Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis
Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis
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DOI：
10.1007/s10689-016-9870-z
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发表时间：
2016-04-01
期刊：
影响因子：
2.2
通讯作者：
Aretz, Stefan
中科院分区：
文献类型：
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作者：
Spier, Isabel;Kerick, Martin;Aretz, Stefan
在高达30%的结直肠腺瘤性息肉病患者中，在已知基因APC（引起家族性腺瘤性息肉病）、MUTYH（引起MUTYH相关息肉病）和POLE或POLD 1（引起聚合酶校正相关息肉病）中没有发现种系突变，尽管可能存在遗传病因。为了发现新的致病基因，使用白细胞和来自7名不明原因的散发性腺瘤性息肉病患者的共12个结直肠腺瘤的DNA进行外显子组测序。对于数据分析和变体过滤，应用了包括内部工具在内的已建立的生物信息学管道。假设遗传的显性、隐性或肿瘤抑制模型，筛选罕见截短点突变和拷贝数变异的变异体。随后，在191名无关患者的验证队列中对最有希望的候选基因进行靶向序列分析。通过桑格测序验证所有相关变体。外显子组测序数据的分析导致在三个有希望的候选基因（DSC2，PIEZO 1，PIEWIM 7）中鉴定出罕见的功能丧失性种系突变。在验证队列中，在DSC 2和PIEZO 1中鉴定了预测为致病性的其他变体。根据体细胞突变谱，该患者队列中的腺瘤遵循结直肠肿瘤发生的经典途径。目前的研究确定了三个候选基因，这可能是导致结直肠腺瘤形成的罕见原因。特别是PIEZO 1（FAM 38A）和PIEWIM 7（SWS1）值得进一步研究。为了评估这些基因的临床相关性，需要对更大的患者队列和功能研究进行调查。
In up to 30 % of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, and POLE or POLD1, causing Polymerase-Proofreading-associated polyposis can be identified, although a hereditary etiology is likely. To uncover new causative genes, exome sequencing was performed using DNA from leukocytes and a total of 12 colorectal adenomas from seven unrelated patients with unexplained sporadic adenomatous polyposis. For data analysis and variant filtering, an established bioinformatics pipeline including in-house tools was applied. Variants were filtered for rare truncating point mutations and copy-number variants assuming a dominant, recessive, or tumor suppressor model of inheritance. Subsequently, targeted sequence analysis of the most promising candidate genes was performed in a validation cohort of 191 unrelated patients. All relevant variants were validated by Sanger sequencing. The analysis of exome sequencing data resulted in the identification of rare loss-of-function germline mutations in three promising candidate genes (DSC2, PIEZO1, ZSWIM7). In the validation cohort, further variants predicted to be pathogenic were identified in DSC2 and PIEZO1. According to the somatic mutation spectra, the adenomas in this patient cohort follow the classical pathways of colorectal tumorigenesis. The present study identified three candidate genes which might represent rare causes for a predisposition to colorectal adenoma formation. Especially PIEZO1 (FAM38A) and ZSWIM7 (SWS1) warrant further exploration. To evaluate the clinical relevance of these genes, investigation of larger patient cohorts and functional studies are required.