Molecular classification and genetic pathways in hyperplastic polyposis syndrome
Molecular classification and genetic pathways in hyperplastic polyposis syndrome
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DOI：
10.1002/path.2187
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发表时间：
2007-08-01
影响因子：
7.3
通讯作者：
Tomlinson, I. P. M.
中科院分区：
文献类型：
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作者：
Carvajal-Carmona, L. G.;Howarth, K. M.;Tomlinson, I. P. M.
增生性息肉病(HPPS)是一种特征不佳的综合征，会增加结直肠癌(CRC)的风险。我们的目的是提供一种HPP的分子分类。我们从32例疑似HPP患者中获得了282个肿瘤，这些患者中有10个增生性息肉(HPS)；一些患者也有腺瘤和癌。我们在我们的样本中没有发现微卫星不稳定(MSI)的良好证据。HPS上皮为单克隆性。我们的患者三分之二的HPS中发生了体细胞BRAF突变，10%的患者发生了KPAS2突变；这两种突变在年轻患者中更常见。一组散发性HPS的突变频率分别为18%和10%。重要的是，假定的HPPS患者通常分为两组，一组息肉有BRAF突变，另一组息肉有KRAS2突变。对这一观察结果最合理的解释是，存在不同形式的HPP遗传易感性，这些遗传易感性决定了息肉是遵循BRAF还是KRAS2途径。我们推测的HPPS患者的大多数腺瘤和癌细胞具有典型的形态，这些病变中很少有BRAF或KKAS2突变。这些发现表明，HPP中的肿瘤发生并不一定遵循“锯齿状”途径。虽然目前对HPPs的定义不太理想，但我们认为分子分析有助于诊断。具体地说，在多发性息肉中检测BRAF和KRAS2突变，或许还有MSI，可能有助于区分HPP和散发性HPS。我们提出了一个特定的模型，与世界卫生组织的临床标准相比，该模型将多诊断我们的5例HPP病例。版权所有(C)2007年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Hyperplastic Polyposis (HPPS) is a poorly characterized syndrome that increases colorectal cancer (CRC) risk. We aimed to provide a molecular classification of HPPS. We obtained 282 tumours from 32 putative HPPS patients with >= 10 hyperplastic polyps (HPs); some patients also had adenomas and CRCs. We found no good evidence of microsatellite instability (MSI) in our samples. The epithelium of HPs was monoclonal. Somatic BRAF mutations occurred in two-thirds of our patients' HPs, and KPAS2 mutations in 10%; both mutations were more common in younger cases. The respective mutation frequencies in a set of 'sporadic' HPs were 18% and 10%. Importantly, the putative HPPS patients generally fell into two readily defined groups, one set whose polyps had BRAF mutations, and another set whose polyps had KRAS2 mutations. The most plausible explanation for this observation is that there exist different forms of inherited predisposition to HPPS, and that these determine whether polyps follow a BRAF or KRAS2 pathway. Most adenomas and CRCs from our putative HPPS patients had 'classical' morphology and few of these lesions had BRAF or KKAS2 mutations. These findings suggest that tumourigenesis in HPPS does not necessarily follow the 'serrated' pathway. Although current definitions of HPPS are sub-optimal, we suggest that diagnosis could benefit from molecular analysis. Specifically, testing BRAF and KRAS2 mutations, and perhaps MSI, in multiple polyps could help to distinguish HPPS from sporadic HPs. We propose a specific model which would have diagnosed five more of our cases as HPPS compared with the WHO clinical criteria. Copyright (C) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.