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Gottlieb et al. J Cancer Metastasis Treat 2018;4:37 I http://dx.doi.org/10.20517/2394-4722.2018.26 Page 9 of 14

How can identifying CSGV in tumors contribute to our understanding of cancer genetics?
Clearly, the presence of CSGV within cancer tissues clashes with our present understanding that carcino-
genesis is the result of “purifying” selection pressure on single gene variants in a tumor that eventually will
[36]
lead to removal of all the non-selected variants of that gene . This argument in turn justifies being satisfied
with the identification of a single variant per gene, and therefore to ignore any other low frequency variants
within the same gene, on the assumption that they must be artifacts, possibly due to PCR or sequencing er-
rors. The recognition that a selection of different single gene variants can remain in individual tumors, is
clearly not in line with our present understanding of the occurrence and distribution of cancer mutations.
However, our present results would question the validity of this understanding as CSGV were identified in
the AR within all 6 breast tumors examined and suggests that the role of mutations in carcinogenesis is more
complex than previously thought.

How can identifying CSGV help in understanding treatment resistance?
First, it suggests a mechanism to explain how some tumors can become rapidly resistant to treatment by
proposing the existence of genetic variants that can be selected for in genes that have been targeted by che-
motherapy. Indeed, the selection of such variants could be a response to ensure the survival of cells that
[37]
contained the targeted gene as postulated by the atavistic model , which considers resistance of cancer cells
to treatment as one of their major characteristics. Second, it places much more emphasis on understanding
the role of selection pressures generated by different tissue microenvironments on carcinogenesis [38,39] . It also
suggests that analyzing the makeup of tissue microenvironments may facilitate the recognition of specific
factors involved in the selection of cancer-associated variants.

A different paradigm to explain carcinogenesis
The principle of “parsimony” has underwritten our understanding of science since the middle of the 19th
century by telling us to choose the simplest scientific explanation that fits (all) the observed evidence. In
studying the genetics of cancer this has been reflected in our belief that identifying common gene mutations
present in tumor tissues is one of the keys to understanding the ontology of solid tumors. However, the va-
lidity of this concept is being challenged by accumulating evidence of genetic diversity within individual tu-
mors, which this study has further expanded by revealing evidence of AR CSGV in breast tumors. As noted
previously, current cancer hypotheses are almost all based on the concept that accumulation of specific de
novo individual driver mutations within specific tissues can result in carcinogenesis. However, the lack of
a consistent relationship between driver mutations and cancer types and the discovery of the presence of
many different driver mutant genes within the same types of cancer tissues has resulted in complex genetic
profiles. These have effectively meant that many of these driver gene mutations have been reduced to risk
factors, albeit with significant clinical implications, rather than gene mutations that are directly responsible
for carcinogenesis.

Interestingly, such phenotype/genotype lack of precision has been found not just in multifactorial diseases
such as cancer, but in locus specific genetic disorders as well. For example, in certain locus specific diseases
a significant number of individuals that exhibit the disease phenotype do not have a mutation in the puta-
[24]
[40]
tive disease-causing gene, such as in the case of androgen insensitivity syndrome and PKU . Further, a
review of genotype-phenotype relationships in a wide range of genetic diseases has revealed many cases of
[41]
reduced or even zero penetrance . While whole genome sequencing studies have found individuals that
[42]
can have well known disease-causing gene mutations but do not exhibit the disease phenotypes including
[43]
cancer-associated genes in healthy individuals .
Other recent evidence has further complicated the genetics of cancer, by revealing the effect on cancer
phenotypes of processes such as epigenetic regulation, DNA and RNA editing, cellular differentiation hier-