Revisiting the tumorigenesis timeline with a data-driven generative model

被引：48

作者：

Lahouel, Kamel ^{[1
]}

Younes, Laurent ^{[2
]}

Danilova, Ludmila ^{[1
]}

Giardiello, Francis M. ^{[3
]}

Hruban, Ralph H. ^{[4
]}

Groopman, John ^{[5
]}

Kinzler, Kenneth W. ^{[6
,7
]}

Vogelstein, Bert ^{[6
,7
]}

Geman, Donald ^{[2
]}

Tomasetti, Cristian ^{[1
,8
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Div Biostat & Bioinformat,Dept Oncol, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Dept Appl Math & Stat, Baltimore, MD 21218 USA

[3] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA

[4] Johns Hopkins Univ, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21231 USA

[5] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth & Engn, Baltimore, MD 21231 USA

[6] Johns Hopkins Kimmel Canc Ctr, Ludwig Ctr, Baltimore, MD 21287 USA

[7] Johns Hopkins Kimmel Canc Ctr, Howard Hughes Med Inst, Baltimore, MD 21287 USA

[8] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2020年 / 117卷 / 02期

关键词：

cancer; driver genes; mutations; tumorigenesis; fitness; CANCER; MUTATIONS; TISSUES; COLON;

D O I：

10.1073/pnas.1914589117

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Cancer is driven by the sequential accumulation of genetic and epigenetic changes in oncogenes and tumor suppressor genes. The timing of these events is not well understood. Moreover, it is currently unknown why the same driver gene change appears as an early event in some cancer types and as a later event, or not at all, in others. These questions have become even more topical with the recent progress brought by genome-wide sequencing studies of cancer. Focusing on mutational events, we provide a mathematical model of the full process of tumor evolution that includes different types of fitness advantages for driver genes and carrying capacity considerations. The model is able to recapitulate a substantial proportion of the observed cancer incidence in several cancer types (colorectal, pancreatic, and leukemia) and inherited conditions (Lynch and familial adenomatous polyposis), by changing only 2 tissue-specific parameters: the number of stem cells in a tissue and its cell division frequency. The model sheds light on the evolutionary dynamics of cancer by suggesting a generalized early onset of tumorigenesis followed by slow mutational waves, in contrast to previous conclusions. Formulas and estimates are provided for the fitness increases induced by driver mutations, often much larger than previously described, and highly tissue dependent. Our results suggest a mechanistic explanation for why the selective fitness advantage introduced by specific driver genes is tissue dependent.

引用

页码：857 / 864

页数：8

共 44 条

[1]

Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma [J].