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2017 ; 15
(2
): 1559325817716585
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English Wikipedia
"Bad Luck Mutations": DNA Mutations Are not the Whole Answer to Understanding
Cancer Risk
#MMPMID28717349
Trosko JE
; Carruba G
Dose Response
2017[Apr]; 15
(2
): 1559325817716585
PMID28717349
show ga
It has been proposed that many human cancers are generated by intrinsic
mechanisms that produce "Bad Luck" mutations by the proliferation of
organ-specific adult stem cells. There have been serious challenges to this
interpretation, including multiple extrinsic factors thought to be correlated
with mutations found in cancers associated with these exposures. While support
for both interpretations provides some validity, both interpretations ignore
several concepts of the multistage, multimechanism process of carcinogenesis,
namely, (1) mutations can be generated by both "errors of DNA repair" and "errors
of DNA replication," during the "initiation" process of carcinogenesis; (2)
"initiated" stem cells must be clonally amplified by nonmutagenic, intrinsic or
extrinsic epigenetic mechanisms; (3) organ-specific stem cell numbers can be
modified during in utero development, thereby altering the risk to cancer later
in life; and (4) epigenetic tumor promoters are characterized by species,
individual genetic-, gender-, developmental state-specificities, and threshold
levels to be active; sustained and long-term exposures; and exposures in the
absence of antioxidant "antipromoters." Because of the inevitability of some of
the stem cells generating "initiating" mutations by either "errors of DNA repair"
or "errors of DNA replication," a tumor is formed depending on the promotion
phase of carcinogenesis. While it is possible to reduce our frequencies of
mutagenic "initiated" cells, one can never reduce it to zero. Because of the
extended period of the promotion phase of carcinogenesis, strategies to reduce
the appearance of cancers must involve the interruption of the promotion of these
initiated cells.
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