---
_id: '1400'
abstract:
- lang: eng
text: Cancer results from an uncontrolled growth of abnormal cells. Sequentially
accumulated genetic and epigenetic alterations decrease cell death and increase
cell replication. We used mathematical models to quantify the effect of driver
gene mutations. The recently developed targeted therapies can lead to dramatic
regressions. However, in solid cancers, clinical responses are often short-lived
because resistant cancer cells evolve. We estimated that approximately 50 different
mutations can confer resistance to a typical targeted therapeutic agent. We find
that resistant cells are likely to be present in expanded subclones before the
start of the treatment. The dominant strategy to prevent the evolution of resistance
is combination therapy. Our analytical results suggest that in most patients,
dual therapy, but not monotherapy, can result in long-term disease control. However,
long-term control can only occur if there are no possible mutations in the genome
that can cause cross-resistance to both drugs. Furthermore, we showed that simultaneous
therapy with two drugs is much more likely to result in long-term disease control
than sequential therapy with the same drugs. To improve our understanding of the
underlying subclonal evolution we reconstruct the evolutionary history of a patient's
cancer from next-generation sequencing data of spatially-distinct DNA samples.
Using a quantitative measure of genetic relatedness, we found that pancreatic
cancers and their metastases demonstrated a higher level of relatedness than that
expected for any two cells randomly taken from a normal tissue. This minimal amount
of genetic divergence among advanced lesions indicates that genetic heterogeneity,
when quantitatively defined, is not a fundamental feature of the natural history
of untreated pancreatic cancers. Our newly developed, phylogenomic tool Treeomics
finds evidence for seeding patterns of metastases and can directly be used to
discover rules governing the evolution of solid malignancies to transform cancer
into a more predictable disease.
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Johannes
full_name: Reiter, Johannes
id: 4A918E98-F248-11E8-B48F-1D18A9856A87
last_name: Reiter
orcid: 0000-0002-0170-7353
citation:
ama: Reiter J. The subclonal evolution of cancer. 2015.
apa: Reiter, J. (2015). The subclonal evolution of cancer. Institute of Science
and Technology Austria.
chicago: Reiter, Johannes. “The Subclonal Evolution of Cancer.” Institute of Science
and Technology Austria, 2015.
ieee: J. Reiter, “The subclonal evolution of cancer,” Institute of Science and Technology
Austria, 2015.
ista: Reiter J. 2015. The subclonal evolution of cancer. Institute of Science and
Technology Austria.
mla: Reiter, Johannes. The Subclonal Evolution of Cancer. Institute of Science
and Technology Austria, 2015.
short: J. Reiter, The Subclonal Evolution of Cancer, Institute of Science and Technology
Austria, 2015.
date_created: 2018-12-11T11:51:48Z
date_published: 2015-04-01T00:00:00Z
date_updated: 2023-09-07T11:40:44Z
day: '01'
degree_awarded: PhD
department:
- _id: KrCh
language:
- iso: eng
month: '04'
oa_version: None
page: '183'
publication_identifier:
issn:
- 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
publist_id: '5807'
related_material:
record:
- id: '1709'
relation: part_of_dissertation
status: public
- id: '2000'
relation: part_of_dissertation
status: public
- id: '2247'
relation: part_of_dissertation
status: public
- id: '2816'
relation: part_of_dissertation
status: public
- id: '2858'
relation: part_of_dissertation
status: public
- id: '3157'
relation: part_of_dissertation
status: public
- id: '3260'
relation: part_of_dissertation
status: public
status: public
supervisor:
- first_name: Krishnendu
full_name: Chatterjee, Krishnendu
id: 2E5DCA20-F248-11E8-B48F-1D18A9856A87
last_name: Chatterjee
orcid: 0000-0002-4561-241X
title: The subclonal evolution of cancer
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2015'
...