TY - JOUR
T1 - Multi-Modality Analysis Improves Survival Prediction in Enucleated Uveal Melanoma Patients
AU - Drabarek, Wojtek
AU - Yavuzyigitoglu, Serdar
AU - Obulkasim, Askar
AU - van Riet, Job
AU - Smit, Kyra N
AU - van Poppelen, Natasha M
AU - Vaarwater, Jolanda
AU - Brands, Tom
AU - Eussen, Bert
AU - Verdijk, Robert M
AU - Naus, Nicole C
AU - Mensink, Hanneke W
AU - Paridaens, Dion
AU - Boersma, Eric
AU - van de Werken, Harmen J G
AU - Kilic, Emine
AU - de Klein, Annelies
AU - Rotterdam Ocular Melanoma Study Group
PY - 2019/8/1
Y1 - 2019/8/1
N2 - Purpose: Uveal melanoma (UM) is characterized by multiple chromosomal rearrangements and recurrent mutated genes. The aim of this study was to investigate if copy number variations (CNV) alone and in combination with other genetic and clinico-histopathological variables can be used to stratify for disease-free survival (DFS) in enucleated patients with UM.Methods: We analyzed single nucleotide polymorphisms (SNP) array data of primary tumors and other clinical variables of 214 UM patients from the Rotterdam Ocular Melanoma Study (ROMS) cohort. Nonweighted hierarchical clustering of SNP array data was used to identify molecular subclasses with distinct CNV patterns. The subclasses associate with mutational status of BAP1, SF3B1, or EIF1AX. Cox proportional hazard models were then used to study the predictive performance of SNP array cluster-, mutation-, and clinico-histopathological data, and their combination for study endpoint risk.Results: Five clusters with distinct CNV patterns and concomitant mutations in BAP1, SF3B1, or EIF1AX were identified. The sample's cluster allocation contributed significantly to mutational status of samples in predicting the incidence of metastasis during a median of 45.6 (interquartile range [IQR]: 24.7-81.8) months of follow-up (P < 0.05) and vice versa. Furthermore, incorporating all data sources in one model yielded a 0.797 C-score during 100 months of follow-up.Conclusions: UM has distinct CNV patterns that correspond to different mutated driver genes. Incorporating clinico-histopathological, cluster and mutation data in the analysis results in good performance for UM-related DFS prediction.
AB - Purpose: Uveal melanoma (UM) is characterized by multiple chromosomal rearrangements and recurrent mutated genes. The aim of this study was to investigate if copy number variations (CNV) alone and in combination with other genetic and clinico-histopathological variables can be used to stratify for disease-free survival (DFS) in enucleated patients with UM.Methods: We analyzed single nucleotide polymorphisms (SNP) array data of primary tumors and other clinical variables of 214 UM patients from the Rotterdam Ocular Melanoma Study (ROMS) cohort. Nonweighted hierarchical clustering of SNP array data was used to identify molecular subclasses with distinct CNV patterns. The subclasses associate with mutational status of BAP1, SF3B1, or EIF1AX. Cox proportional hazard models were then used to study the predictive performance of SNP array cluster-, mutation-, and clinico-histopathological data, and their combination for study endpoint risk.Results: Five clusters with distinct CNV patterns and concomitant mutations in BAP1, SF3B1, or EIF1AX were identified. The sample's cluster allocation contributed significantly to mutational status of samples in predicting the incidence of metastasis during a median of 45.6 (interquartile range [IQR]: 24.7-81.8) months of follow-up (P < 0.05) and vice versa. Furthermore, incorporating all data sources in one model yielded a 0.797 C-score during 100 months of follow-up.Conclusions: UM has distinct CNV patterns that correspond to different mutated driver genes. Incorporating clinico-histopathological, cluster and mutation data in the analysis results in good performance for UM-related DFS prediction.
KW - Aged
KW - DNA Copy Number Variations
KW - DNA, Neoplasm/genetics
KW - Disease-Free Survival
KW - Eukaryotic Initiation Factor-1/genetics
KW - Eye Enucleation
KW - Female
KW - Humans
KW - Male
KW - Melanoma/diagnosis
KW - Middle Aged
KW - Phosphoproteins/genetics
KW - Polymorphism, Single Nucleotide
KW - Proportional Hazards Models
KW - RNA Splicing Factors/genetics
KW - Tumor Suppressor Proteins/genetics
KW - Ubiquitin Thiolesterase/genetics
KW - Uveal Neoplasms/diagnosis
U2 - 10.1167/iovs.18-24818
DO - 10.1167/iovs.18-24818
M3 - Article
C2 - 31425584
SN - 0146-0404
VL - 60
SP - 3595
EP - 3605
JO - Investigative ophthalmology & visual science
JF - Investigative ophthalmology & visual science
IS - 10
ER -