Intratumor Heterogeneity in Uveal Melanoma BAP-1 Expression

Stålhammar, Gustav; Grossniklaus, Hans E.

doi:10.3390/cancers13051143

Cited by 20 publications

(12 citation statements)

References 30 publications

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“…All small tumors may not necessarily grow large and acquire monosomy 3, BAP1 mutations, vasculogenic mimicry or other high-risk features even if left untreated ( 4 ). Some, but not all, tumors seem to have these features from the outset, and there is marked variability in their growth rate and considerable intratumor heterogeneity of various risk factors ( 8 , 35 – 39 ). Nonetheless, the likelihood of high-risk features increases with increasing tumor size ( 8 , 40 – 42 ).…”

Section: Discussionmentioning

confidence: 99%

Trends in Uveal Melanoma Presentation and Survival During Five Decades: A Nationwide Survey of 3898 Swedish Patients

et al. 2022

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BackgroundIn contrast to most other cancers, uveal melanoma (UM) is characterized by an absence of major improvements in patient survival during the last several decades. In this study, we examine changes in incidence rates, patient age and tumor size at diagnosis, treatment practices and survival for patients diagnosed in Sweden during the period 1960–2010.MethodsAll patients diagnosed with posterior UM between January 1st, 1960, and December 31st, 2009, in Sweden, were included (n = 3898). Trends in incidence, primary treatment modality, patient age and tumor size were analyzed. Disease-specific survival was plotted in Kaplan–Meier curves and the cumulative incidence of UM-related mortality was evaluated in competing risk analysis.ResultsCrude (6.5–11.6 cases/million/year) and age-standardized incidence rates (5.6–9.6 cases/million/year) varied between individual years during the study period, but both had a stable linear trend overall (p ≥ 0.12). Gradually, plaque brachytherapy with ruthenium-106 replaced enucleation as the most common primary treatment. The mean patient age at diagnosis increased from 59.8 years in 1960 to 66.0 in 2009. Conversely, the mean tumor size became gradually smaller during the period. In linear regression, the basal diameter and tumor apical thickness decreased with a slope coefficient of −0.03 mm (p = 0.012) and −0.05 mm (p = 1.2 × 10–5) per year after 1960, respectively. Patients diagnosed after 1990 had significantly better disease-specific survival than patients diagnosed before 1990 (p = 2.0 × 10–17). Similarly, the cumulative incidence of UM-related mortality was highest for patients diagnosed 1960–1969 and 1970–1979, with slightly lower incidences for patients diagnosed 1980–1989 and even lower for those diagnosed after 1990 (p = 7.1 × 10–13). The incidence of mortality from other causes than UM did not differ between periods (p = 0.16).ConclusionIn the period from 1960–2010, crude and age-standardized incidence rates of UM have remained stable in Sweden. Several other aspects have changed: Plaque brachytherapy with ruthenium-106 has replaced enucleation as the most common primary treatment modality; patients have become older and their tumors smaller at the time of diagnosis; and their survival has improved. This might indicate a beneficial survival effect of earlier diagnosis and treatment, but the potential influence from lead-time bias should be taken into consideration.

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Section: Discussionmentioning

confidence: 99%

Trends in Uveal Melanoma Presentation and Survival During Five Decades: A Nationwide Survey of 3898 Swedish Patients

et al. 2022

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“…All large tumors were once small, but all small tumors may not necessarily grow large and acquire monosomy 3, BAP1 mutations, vasculogenic mimicry or other highrisk features even if left untreated [3]. Some tumors seem to have these features from the onset, and there is marked variability in the growth rate of uveal melanomas as well as intratumor heterogeneity of risk factors [4,[26][27][28][29][30]. Nonetheless, there is no doubt that the likelihood of high-risk features increases with increasing tumor size [4,[31][32][33].…”

Section: Discussionmentioning

confidence: 99%

No differences in the long-term prognosis of iris and choroidal melanomas when adjusting for tumor thickness and diameter

et al. 2021

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Objective To assess the long-term prognosis for patients with iris melanomas and compare it with the prognosis for small choroidal melanomas. Design Retrospective observational case series. Methods All patients treated for iris melanomas at a single referral institution between January 1st 1986 and January 1st 2016 were included. Patients treated for small choroidal melanomas during the same period were included for comparison. The cumulative incidence of melanoma-related mortality was calculated. Patient and tumor characteristics and size-adjusted hazard ratio (HR) for melanoma-related mortality were compared between iris and small choroidal melanomas. Results Forty-five iris melanomas and 268 small choroidal melanomas were included. Twenty-four iris melanomas (53%) had been treated with local resection, 12 (27%) with Ruthenium-106 brachytherapy, 7 (16%) with enucleation and 2 (4%) with proton beam irradiation. Twenty-one (68%), 7 (16%) and 2 (4%) of the iris melanomas were of the spindle, mixed and epithelioid cell types, respectively. Twenty-three patients had deceased before the end of follow-up. Median follow-up for the 22 survivors was 13.3 years (SD 9.4). Patients with iris melanomas were more often asymptomatic at presentation and had a trend towards significantly lower age (59 versus 63 years, Student’s T-tests p = 0.057). Further, iris melanomas had significantly smaller basal diameter (5.8 versus 8.0 mm, p < 0.0001) and tumor volume (79 mm3 versus 93 mm mm3, p < 0.0001) but greater thickness (3.0 versus 2.5 mm, p < 0.0001). The cumulative incidence of iris melanoma-related mortality was 5% at 5 years after diagnosis, and 8% at 10, 15 and 20 years. The incidence was not significantly different to small choroidal melanomas (Wilcoxon p = 0.46). In multivariate Cox regression with tumor diameter and thickness as covariates, patients with choroidal melanomas did not have increased HR for melanoma-related mortality (HR 2.2, 95% CI 0.5–9.6, p = 0.29). Similarly, there were no significant survival differences in matched subgroups (Wilcoxon p = 0.82). Conclusions There are no survival differences between iris and choroidal melanomas when adjusting for tumor size. The reason for the relatively favorable prognosis of iris melanomas compared to melanomas of the choroid and ciliary body is likely that they are diagnosed at a smaller size.

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“…Significant intratumor heterogeneity exists in both genomes and transcriptome of UM patients ( 33 ). The heterogeneity in one group may have a complex relationship with the heterogeneity in another group.…”

Section: Discussionmentioning

confidence: 99%

Integration of Bulk RNA Sequencing and Single-Cell RNA Sequencing to Reveal Uveal Melanoma Tumor Heterogeneity and Cells Related to Survival

et al. 2022

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Molecular classification based on transcriptional characteristics is often used to study tumor heterogeneity. Human cancer has different cell populations with distinct transcription in tumors, and their heterogeneity is the focus of tumor therapy. Our purpose was to explore the tumor heterogeneity of uveal melanoma (UM) through RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq). Based on the consensus clustering assays of the prognosis-related immune gene set, the immune subtype (IS) of UM and its corresponding immune characteristics were comprehensively analyzed. The heterogeneous cell groups and corresponding marker genes of UM were identified from GSE138433 using scRNA-seq analysis. Pseudotime trajectory analysis and SCENIC analysis were conducted to explore the trajectory of cell differentiation and the regulatory network of single-cell transcription factors (TFs). Based on 37 immune gene sets, UM was divided into two different immune subtypes (IS1 and IS2). The two kinds of ISs have different characteristics in prognosis, immune-related molecules, immune score, and immune cell infiltration. According to 11,988 cells of scRNA-seq data from six UM samples, 11 cell clusters and 10 cell types were identified. The subsets of C1, C4, C5, C8, and C9 were related to the prognosis of UM, and different TF–target gene regulatory networks were involved. These five cell subsets differentiated into 3 different states. Our results provided valuable information about the heterogeneity of UM tumors and the expression patterns of TFs in different cell types.

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Intratumor Heterogeneity in Uveal Melanoma BAP-1 Expression

Cited by 20 publications

References 30 publications

Trends in Uveal Melanoma Presentation and Survival During Five Decades: A Nationwide Survey of 3898 Swedish Patients

Trends in Uveal Melanoma Presentation and Survival During Five Decades: A Nationwide Survey of 3898 Swedish Patients

No differences in the long-term prognosis of iris and choroidal melanomas when adjusting for tumor thickness and diameter

Integration of Bulk RNA Sequencing and Single-Cell RNA Sequencing to Reveal Uveal Melanoma Tumor Heterogeneity and Cells Related to Survival

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