Determining the frequency of de novo germline mutations in DNA mismatch repair genes.
Determining the frequency of de novo germline mutations in DNA mismatch repair genes.
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DOI：
10.1136/jmedgenet-2011-100082
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发表时间：
2011-08
影响因子：
4
通讯作者：
Lindor NM
中科院分区：
文献类型：
--
作者：
Win AK;Jenkins MA;Buchanan DD;Clendenning M;Young JP;Giles GG;Goldblatt J;Leggett BA;Hopper JL;Thibodeau SN;Lindor NM
DNA错配修复（MMR）基因的生殖系突变携带者，即林奇综合征患者，患结直肠癌（CRC）、子宫内膜癌和其他几种癌症的风险很高。有新生突变（不是从父母任何一方遗传的）的携带者的比例尚不清楚。本研究报告了一系列MMR基因新发突变的病例，并使用结肠癌家族登记估计了MMR基因新发突变的频率。对从癌症登记处招募的所有通过免疫组织化学（IHC）显示微卫星不稳定性（MSI）或MMR基因表达缺失的CRC病例（基于人群的先证者）和从诊所招募的多病例家族中的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。所有具有致病性突变的先证者的亲属捐献血液样本，进行先证者中确定的突变检测。在261例MMR基因突变的先证者（202例基于临床，59例基于人群）中，有6例（2.3%，95% CI 0.9%至5.0%）被证实为新发，其余255例（97.7%，95% CI 95.0%至99.1%）为遗传性。在新发突变携带者中，3名是基于临床的先证者（1.5%，95%CI 0.3%至4.5%），3名是基于人群的先证者（5.1%，95%CI 1.2%至14.5%）。两个在MLH1中，三个在MSH2中，一个在MSH6中。新生MMR基因突变是Lynch综合征的罕见原因。
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.
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影响因子：
45.3
作者：
Southey, MC;Jenkins, MA;Hopper, JL
通讯作者：
Hopper, JL
影响因子：
1.8
作者：
Agresti, A;Coull, BA
通讯作者：
Coull, BA
影响因子：
24.5
作者：
Woods MO;Younghusband HB;Parfrey PS;Gallinger S;McLaughlin J;Dicks E;Stuckless S;Pollett A;Bapat B;Mrkonjic M;de la Chapelle A;Clendenning M;Thibodeau SN;Simms M;Dohey A;Williams P;Robb D;Searle C;Green JS;Green RC
通讯作者：
Green RC
影响因子：
120.7
作者：
Chen, Sining;Wang, Wenyi;Parmigiani, Giovanni
通讯作者：
Parmigiani, Giovanni
影响因子：
2.4
作者：
M端ller, A;Fishel, R
通讯作者：
Fishel, R