Molecular profiling reveals low- and high-grade forms of primary melanoma.
OBJECTIVE
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, which 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.


METHODS
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. Because 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 with low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P < 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, whereas low-grade lesions harbored higher expression of immune genes. Importantly, the molecular-grade signature was validated in two external gene expression data sets.


CONCLUSIONS
We provide evidence for a molecular organization within melanomas, which is preserved across all stages of disease.
Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
Katja
K
Harbst
Johan
J
Staaf
Martin
M
Lauss
Anna
A
Karlsson
Anna
A
Måsbäck
Iva
I
Johansson
Pär-Ola
PO
Bendahl
Johan
J
Vallon-Christersson
Therese
T
Törngren
Henrik
H
Ekedahl
Jürgen
J
Geisler
Mattias
M
Höglund
Markus
M
Höglund
Markus
M
Ringnér
Mattias
M
Ringnér
Lotta
L
Lundgren
Karin
K
Jirström
Håkan
H
Olsson
Christian
C
Ingvar
Åke
Å
Borg
Hensin
H
Tsao
Göran
G
Jönsson
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D055815:Young Adult
D019313:BRCA1 Protein