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Gottlieb et al. J Cancer Metastasis Treat 2018;4:37 Journal of Cancer
DOI: 10.20517/2394-4722.2018.26 Metastasis and Treatment

Original Article Open Access

New insights into the role of intra-tumor genetic
heterogeneity in carcinogenesis: identification of

complex single gene variance within tumors

Bruce Gottlieb 1,2,3 , Farbod Babrzadeh , Kathleen Klein Oros , Carlos Alvarado , Chunlin Wang , Baback
1
4
1
4
Gharizadeh , Mark Basik , Celia M.T. Greenwood , Lenore K. Beitel 1,3,5 , Mark Trifiro 1,2,3,5
4
1
2,5
1 Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
2 Segal Cancer Centre, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
3 Department of Human Genetics, McGill University, Montreal, QC H3A 0G4, Canada.
4 Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA.
5 Department of Medicine, McGill University, Montreal, QC H3A 0G4, Canada.
Correspondence to: Dr. Bruce Gottlieb, Lady Davis Institute for Medical Research, 3755 Côte Ste Catherine Road, Montreal, QC
H3T 1E2, Canada. E-mail: bruce.gottlieb@mcgill.ca
How to cite this article: Gottlieb B, Babrzadeh F, Oros KK, Alvarado C, Wang C, Gharizadeh B, Basik M, Greenwood CMT, Beitel
LK, Trifiro M. New insights into the role of intra-tumor genetic heterogeneity in carcinogenesis: identification of complex single
gene variance within tumors. J Cancer Metastasis Treat 2018;4:37. http://dx.doi.org/10.20517/2394-4722.2018.26

Received: 14 Apr 2018 First Decision: 28 May 2018 Revised: 9 Jun 2018 Accepted: 12 Jun 2018 Published: 19 Jul 2018

Science Editors: Yi-Hong Zhou Copy Editor: Jun-Yao Li Production Editor: Huan-Liang Wu

Abstract
Aim: Present cancer hypotheses are almost all based on the concept that accumulation of specific driver gene mutations
cause carcinogenesis. The discovery of intra-tumor genetic heterogeneity (ITGH), has resulted in this hypothesis being
modified by assuming that most of these ITGH mutations are in passenger genes. In addition, accumulating ITGH
data on driver gene mutations have revealed considerable genotype/phenotype disconnects. This study proposes to
investigate this disconnect by examining the nature and degree of ITGH in breast tumors.

Methods: ITGH was examined in tumors using next generation sequencing of up to 68,000 reads and analysis tools that
allowed for identification of distinct minority variants within single genes, i.e., complex single gene variance (CSGV).

Results: CSGV was identified in the androgen receptor genes in all breast tumors examined.

Conclusion: Evidence of CSGV suggests that a selection - as opposed to a mutation - centric hypothesis could better
explain carcinogenesis. Our hypothesis proposes that tumors develop by the selection of preexisting de novo mutations
rather than just the accumulation of de novo mutations. Thus, the role of selection pressures, such as changes in tissue
microenvironments will likely be critical to our understanding of tumor resistance as well as the development of more
effective treatment protocols.

© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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