Impact of tumor progression on cancer incidence curves.
Impact of tumor progression on cancer incidence curves.
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DOI：
10.1158/0008-5472.can-12-2198
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发表时间：
2013-02-01
期刊：
影响因子：
11.2
通讯作者：
Hazelton WD
中科院分区：
文献类型：
--
作者：
Luebeck EG;Curtius K;Jeon J;Hazelton WD
癌症的发生是一个多阶段的过程，但这一过程如何影响特定年龄段的发病率曲线尚不完全清楚。用多阶段克隆扩增(MSCE)模型对结直肠癌和胰腺癌的研究发现，发病曲线有两个阶段。其中一个阶段大约在60岁左右呈线性开始，这表明至少有两个罕见的限速突变发生在癌前细胞的克隆性扩张之前。第二阶段是指数阶段，见于60岁之前发生的较早发病的癌症，与癌前克隆性扩张有关。在这里，我们将MSCE模型扩展到包括恶性细胞的克隆性扩增，这一进展允许研究肿瘤生长和消退对消化道结直肠癌、胃腺癌、胰腺癌和食管腺癌发病率的影响。在调整出生队列和历年趋势的特定年龄发病率后，我们发现启动突变和癌前细胞动力学可以解释发病率曲线的主要特征。然而，我们也发现，在临床检测之前，这些癌症的发病率数据包含了关于恶性克隆扩张动力学的信息，包括肿瘤生长速度和肿瘤进展的三个特征时间尺度上的消亡概率。此外，数据还保存了前恶性克隆的平均逗留时间的信息，直到出现第一个恶性细胞或第一个持续的(存活的)恶性克隆。最后，数据还保存了持续恶性克隆的平均逗留时间到诊断时间的信息。综上所述，肿瘤发病曲线可以包含关于肿瘤发生、癌前克隆扩张和恶变等隐藏过程的重要信息，甚至可以在临床发现之前包含一些关于肿瘤生长的有限信息。
Cancer arises through a multistage process, but it is not fully clear how this process influences the age-specific incidence curve. Studies of colorectal and pancreatic cancer using the multistage-clonal-expansion (MSCE) model have identified two phases of the incidence curves. One phase is linear beginning about age of 60, suggesting that at least two rare rate-limiting mutations occur prior to clonal expansion of premalignant cells. A second phase is exponential, seen in earlier-onset cancers occurring before the age of 60 that are associated with premalignant clonal expansion. Here we extend the MSCE model to include clonal expansion of malignant cells, an advance that permits study of the effects of tumor growth and extinction on the incidence of colorectal, gastric, pancreatic and esophageal adenocarcinomas in the digestive tract. After adjusting the age-specific incidence for birth-cohort and calendar-year trends, we found that initiating mutations and premalignant cell kinetics can explain the primary features of the incidence curve. However, we also found that the incidence data of these cancers harbored information on the kinetics of malignant clonal expansion prior to clinical detection, including tumor growth rates and extinction probabilities on three characteristic time scales for tumor progression. Additionally, the data harbored information on the mean sojourn times for prema-lignant clones until occurrence of either the first malignant cell or the first persistent (surviving) malignant clone. Lastly, the data also harbored information on the mean sojourn time of persistent malignant clones to the time of diagnosis. In conclusion, cancer incidence curves can harbor significant information about hidden processes of tumor initiation, premalignant clonal expansion and malignant transformation, and even some limited information on tumor growth before clinical detection.