Colorectal cancer (CRC) development is generally accepted as a sequential process, with genetic mutations determining phenotypic tumor progression. However, matching genetic profiles with histological transition requires the analyses of temporal samples from the same patient at key stages of progression. Here, we compared the genetic profiles of 34 early carcinomas with their respective adenomatous precursors to assess timing and heterogeneity of driver alterations accompanying the switch from benign adenoma to malignant carcinoma. In almost half of the cases, driver mutations specific to the carcinoma stage were not observed. In samples where carcinoma-specific alterations were present, TP53 mutations and chromosome 20 copy gains commonly accompanied the switch from adenomatous tissue to carcinoma. Remarkably, 40% and 50% of high-grade adenomas shared TP53 mutations and chromosome 20 gains, respectively, with their matched carcinomas. In addition, multi-regional analyses revealed greater heterogeneity of driver mutations in adenomas compared to their matched carcinomas. Genetic alterations in TP53 and chromosome 20 occur at the earliest histological stage in colorectal carcinomas (pTis and pT1). However, high-grade adenomas can share these alterations despite their histological distinction. Based on the well-defined sequence of CRC development, we suggest that the timing of genetic changes during neoplastic progression is frequently uncoupled from histological progression.

中文翻译：

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在大肠癌的早期进展中，恶性转化和遗传改变是不相关的。

大肠癌（CRC）的发展通常被认为是一个顺序过程，其遗传突变决定了表型肿瘤的进展。但是，要使遗传图谱与组织学转变相匹配，就需要分析同一患者处于进展关键阶段的时间样本。在这里，我们比较了34种早期癌及其各自的腺瘤前体的遗传特征，以评估伴随从良性腺瘤向恶性癌转变的驱动程序改变的时机和异质性。在几乎一半的情况下，未观察到特定于癌症阶段的驱动程序突变。在存在癌特异性改变的样品中，TP53突变和20号染色体复制获得通常伴随着从腺瘤组织向癌的转变。值得注意的是 40％和50％的高级腺瘤与其匹配的癌分别共享TP53突变和20号染色体增益。此外，多区域分析显示，与匹配癌相比，腺瘤中驱动突变的异质性更高。TP53和20号染色体的遗传改变发生在大肠癌（pTis和pT1）的最早的组织学阶段。然而，高级腺瘤尽管具有组织学上的区别，却可以共享这些改变。基于明确定义的CRC发育序列，我们建议在肿瘤进展期间进行基因改变的时机通常与组织学进展无关。多区域分析显示，与匹配癌相比，腺瘤中驱动突变的异质性更高。TP53和20号染色体的遗传改变发生在大肠癌（pTis和pT1）的最早的组织学阶段。然而，高级腺瘤尽管具有组织学上的区别，却可以共享这些改变。基于明确定义的CRC发育序列，我们建议在肿瘤进展期间进行基因改变的时机通常与组织学进展无关。多区域分析显示，与匹配癌相比，腺瘤中驱动突变的异质性更高。TP53和20号染色体的遗传改变发生在大肠癌（pTis和pT1）的最早的组织学阶段。然而，高级腺瘤尽管具有组织学上的区别，却可以共享这些改变。基于明确定义的CRC发育序列，我们建议在肿瘤进展期间进行基因改变的时机通常与组织学进展无关。