Precancers: A Model
Precancers and endometrial
Endometrioid endometrial adenocarcinoma, the most
common form of endometrial cancer in the United States, is often preceded by a
physical precursor lesion which mediates subsequent cancer risk. These precancers are initiated from a polyclonal normal
field by mutations conferring marginal increases in growth potential that under
the mitogenic stimulus of unopposed estrogen successfully proliferate as a clone
(indicated by expanding arrows). The monoclonal precancer develops internal
heterogeneity through mutation, and advantageous events selected by local conditions
result in hierarchical subclones (left to right) of varying success. Some
premalignant clones involute. Others progress
by additional mutation and selection, eventually reaching a stage where hormonal support
is no longer required for survival. Malignant transformation to Cancer (red
irregular clones) is defined
by accumulation of sufficient genetic damage to permit invasion of adjacent stromal
Endometrial precancers have been
usually diagnosed as atypical endometrial hyperplasias, but may be designated in
functional terms as Endometrial Intraepithelial Neoplasia (EIN). Precancers are
the targets of, and effectors for, hormonally mediated tumor
risk. The PTEN gene is a hormonally
responsive tumor suppressor gene mutated at the time of initiation in many endometrial neoplasms which may
be an informative biomarker for premalignant and malignant clones. These and other
features of the model are presented in Precancer
Summary Model of endometrial
cancer pathways. Endometrioid
endometrial adenocarcinoma (excluding papillary serous and non-endometrioid
cancers) can arise through a PTEN dependent (left) or independent (right)
pathway. Three stages of EIN-mediated endometrial carcinogenesis are shown, top
to bottom, as tissue compartments proportionately shaded to show that fraction
(% PTEN defect) of endometrial glands at each stage which have PTEN mutation
and/or deletion (black) or normal PTEN (white). Normal proliferative endometria
contains a small fraction (42% of women have 2-3% PTEN mutated/deleted glands,
for overall PTEN null rate estimated here as 1%) of PTEN-defective cells. EIN
and cancer (CA) are usually homogenous regarding PTEN expression, so defective
and non-defective fractions are reported as published PTEN mutation/deletion
rates for these diagnoses in cases with a documented premalignant phase.
Latent PTEN mutant clones within proliferative endometria are, individually, at
least 50 times more susceptible to EIN conversion than glands with normal PTEN
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