High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients.
Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is--BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (P<0.001) BRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)(-) mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease.
aOncoMark Ltd, NovaUCD bDepartment of Medical Oncology, Royal College of Surgeons cUCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin Departments of dPathology eSurgery fMedical Oncology, St Vincent's University Hospital gDepartment of Histopathology, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital hDepartment of Histopathology, St James's Hospital iDepartment of Histopathology, Trinity College, Dublin jDepartment of Pathology, Cork University Hospital, Cork Departments of kSurgery lMedical Oncology, University Hospital Galway mDepartment of Medicine, National University of Ireland Galway nDepartment of Histopathology, University Hospital Galway, Galway, Ireland oDepartment of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands pLaboratory of Morphology and Molecular Pathology, Katholieke Universiteit Leuven, Leuven, Belgium.
Karin
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van den Hurk
Balazs
B
Balint
Sinead
S
Toomey
Patrick C
PC
O'Leary
Louise
L
Unwin
Kieran
K
Sheahan
Enda W
EW
McDermott
Ian
I
Murphy
Joost J
JJ
van den Oord
Mairin
M
Rafferty
Dara M
DM
FitzGerald
Julie
J
Moran
Robert
R
Cummins
Owen
O
MacEneaney
Elaine W
EW
Kay
Cathal P
CP
O'Brien
Stephen P
SP
Finn
Cynthia C B B
CC
Heffron
Michelle
M
Murphy
Ruben
R
Yela
Derek G
DG
Power
Padraic J
PJ
Regan
Clodagh M
CM
McDermott
Allan
A
O'Keeffe
Zsolt
Z
Orosz
Paul P
PP
Donnellan
John P
JP
Crown
Bryan T
BT
Hennessy
William M
WM
Gallagher
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D001530:Belgium; D058543:Class Ia Phosphatidylinositol 3-Kinase; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007494:Ireland; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D000096142:Cutaneous Malignant Melanoma
D058543:Class Ia Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D019859:Proto-Oncogene Proteins c-met; C588001:PIK3R1 protein, human; C491743:MET protein, human; C482119:BRAF protein, human