NcXHF

SHLUSH AND HERSHKOVITZ
FIGURE 1. Tissue-specific Early Evolutionary Events versus Common Late Hallmarks of Cancer Events
Early mutations are tissue specific and increase the fitness of the cell of origin under a changing environment. Initial clonal expansion of functional cells will eventually lead to changes in the
environment that will in turn lead to selective pressure for the various hallmarks of cancer. Mutations (X,Y,Z) that have accumulated in the premalignant clones will be selected and gradually
reduce the functionality of the cell of origin.
Abbreviations: AML, acute myeloid leukemia; ITH, intratumoral heterogeneity.
by all of the tumor cells. Unfortunately, it is not necessarily
suffıcient to target the tissue-specifıc phenotypes, because at
the time of diagnosis (usually late in the evolution process)
they might be unnecessary for survival. On a practical level,
oncologists need to know what the major evolutionary events
are in their tumor of interest, and in what order they occurred.
This knowledge can be used in the planning of clinical
trials and combination therapies. It is important to
understand that a tumor presenting with the hallmarks of
cancer has most probably evolved over a long period and
might have lost some of the initial phenotypes that subsequently
became superfluous for survival. Many cancers are
diagnosed late in their evolution and if identifıed earlier they
might have been targetable through their tissue-specifıc genotype/phenotypes.
INTRATUMORAL GENETIC HETEROGENEITY AND
CANCER PROGNOSIS
Intratumoral heterogeneity has been demonstrated to be a
predictive marker for cancer mortality. In Barrett’s esophagus,
the higher the diversity in a single biopsy the worse the
prognosis. 17 Heterogeneity in HER2 amplifıcation is associated
with a higher cancer-specifıc death rate. 18 Similar fındings
were noted in breast carcinoma. 19 In head and neck
cancer, intratumoral heterogeneity at the whole genomic
level was signifıcantly associated with shorter survival. 20 Additionally,
the presence of sub-clonal driver mutations was
associated with reduced survival in chronic lymphocytic leukemia,
21 and patients with localized resected lung carcinoma
that had a higher fraction of sub-clonal mutations were more
likely to relapse. 6 These recent fındings suggest that the degree
of sub-clonality might serve as a cancer marker per se.
Higher diversity is related to a higher mutation rate or longer
tumor evolution with more replications. However, as discussed
above, the survival of multiple clones suggests that
multiple phenotypes were selected under different environments
(branched evolution), all of which tell us something
about the tumor biology and history.
FUTURE DIRECTIONS
The study of evolution, like the study of history, involves
looking at the past to create a better future. Recent studies 14,15
suggest that early mutations in leukemia occur in cells capable
of mainlining their functionality. These early events lead
to clonal expansion of cells trying to maintain function.
Clonal expansion is relatively common in the general
population. 22-24 The early clonal expansion, which can last
for years, will eventually progress to uncontrolled cell growth
and the emergence of dysfunctional cells. From these studies
we learn that cancer in adults is a longstanding state, with
precancerous lesions most likely evolving as a result of the
aging environment. Accordingly, we suggest that changing
the environment and targeting early events might change the
evolutionary trajectory of cancer.
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2015 ASCO EDUCATIONAL BOOK | asco.org/edbook