Number and size distribution of colorectal adenomas under the multistage clonal expansion model of cancer.
Number and size distribution of colorectal adenomas under the multistage clonal expansion model of cancer.
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DOI：
10.1371/journal.pcbi.1002213
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发表时间：
2011-10
影响因子：
4.3
通讯作者：
Luebeck EG
中科院分区：
文献类型：
--
作者：
Dewanji A;Jeon J;Meza R;Luebeck EG
结直肠癌（CRC）被认为是由结肠隐窝中的突变干细胞引起的，该突变干细胞经历了一个典型的进展，包括良性腺瘤，浸润性癌的前体。虽然许多遗传事件已被确定为这一过程的驱动因素，但从腺瘤的首次出现到最终转化为恶性癌症的分阶段进展的动力学知之甚少。当腺瘤在内窥镜下可以检测到时（即直径在1-2毫米范围内），腺瘤已经由数十万个细胞组成，可能已经存在了几年甚至几十年。因此，很大一部分腺瘤实际上可能在内窥镜筛查中未被发现，至少在原则上，可能在被发现之前就已经发展成癌症。因此，确定腺瘤可检出的比例是很重要的，这既与结肠肿瘤筛查的时间有关，也与可达到的检出限有关。为此，我们基于最近发展的CRC随机模型推导出可检测腺瘤数量和大小分布的数学表达式。我们的结果和使用这些表达的插图表明：(1)筛选效果严重依赖于检测阈值和对腺瘤中相关干细胞部分的隐性知识；(2)假设合理的检测阈值和细胞分裂率，很大一部分未灭绝的腺瘤仍然可能未被检测到；(3)在腺瘤的发生、生长和进展到CRC的现实描述下，腺瘤的经验患病率可能是膨胀的病变，而不是在途径上的癌症。腺瘤性息肉（或腺瘤）被认为是结直肠癌（CRC）的常见前体病变。尽管腺瘤的自然历史在其组织病理学和（epi）基因组变化方面具有很好的特征，但从腺瘤的首次出现到其转化为恶性癌症的分期进展中，人们对其动力学知之甚少。当腺瘤在内窥镜下可以检测到时（即直径在1-2毫米范围内），腺瘤已经由数十万个细胞组成。因此，在筛查过程中，很大一部分腺瘤可能未被发现，尽管它们的体积很小（低于阈值），但可能在被发现之前就发展为癌症。因此，确定可检测到的腺瘤比例是很重要的，这既与筛查结直肠肿瘤时的年龄有关，也与可可靠检测到的腺瘤大小（阈值）有关。在这里，我们基于最近开发的CRC随机模型推导出腺瘤数量和大小分布的数学表达式，该模型先前已根据年龄特异性CRC发病率数据进行校准和验证。
Colorectal cancer (CRC) is believed to arise from mutant stem cells in colonic crypts that undergo a well-characterized progression involving benign adenoma, the precursor to invasive carcinoma. Although a number of (epi)genetic events have been identified as drivers of this process, little is known about the dynamics involved in the stage-wise progression from the first appearance of an adenoma to its ultimate conversion to malignant cancer. By the time adenomas become endoscopically detectable (i.e., are in the range of 1–2 mm in diameter), adenomas are already comprised of hundreds of thousands of cells and may have been in existence for several years if not decades. Thus, a large fraction of adenomas may actually remain undetected during endoscopic screening and, at least in principle, could give rise to cancer before they are detected. It is therefore of importance to establish what fraction of adenomas is detectable, both as a function of when the colon is screened for neoplasia and as a function of the achievable detection limit. To this end, we have derived mathematical expressions for the detectable adenoma number and size distributions based on a recently developed stochastic model of CRC. Our results and illustrations using these expressions suggest (1) that screening efficacy is critically dependent on the detection threshold and implicit knowledge of the relevant stem cell fraction in adenomas, (2) that a large fraction of non-extinct adenomas remains likely undetected assuming plausible detection thresholds and cell division rates, and (3), under a realistic description of adenoma initiation, growth and progression to CRC, the empirical prevalence of adenomas is likely inflated with lesions that are not on the pathway to cancer. The adenomatous polyp (or adenoma) is considered the common precursor lesion for colorectal cancer (CRC). Although the natural history of adenomas is well-characterized in terms of their histopathology and (epi)genomic changes, little is known about their dynamics in the stage-wise progression from the first appearance of an adenoma to its conversion to malignant cancer. By the time adenomas become endoscopically detectable (i.e., are in the range of 1–2 mm in diameter), adenomas are already comprised of hundreds of thousands of cells. A large fraction of adenomas may therefore remain undetected during screening and, in spite of their small (subthreshold) size, could give rise to cancer prior to being detected. It is therefore of importance to establish what fraction of adenomas is detectable, both as a function of the age at screening for colorectal neoplasia and the size (threshold) above which adenomas can be detected reliably. Here we derive mathematical expressions for the distribution of adenoma number and sizes based on a recently developed stochastic model for CRC, which has previously been calibrated and validated against age-specific CRC incidence data.
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DOI：
10.1073/pnas.222118199
发表时间：
2002-11-12
影响因子：
11.1
作者：
Luebeck, EG;Moolgavkar, SH
通讯作者：
Moolgavkar, SH
影响因子：
11.2
作者：
Meza, Rafael;Jeon, Jihyoun;Luebeck, E. Georg
通讯作者：
Luebeck, E. Georg
影响因子：
11.2
作者：
Enderling, Heiko;Anderson, Alexander R. A.;Hahnfeldt, Philip
通讯作者：
Hahnfeldt, Philip
DOI：
10.1073/pnas.0712345105
发表时间：
2008-03-18
影响因子：
11.1
作者：
Jones, Sian;Chen, Wei-dong;Markowitz, Sanford D.
通讯作者：
Markowitz, Sanford D.
影响因子：
4.3
作者：
Meza, R;Luebeck, EG;Moolgavkar, SH
通讯作者：
Moolgavkar, SH