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Molecular profiling reveals low- and high-grade forms of primary melanoma

Harbst, Katja LU ; Staaf, Johan LU ; Lauss, Martin LU ; Karlsson, Anna; Måsbäck, Anna; Johansson, Iva LU ; Bendahl, Pär-Ola LU ; Vallon-Christersson, Johan LU ; Törngren, Therese LU and Ekedahl, Henrik LU , et al. (2012) In Clinical Cancer Research 18(15). p.4026-4036
Abstract
PURPOSE:

For primary melanomas, tumor thickness, mitotic rate and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma that predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome. Experimental design: We subjected 223 archival primary melanomas to a horizontally-integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry and survival data.



RESULTS:... (More)
PURPOSE:

For primary melanomas, tumor thickness, mitotic rate and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma that predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome. Experimental design: We subjected 223 archival primary melanomas to a horizontally-integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry and survival data.



RESULTS:

Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Since these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between "high" and "low" grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared to low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P less than 0.01) and poorer relapse-free (HR=4.94; 95%CI 2.84-8.59) and overall (HR=3.66; 95%CI 2.40-5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes while low-grade lesions harbored higher expression of immune genes. Importantly, the molecular grade signature was validated in two external gene expression datasets.



CONCLUSIONS:

We provide evidence for a molecular organization within melanomas that is preserved across all stages of disease. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
18
issue
15
pages
4026 - 4036
publisher
American Association for Cancer Research
external identifiers
  • wos:000307503600005
  • pmid:22675174
  • scopus:84864443974
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-12-0343
language
English
LU publication?
yes
id
d426b740-fe89-4021-a8b7-f08f0d1e82bd (old id 2859693)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22675174?dopt=Abstract
date added to LUP
2012-07-04 12:27:44
date last changed
2017-11-19 04:18:49
@article{d426b740-fe89-4021-a8b7-f08f0d1e82bd,
  abstract     = {PURPOSE: <br/><br>
For primary melanomas, tumor thickness, mitotic rate and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma that predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome. Experimental design: We subjected 223 archival primary melanomas to a horizontally-integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry and survival data. <br/><br>
<br/><br>
RESULTS: <br/><br>
Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Since these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between "high" and "low" grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared to low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P less than 0.01) and poorer relapse-free (HR=4.94; 95%CI 2.84-8.59) and overall (HR=3.66; 95%CI 2.40-5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes while low-grade lesions harbored higher expression of immune genes. Importantly, the molecular grade signature was validated in two external gene expression datasets. <br/><br>
<br/><br>
CONCLUSIONS: <br/><br>
We provide evidence for a molecular organization within melanomas that is preserved across all stages of disease.},
  author       = {Harbst, Katja and Staaf, Johan and Lauss, Martin and Karlsson, Anna and Måsbäck, Anna and Johansson, Iva and Bendahl, Pär-Ola and Vallon-Christersson, Johan and Törngren, Therese and Ekedahl, Henrik and Geisler, Jurgen and Höglund, Mattias and Ringnér, Markus and Lundgren, Lotta and Jirström, Karin and Olsson, Håkan and Ingvar, Christian and Borg, Åke and Tsao, Hensin and Jönsson, Göran B},
  issn         = {1078-0432},
  language     = {eng},
  number       = {15},
  pages        = {4026--4036},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {Molecular profiling reveals low- and high-grade forms of primary melanoma},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-12-0343},
  volume       = {18},
  year         = {2012},
}