Increased frequency of disease-causing MYH mutations in colon cancer families
Increased frequency of disease-causing MYH mutations in colon cancer families
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DOI：
10.1093/carcin/bgl093
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发表时间：
2006-11-01
期刊：
影响因子：
4.7
通讯作者：
Ellis, Nathan A.
中科院分区：
文献类型：
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作者：
Peterlongo, Paolo;Mitra, Nandita;Ellis, Nathan A.
除错配修复（MMR）基因突变外，导致结直肠癌（crc）聚集的遗传因素尚不清楚。在缺乏MMR基因突变的家庭中聚集可能归因于低外显率突变。假设，单等位基因MYH突变可能导致这些家庭发生结直肠癌的风险。使用Fisher精确检验和逻辑回归，我们比较了来自三个或更多CRC但MMR基因突变阴性的家庭的137个先证（117例结直肠癌和20例仅根据腺瘤性息肉诊断）和967个具有相似种族背景的健康对照者中已知的致病MYH突变Y165C、G382D和466delE的频率。137例中，6例（4.4%）携带单等位基因MYH突变，而对照组967例中有16例（1.6%）携带单等位基因MYH突变。此外，在家谱结构与结直肠癌易感性显性遗传一致的家族中，也发现了三个双等位基因MYH突变携带者，最终发展为MYH相关的息肉病。通过Fisher精确检验，与对照组相比，任何MYH突变（单等位基因携带者或双等位基因携带者，P值= 0.002）和单等位基因MYH突变（P = 0.04）的病例频率有统计学差异。使用逻辑回归模型，与任何MYH突变相关的未经调整的优势比为4.14 (p值< 0.001)；单等位基因携带者为2.79 （p值= 0.04）。调整种族背景、性别和年龄后，与任何致病MYH突变相关的比值比为3.23 (p值= 0.01)；单等位基因携带者为1.99 （p值= 0.20）。总的来说，结果支持了先前的研究，即MYH的单等位基因突变构成了低外显率引起crc的等位基因。这些数据进一步支持了低外显率等位基因在MMR基因突变阴性的CRC家族中富集的模型。
The genetic factors that cause clustering of colorectal cancers (CRCs) other than mutations in the mismatch repair (MMR) genes are not well understood. Clustering in families who lack MMR gene mutations may be attributable to low-penetrance mutations. Hypothetically, mono-allelic MYH mutations could contribute to the risk of CRC in these families. Using Fisher's exact test and logistic regression, we compared the frequency of the known disease-causing MYH mutations Y165C, G382D and 466delE in 137 probands (117 cases with CRC and 20 cases diagnosed on the basis of adenomatous polyps only) from families with three or more CRCs but negative for mutations in the MMR genes and in 967 healthy controls with comparable ethnic backgrounds. Of 137 cases, 6 (4.4%) carried mono-allelic MYH mutations compared with 16 of 967 (1.6%) controls. In addition, three bi-allelic MYH mutation carriers, who eventually developed MYH-associated polyposis, were also identified in families with pedigree structures consistent with dominant inheritance of CRC susceptibility. By Fisher's exact tests, there was a statistically different frequency of cases with any MYH mutation (mono- or bi-allelic carriers; P-value = 0.002) and of cases with mono-allelic MYH mutation (P = 0.04) compared with the controls. Using a logistic regression model, the unadjusted odds ratio associated with any MYH mutation was 4.14 (P-value < 0.001); for mono-allelic carriers, it was 2.79 (P-value = 0.04). Adjusting for ethnic backgrounds, gender and age, the odds ratio associated with any disease-causing MYH mutation was 3.23 (P-value = 0.01); for mono-allelic carriers, it was 1.99 (P-value = 0.20). Overall, the results support previous studies suggesting that mono-allelic mutations of MYH constitute low-penetrance CRC-causing alleles. These data further support a model in which low-penetrance alleles are enriched in MMR gene mutation-negative CRC families.