Linhart Heinz, Bormann Felix, Hutter Barbara, Brors Benedikt, Lyko Frank
Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Asklepios Klinik Lindau, 88131 Lindau, Germany.
Cold Spring Harb Mol Case Stud. 2017 May;3(3):a001610. doi: 10.1101/mcs.a001610.
Colon polyps represent precursor lesions of colon cancers and their malignant potential varies according to histological subtype. A rare subtype of colon polyps is the Peutz-Jeghers (PJ) polyp. PJ polyps mostly occur in the context of Peutz-Jeghers syndrome, which is characterized by the development of multiple polyps in the intestinal tract and hyperpigmentation of oral mucosa and lips. Peutz-Jeghers is an autosomal dominant disorder caused by pathogenic variants of the serine threonine kinase STK11. PJ polyps very rarely occur outside of the syndrome and are then referred to as solitary PJ polyps. Contrary to the situation in Peutz-Jeghers, the genetic basis and the malignant potential of solitary PJ polyps are currently unknown. Here we describe a detailed and comprehensive genetic profile of a solitary PJ polyp. Pathological examination revealed a high tissue homogeneity with >80% epithelial cells. Whole-genome sequencing failed to identify any clonal mutations but demonstrated a significant number of subclonal mutations. No somatic or germline mutations were found at the locus, suggesting that solitary PJ polyps are genetically distinct from Peutz-Jeghers polyps. In addition, methylome analysis revealed global hypomethylation and CpG island hypermethylation, two features that have been described as hallmarks of the colorectal cancer epigenome. These results provide an example of a premalignant lesion that is defined by epigenetic, rather than genetic changes. Furthermore, our findings support the notion that solitary PJ polyps constitute neoplastic tissue with malignant potential that should be removed for cancer prevention.
结肠息肉是结肠癌的前驱病变，其恶性潜能因组织学亚型而异。结肠息肉的一种罕见亚型是黑斑息肉病（PJ）息肉。PJ息肉大多发生在黑斑息肉综合征的背景下，其特征是肠道内出现多个息肉以及口腔黏膜和嘴唇色素沉着。黑斑息肉病是一种常染色体显性疾病，由丝氨酸苏氨酸激酶STK11的致病变异引起。PJ息肉在该综合征之外非常罕见，此时被称为孤立性PJ息肉。与黑斑息肉病的情况相反，孤立性PJ息肉的遗传基础和恶性潜能目前尚不清楚。在此，我们描述了一个孤立性PJ息肉的详细且全面的基因图谱。病理检查显示组织同质性高，上皮细胞>80%。全基因组测序未能识别出任何克隆性突变，但显示出大量亚克隆性突变。在该位点未发现体细胞或种系突变，这表明孤立性PJ息肉在基因上与黑斑息肉病息肉不同。此外，甲基化组分析揭示了整体低甲基化和CpG岛高甲基化，这两个特征已被描述为结直肠癌表观基因组的标志。这些结果提供了一个由表观遗传而非基因变化定义的癌前病变的例子。此外，我们的研究结果支持这样一种观点，即孤立性PJ息肉构成具有恶性潜能的肿瘤组织，为预防癌症应将其切除。
