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Dear Madams and Sirs,
I read with much interest the article by Professor Watson (Watson,
2013) and strongly agree with the belief that big investments in TCGA will
not lead to the future development of real breakthrough drugs.
Taking this into account, I would like to propose an alternative
perspective on cancer and on the future of RNAi methodologies to screen
for novel/additional molecular targets.
During my postdoctoral work in Zurich, during which I investigated
tumors on the molecular level, I made an unexpected discovery. After
having analyzed more than 3000 tumors of 12 different cancer indications
(solid and non-solid tumors), I found that I could stratify these 3000
tumors into only 3-5 groups, on the level of gene expression
(www.pareq.com & Beleut et al. 2012). This grouping was independent of
histology, mutational spectra, pathways, and surprisingly, even of the
cancer indication itself!
I have realized that while each tumor looks different on the
molecular (mutational) level, every such individual mutation spectrum of
each single tumor ends up in one of these five "gene-expression-groups"
which we called "Cancer States," reflected as homologues in all 12 cancer
indications analyzed. It looks as if the establishment of these distinct
and non-transient Cancer States are a destination each tumor was
predetermined to reach.
I am therefore convinced that unravelling the mystery of cancer
requires a general change in focus going away from the quest for high
frequency alterations and the subsequent efforts of integrating them into
molecular and biological pathways, to an unbiased, nonhypothesis-driven
approach in which the accumulated effects of the entire mutational
spectrum of each tumor are integrated and interpreted. From the scientific
point of view, it will therefore be relevant to understand the unique
strategy each tumor uses to reach its Cancer State.
It may indeed turn out that RNAi candidates prove to be sensitive co-
regulators, eventually enabling - together with all other individual
mutations and mutation types per tumor - a change of global gene
expression and thus movement into one of the five distinct Cancer State
Manfred Beleut, PhD
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