Institute of Radiation Medicine, Helmholtz Munich, Oberschleissheim, Germany.
Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
PLoS Comput Biol. 2023 Jan 23;19(1):e1010831. doi: 10.1371/journal.pcbi.1010831. eCollection 2023 Jan.
Colorectal adenoma are precursor lesions on the pathway to cancer. Their removal in screening colonoscopies has markedly reduced rates of cancer incidence and death. Generic models of adenoma growth and transition to cancer can guide the implementation of screening strategies. But adenoma shape has rarely featured as a relevant risk factor. Against this backdrop we aim to demonstrate that shape influences growth dynamics and cancer risk. Stochastic cell-based models are applied to a data set of 197,347 Bavarian outpatients who had colonoscopies from 2006-2009, 50,649 patients were reported with adenoma and 296 patients had cancer. For multi-stage clonal expansion (MSCE) models with up to three initiating stages parameters were estimated by fits to data sets of all shapes combined, and of sessile (70% of all adenoma), peduncular (17%) and flat (13%) adenoma separately for both sexes. Pertinent features of adenoma growth present themselves in contrast to previous assumptions. Stem cells with initial molecular changes residing in early adenoma predominantly multiply within two-dimensional structures such as crypts. For these cells mutation and division rates decrease with age. The absolute number of initiated cells in an adenoma of size 1 cm is small around 103, related to all bulk cells they constitute a share of about 10-5. The notion of very few proliferating stem cells with age-decreasing division rates is supported by cell marker experiments. The probability for adenoma transiting to cancer increases with squared linear size and shows a shape dependence. Compared to peduncular and flat adenoma, it is twice as high for sessile adenoma of the same size. We present a simple mathematical expression for the hazard ratio of interval cancers which provides a mechanistic understanding of this important quality indicator. We conclude that adenoma shape deserves closer consideration in screening strategies and as risk factor for transition to cancer.
结直肠腺瘤是癌症发生途径中的前体病变。在筛查结肠镜检查中切除这些腺瘤可显著降低癌症发病率和死亡率。腺瘤生长和向癌症转化的通用模型可以指导筛查策略的实施。但是，腺瘤的形状很少作为相关的危险因素出现。在此背景下，我们旨在证明形状会影响生长动态和癌症风险。我们应用随机细胞模型来分析 197347 名来自巴伐利亚州的门诊患者的数据，这些患者在 2006 年至 2009 年间接受了结肠镜检查，其中 50649 例报告有腺瘤，296 例有癌症。对于具有三个起始阶段的多阶段克隆扩张（MSCE）模型，通过将所有形状的数据集拟合到数据集中来估计参数，以及将息肉状（所有腺瘤的 70%）、带蒂（17%）和扁平（13%）腺瘤分别拟合到男女数据集中。与之前的假设相比，腺瘤生长的相关特征表现为，具有初始分子变化的干细胞主要在类器官等二维结构中倍增。对于这些细胞，突变和分裂率会随着年龄的增长而降低。大小为 1cm 的腺瘤中起始细胞的绝对数量很少，约为 10^3，与所有体细胞相比，它们构成了约 10^-5 的比例。随着年龄的增长，分裂率降低的增殖干细胞数量很少的观点得到了细胞标记实验的支持。腺瘤向癌症转化的概率随线性尺寸的平方增加而增加，并表现出形状依赖性。与带蒂和扁平腺瘤相比，相同大小的息肉状腺瘤的风险要高两倍。我们提出了一个用于计算间隔癌风险比的简单数学表达式，该表达式提供了对这一重要质量指标的机制理解。我们的结论是，在筛查策略中以及作为癌症转化的危险因素方面，腺瘤的形状值得更密切的考虑。
