A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer
A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer
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DOI：
10.1038/ng.3287
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发表时间：
2015-06-01
期刊：
影响因子：
30.8
通讯作者：
Hoogerbrugge, Nicoline
中科院分区：
文献类型：
--
作者：
Weren, Robbert D. A.;Ligtenberg, Marjolijn J. L.;Hoogerbrugge, Nicoline
在腺瘤性息肉病患者中，多发结肠腺瘤（结直肠癌的癌前前体）发生的遗传原因往往仍未得到解决。在这里，我们对来自48个家族的51例多发性结肠腺瘤患者进行了全外显子组测序。在来自三个不相关家族的七个受影响个体中，我们在碱基切除修复（BER）基因NTHL1中发现了纯合子无义突变。该突变仅在对照中以杂合状态存在（小等位基因频率为0.0036;n = 2329）。所有三个家族均表现出腺瘤性息肉病表型的隐性遗传，并在至少一个成员中进展为结直肠癌。所有三名受影响的妇女都发展为子宫内膜恶性肿瘤或恶性前病变。来自不同受影响个体的三种癌和五种腺瘤的遗传分析显示，细胞嘧啶向胸腺嘧啶转变的非高突变谱丰富。我们得出结论，NTHL1基因的纯合子功能缺失种系突变易导致bier相关腺瘤性息肉病和CRC的新亚型。
The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene NTHL1. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036; n = 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BIER-associated adenomatous polyposis and CRC.