Publication: Frequent intra-tumoural heterogeneity of promoter hypermethylation in malignant melanoma
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Date
2007
Authors
Rastetter, M. ; Schagdarsurengin, U. ; Lahtz, C. ; Fiedler, E. ; Marsch, V.Ch. ; Dammann, R. ; Helmbold, P.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
To investigate intra-tumoural coexistence and
heterogeneity of aberrant promoter hypermethylation of
different tumour suppressor genes in melanoma, we
analyzed the intra-tumoural distribution of promoter
methylation of RASSF1A, p16, DAPK, MGMT, and Rb
in 339 assays of 34 tumours (15 melanoma primaries, 19
metastases) by methylation-specific PCR, correlation to
histopathology and RASSF1A expression. We detected
promoter hypermethylation of at least one gene in 74%
of tumours (30%, 52%, 33%, 20%, and 40% for
RASSF1A, p16, DAPK, MGMT and Rb, respectively).
70% of the cases exhibited an inhomogeneous
methylation pattern (17%, 45%, 33%, 20%, and 40% for
RASSF1A, p16, DAPK, MGMT and Rb, respectively).
Samples from the core of the tumours represented the
methylation state of the whole tumours more accurately
than the periphery. Local intra-tumoural correlation was
found between the promoter hypermethylation state of
p16 and Rb or p16 and DAPK, or epitheloid tumour cell
type and RASSF1A or p16 methylation. Mitosis rate and
sex was correlated with methylation of RASSF1A.
Histological results confirmed that promoter
hypermethylation of RASSF1A led to aberrant expression
patterns. We conclude that intra-tumoural inhomogeneity of promoter hypermethylation is frequent in melanoma
and this supports the hypothesis of clonal instability
during progression of melanomas. In prognosis studies,
missing the intra-tumoural sample representativeness
may result in a reduction of the sensitivities or
specificities.
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