Åke Borg
Principal investigator
Molecular profiling reveals low- and high-grade forms of primary melanoma
Author
Summary, in English
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.
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.
Department/s
- Breastcancer-genetics
- Tumor microenvironment
- Surgery (Lund)
- Melanoma Genomics
- EpiHealth: Epidemiology for Health
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2012
Language
English
Pages
4026-4036
Publication/Series
Clinical Cancer Research
Volume
18
Issue
15
Links
Document type
Journal article
Publisher
American Association for Cancer Research
Topic
- Cancer and Oncology
Status
Published
Research group
- Melanoma Genomics
ISBN/ISSN/Other
- ISSN: 1078-0432