人群的先证者）以及从诊所招募的多例家族性 CRC 先证者（基于诊所的先证者）进行种系 MLH1、MSH2、MSH6 和 PMS2 突变筛查，无论 MSI 或 IHC 状态如何。先证者携带致病性突变且捐赠血液样本的所有亲属均接受了先证者所携带突变的检测。
在 261 名 MMR 基因突变的先证者（202 名基于诊所，59 名基于人群）中，有 6 名（2.3%，95%置信区间为 0.9%至 5.0%）被确认为新突变，其余 255 名（97.7%，95%置信区间为 95.0%至 99.1%）为遗传突变。在新突变携带者中，有 3 名是基于诊所的先证者（1.5%，95%置信区间为 0.3%至 4.5%），3 名是基于人群的先证者（5.1%，95%置信区间为 1.2%至 14.5%）。其中 2 人 MLH1 突变，3 人 MSH2 突变，1 人 MSH6 突变。
MMR 基因突变是林奇综合征的罕见病因。
