Find results with:

Add another field

Search by date

to

Searching collections:

Dartmouth Dissertations

Add or remove collections

Home Dartmouth Dissertations Page 1

Reference URL

To link to the entire object, paste this link in email, IM or document

To embed the entire object, paste this HTML in website

To link to this page, paste this link in email, IM or document

To embed this page, paste this HTML in website

Dissecting the heterogeneity of breast tumor subtypes / by Nima Pouladi.

you wish to report:

Your comment:

Your Name:

Submit

Cancel

...

Back to top

Powered by CONTENTdm®

Author	Pouladi, Nima.
Title	Dissecting the heterogeneity of breast tumor subtypes / by Nima Pouladi.
Date	2014
Abstract	Breast cancer is the most common cancer in women. The discovery of breast tumor subtypes and the subsequent development of treatments aimed at them has allowed a reduction in the mortality of breast cancer. However, tumors with similar characteristics continue to respond differently to the same treatment. Thus, further dissection of breast cancer heterogeneity is necessary and several challenges remain unanswered or unaddressed. First, although tumors are heterogeneous it is not clear whether all tumor traits share similar degrees of heterogeneity. Conversely, we may be missing individual traits that are highly heterogeneous among a majority of homogenous traits in tumor classes we believe to understand. Second, it is not obvious how we can find sets of genes that are integral to the tumor biology i.e. traits that are not allowed be heterogeneous. The identification of traits that are constrained in tumor evolution could allow us to reign the tumor's biology more effectively. Third, to date tumor traits have been identified through a variety of measures, but whether traits can be defined solely on the basis of their heterogeneity remains unaddressed. When defined in this manner, it is unclear which tumor traits could be most variable within each subtype, thus contributing disproportionately to intra-subtype heterogeneity. In order to address these three challenges, we re-analyzed previously generated microarray gene expression data from hundreds of breast tumors. Our analytic approaches employ methods developed in the fields of network theory, ecology and evolutionary biology. We address the first challenge by showing that breast cancer heterogeneity is contained in gene modules. This modular heterogeneity increases monotonically across subtypes. We identify a core of two modules that are shared among all subtypes and a number of subtype-specific modules. The genes contained by the core are involved in nucleosome assembly and mammary morphogenesis. Furthermore, our analysis shows that a higher degree of global heterogeneity does not imply a high heterogeneity for all modules. Therefore, tumor traits show independence from each other in their degree of heterogeneity. We then address the second challenge by quantifying the relative degree of constraint for tumor traits. We do this in triple negative breast cancer (TNBC); the subtype which has the poorest prognosis. We also examine how strongly tumor traits are interconnected. In this manner, we show that the module for cellular immune responses has the highest degree of integration. This implies that its genes are tightly controlled and we therefore propose this module as a bridle through which to exert control over TNBC biology. Finally, we address the third challenge by identifying and functionally characterizing sets of genes based on their heterogeneity. We catalogue these variable tumor traits across all subtypes and show that their order of variability is subtype-specific. Through these three projects we lay a foundation for the rigorous dissection of tumor heterogeneity across the vast space of the transcriptome. In doing so we identify and rank sets of genes for their potential utility in further dissecting or more effectively treating specific breast cancer subtypes
Description	xi, 227 leaves : ill. (mostly col.)
Format	application/pdf
College	Dartmouth Medical School. Department of Genetics.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1205

Find results with:

Searching collections:

Home Dartmouth Dissertations Page 1

Dissecting the heterogeneity of breast tumor subtypes / by Nima Pouladi.

Object Description

Description

Dissecting the heterogeneity of breast tumor subtypes / by...

Dissecting the heterogeneity of breast tumor subtypes / by...

	All
	Pages Enter page numbers or page ranges separated by commas. For example: 1,3,5-12